Glutamate Spillover Dynamically Strengthens Gabaergic Synaptic Inhibition of the Hypothalamic Paraventricular Nucleus.

The hypothalamic paraventricular nucleus (PVN) is strongly inhibited by γ-aminobutyric acid (GABA) from the surrounding peri-nuclear zone (PNZ). Because glutamate mediates fast excitatory transmission and is substrate for GABA synthesis, we tested its capacity to dynamically strengthen GABA inhibition. In PVN slices from male mice, bath glutamate applied during ionotropic glutamate receptor blockade increased PNZ-evoked inhibitory postsynaptic currents (eIPSCs) without affecting GABA-A receptor agonist currents or single-channel conductance, implicating a presynaptic mechanism(s). Consistent with this interpretation, bath glutamate failed to strengthen IPSCs during pharmacological saturation of GABA-A receptors. Presynaptic analyses revealed that glutamate did not affect paired-pulse ratio, peak eIPSC variability, GABA vesicle recycling speed, or readily releasable pool (RRP) size. Notably, glutamate-GABA strengthening (GGS) was unaffected by metabotropic glutamate receptor blockade and graded external Ca2+ when normalized to baseline amplitude. GGS was prevented by pan- but not glial-specific inhibition of glutamate uptake and by inhibition of glutamic acid decarboxylase (GAD), indicating reliance on glutamate uptake by neuronal excitatory amino acid transporter 3 (EAAT3) and enzymatic conversion of glutamate to GABA. EAAT3 immunoreactivity was strongly localized to presumptive PVN GABA terminals. High bath K+ also induced GGS, which was prevented by glutamate vesicle depletion, indicating that synaptic glutamate release strengthens PVN GABA inhibition. GGS suppressed PVN cell firing, indicating its functional significance. In sum, PVN GGS buffers neuronal excitation by apparent "over-filling" of vesicles with GABA synthesized from synaptically released glutamate. We posit that GGS protects against sustained PVN excitation and excitotoxicity while potentially aiding stress adaptation and habituation.

Molecular insights and the role of 18F-FDG-PET/CT in the diagnosis of spinal gliomas.

BACKGROUND: In recent years, molecular findings on spinal gliomas have become increasingly important. This study aimed to investigate the role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in the diagnosis of spinal glioma. METHODS: This study included patients diagnosed with spinal cord glioma who underwent 18F-FDG-PET examination at the Department of Neurosurgery, Nagoya University Hospital between January 2016 and November 2023. The gliomas were divided into two groups, high-grade and low-grade, based on pathological and molecular studies. The maximum standardized uptake values (SUVmax) of the tumors were quantified and subsequently represented using receiver operating characteristic (ROC) curves. RESULTS: Eighteen participants were included in this study. Of the participants, seven had high-grade glioma with an SUVmax of 6.76 ± 0.72, and eleven had low-grade glioma with an SUVmax of 4.02 ± 1.78, and a statistically significant difference between the two groups. The ROC curve delineated an SUVmax cutoff value of 5.650, with an area under the curve (AUC) of approximately 0.909. Based on the cutoff value, the results of the diagnostic performance rendered a sensitivity and negative predictive value of 1.0, whereas the specificity and positive predictive value were 0.909 and 0.875, respectively. CONCLUSIONS: The present study shows that 18F-FDG-PET exhibits a markedly sensitive and negative predictive value in the assessment of spinal gliomas. Additionally, these findings have potential implications for the qualitative assessment of spinal gliomas using 18F-FDG-PET/CT. This imaging modality may be useful for making timely treatment decisions in situations where a detailed diagnosis by molecular analysis is not possible.

Rapid detection of the MYD88 L265P mutation for pre- and intra-operative diagnosis of primary central nervous system lymphoma.

The myeloid differentiation primary response gene 88 (MYD88) L265P mutation is a disease-specific mutation of primary central nervous system lymphoma (PCNSL) among the central nervous system tumors. Accordingly, this mutation is considered a reliable diagnostic molecular marker of PCNSL. As the intra-operative diagnosis of PCNSL is sometimes difficult to achieve using histological examinations alone, intra-operative detection of the MYD88 L265P mutation could be effective for the accurate diagnosis of PCNSL. Herein, we aimed to develop a novel rapid genotyping system (GeneSoC) using real-time polymerase chain reaction (PCR) based on microfluidic thermal cycling technology. This real-time PCR system shortened the analysis time, which enabled the detection of the MYD88 L265P mutation within 15 min. Rapid detection of the MYD88 L265P mutation was performed intra-operatively using GeneSoC in 24 consecutive cases with suspected malignant brain tumors, including 10 cases with suspected PCNSL before surgery. The MYD88 L265P mutation was detected in eight cases in which tumors were pathologically diagnosed as PCNSL after the operation, while wild-type MYD88 was detected in 16 cases. Although two of the 16 cases with wild-type MYD88 were pathologically diagnosed as PCNSL after the operation, MYD88 L265P could be detected in all eight PCNSL cases harboring MYD88 L265P. The MYD88 L265P mutation could also be detected using cell-free DNA derived from the cerebrospinal fluid of two PCNSL cases. Detection of the MYD88 L265P mutation using GeneSoC might not only improve the accuracy of intra-operative diagnosis of PCNSL but also help the future pre-operative diagnosis through liquid biopsy of cerebrospinal fluid.

Latest classification of ependymoma in the molecular era and advances in its treatment: a review.

Ependymoma is a rare central nervous system (CNS) tumour occurring in all age groups and is one of the most common paediatric malignant brain tumours. Unlike other malignant brain tumours, ependymomas have few identified point mutations and genetic and epigenetic features. With advances in molecular understanding, the latest 2021 World Health Organization (WHO) classification of CNS tumours divided ependymomas into 10 diagnostic categories based on the histology, molecular information and location; this accurately reflected the prognosis and biology of this tumour. Although maximal surgical resection followed by radiotherapy is considered the standard treatment method, and chemotherapy is considered ineffective, the validation of the role of these treatment modalities continues. Although the rarity and long-term clinical course of ependymoma make designing and conducting prospective clinical trials challenging, knowledge is steadily accumulating and progress is being made. Much of the clinical knowledge obtained from clinical trials to date was based on the previous histology-based WHO classifications, and the addition of new molecular information may lead to more complex treatment strategies. Therefore, this review presents the latest findings on the molecular classification of ependymomas and advances in its treatment.

Safety and durability of cavo-tricuspid isthmus linear ablation in the current era: Single-center 9-year experience from 1078 procedures.

BACKGROUND: Cavo-tricuspid isthmus (CTI) linear ablation is performed not only for atrial flutter (AFL) but empirically during atrial fibrillation (AF) ablation in real-world practice.  PURPOSE: We sought to evaluate the safety and durability of the CTI ablation.  METHODS: This retrospective study included 1078 consecutive patients who underwent a CTI ablation. AFL was documented before or during the procedure in 249 (23.1%) patients, and an empirical CTI and AF ablation were performed in 829 (76.9%) patients.  RESULTS: CTI block was successfully created in 1051 (97.5%) patients with a 10.3 ± 6.6 min total radiofrequency time. Repeat procedures were performed for recurrent arrhythmias in 187 (17.3%) patients at a median of 11.0 (5.0-30.0) months postprocedure, and conduction resumption was identified in 68/174 (39.1%). Among those undergoing a CTI ablation with an AF ablation, the durability was significantly higher in those with than without documented AFL (78.1% vs. 58.2%, p = .031).  The total radiofrequency time was significantly shorter (9.0 ± 5.3 vs. 10.0 ± 6.4 [mins], p = .024) and durability significantly higher (78.1 vs. 58.7[%], p = .043) in the large-tip than irrigated-tip catheter group. Iatrogenic AFL was observed after the empiric CTI ablation in 11 (1.3%) patients. Procedure-related complications occurred in 15 (1.4%) patients. Eight patients experienced coronary artery spasms, including one with ventricular fibrillation following ST elevation on the ward. The other six patients experienced transient atrioventricular block and one experienced cardiac tamponade requiring drainage.  CONCLUSIONS: Despite a high acute CTI ablation success, the conduction block durability was relatively low after the empiric ablation. An empiric CTI ablation at the time of the AF ablation is not recommended.

Direct intracranial invasion of eccrine spiradenocarcinoma of the scalp: a case report and literature review.

BACKGROUND: Eccrine spiradenocarcinoma (SC), also known as malignant eccrine spiradenoma, is a rare malignant cutaneous adnexal neoplasm arising from long-standing benign eccrine spiradenoma. Malignant skin tumors rarely show direct intracranial invasion. However, once the intracranial structure is infiltrated, curative excision with sufficient margins can become extremely difficult, particularly when the venous sinuses are involved. No effective adjuvant therapies have yet been established. Here, we report an extremely rare case of scalp eccrine SC with direct intracranial invasion, which does not appear to have been reported previously. CASE PRESENTATION: An 81-year-old woman presented with a large swelling on the parietal scalp 12 years after resection of spiradenoma from the same site. The tumor showed intracranial invasion with involvement of the superior sagittal sinus and repeated recurrences after four surgeries with preservation of the sinus. The histopathological diagnosis was eccrine SC. Adjuvant high-precision external beam radiotherapy (EBRT) proved effective after the third surgery, achieving remission of the residual tumor. The patient died 7 years after the first surgery for SC. CONCLUSIONS: Scalp SC with direct intracranial invasion is extremely rare. Radical resection with tumor-free margins is the mainstay of treatment, but the involvement of venous sinuses makes this unfeasible. High-precision EBRT in combination with maximal resection preserving the venous sinuses could be a treatment option for local tumor control.

Mapping and ablation of left atrial roof-dependent tachycardias using an ultra-high resolution mapping system.

BACKGROUND: Left atrial roof-dependent tachycardias (LARTs) are common macroreentrant atrial tachycardias (ATs). We sought to characterize clinical LARTs using an ultra-high resolution mapping system. METHODS: This study included 22 consecutive LARTs in 21 patients who underwent AT mapping/ablation using Rhythmia systems. RESULTS: Three, 13, 4, and 2 LART patients were cardiac intervention naïve (Group-A), post-roof line ablation (Group-B), post-atrial fibrillation ablation without linear ablation (Group-C), and post-cardiac surgery (Group-D), respectively. The mean AT cycle length was 244 ± 43 ms. Coronary sinus activation was proximal-to-distal or distal-to-proximal in 16 (72.7%) ATs. The activation map revealed 13 (59.1%) clockwise and 9 (40.9%) counter-clockwise LARTs. A 12-lead synchronous isoelectric interval was observed in 10/19 (52.6%) LARTs. The slow conduction area was identified on the LA roof, anterior/septal wall, and posterior wall in 18, 6, and 2 ATs, respectively. Twenty concomitant ATs among 13 procedures were also eliminated, and peri-mitral AT coexisted in 7 of 9 non-group-B patients. In group-B, the conduction gap was predominantly located on the mid-roof. Sustained LARTs were terminated by a single application and linear ablation in 6 (27.3%) and 9 (40.9%), while converting to other ATs in 7 (31.8%) LARTs. Complete linear block was created without any complications in all, however, ablation at the mid-posterior wall was required to achieve block in 4 (18.2%) procedures. During 14.0 (6.5-28.5) months of follow-up, 17 (81.0%) and 19 (90.5%) patients were free from any atrial tachyarrhythmias after single and last procedures. CONCLUSIONS: The LART mechanisms were distinct in individual patients, and elimination of all concomitant ATs was required for the management.

Declines in serum uric acid level after catheter ablation of atrial fibrillation.

BACKGROUND: Few studies have examined whether catheter ablation for AF patients improves biomarkers other than serum levels of brain natriuretic peptide (BNP) and renal function. This study was to explore whether catheter ablation for atrial fibrillation (AF) patients affects uric acid (UA), glucose and lipid metabolism. METHODS AND RESULTS: A total of 206 patients (66.6 ± 10.4 years; 132 men) who underwent initial AF ablation without changes to oral medications were included. Baseline BNP and UA levels significantly decreased at 1 year after ablation (p < 0.05 each). Changes in UA level correlated significantly with pre-procedural UA level (r = 0.57). In multivariable logistic regression modeling, pre-procedural UA level, persistent AF, and hemoglobin A1c (p < 0.05 each) were independent predictors of post-procedural UA level decline. Significant improvements in both persistent and paroxysmal AF patients were identified, and the magnitude of post-procedural serum UA level decline after ablation (ΔUA) was significantly greater in patients with persistent AF (0.8 ± 1.0 mg/dl) than in those with paroxysmal AF (0.2 ± 0.8 mg/dl, p < 0.001). Of the 48 patients with high UA level before procedure, 28 patients showed improvement in UA level to normal range. CONCLUSIONS: Catheter ablation for AF patients significantly improved serum UA levels without obvious influences of heart failure, renal function, or inflammation, suggesting that AF ablation may be effective for AF patients with hyperuricemia. Trial registration The study was approved by the Research Ethics Committee of University of Fukui (no. 20210132) and clinical trial registration (UMIN000044669).

The mechanisms of left septal and anterior wall reentrant atrial tachycardias analyzed with ultrahigh resolution mapping: The role of functional block in the circuit.

BACKGROUND: Low voltage areas (LVAs) are most commonly observed on the left atrial (LA) septal/anterior wall. OBJECTIVE: We explored the mechanisms of LA septal/anterior wall reentrant tachycardias (LASARTs) using ultrahigh resolution mapping. METHODS: This study included seven consecutive LASARTs in six patients (75 [62.2-82.8] years, 4 women) who underwent atrial tachycardia (AT) mapping and ablation using Rhythmia systems. RESULTS: The AT cycle length was 266 (239-321) ms. During ATs, 11.0 (9.0-12.9) cm2 of LVAs were identified in all, and 0.8 (0.7-1.7) cm2 of dense scar was identified in four patients. Five ATs rotated around dense scar, while two rotated around functional linear block, which was confirmed during atrial pacing after AT termination. The AT circuit length was 8.7 ± 2.1 cm with a conduction velocity of 30.4 ± 3.7 cm/s. A median of 3.0 (2.0-4.0) slow conduction areas per circuit were identified, and 17/23 (73.9%) areas were present in LVAs, while they were at the border of the LVA and normal voltage areas in the remaining 6/23 (26.1%). Global activation histograms facilitated the identification of the critical isthmus in all. Tailor-made ablation at critical isthmuses successfully eliminated all ATs. However, one patient with AT related to functional linear block experienced recurrent AT related to dense scar, which progressed after the procedure. During a mean 14 ± 13 month follow-up after the last procedure, no patients experienced recurrent ATs without any complications. CONCLUSION: LASARTs consist of not only fixed conduction blocks but also functional conduction blocks. Ultrahigh resolution mapping is highly useful to decide the optimal tailor-made ablation strategy based on the mechanisms.

Impact of the extent of resection on the survival of patients with grade II and III gliomas using awake brain mapping.

PURPOSE: The aim of this study was to assess the effect of the extent of resection (EOR) of tumors on survival in a series of patients with grade II and III gliomas (GII/III-gliomas) who underwent awake brain mapping. METHODS: We retrospectively analyzed 126 patients with GII/III-gliomas in the dominant and non-dominant hemisphere who underwent awake brain surgery at the same institution between December 2012 and May 2020. RESULTS: EOR cut-off values for improved progression-free survival (PFS) were determined by a receiver operator characteristic (ROC) analysis of 5-year PFS. The ROC for EOR showed a cut-off value of ≥ 85.3%. The median PFS rate of patients with GII/III-gliomas in the group with an EOR ≥ 100%, including supratotal resection (n = 47; median survival [MS], not reached), was significantly higher than that in the group with an EOR < 90% (n = 52; MS, 43.1 months; 95% CI 37.7-48.5 months; p = 0.03). In patients with diffuse astrocytomas and anaplastic astrocytomas, the group with EOR ≥ 100%, including supratotal resection (n = 25; MS, not reached), demonstrated a significantly better PFS rate than did the group with an EOR < 100% (n = 45; MS, 35.8 months; 95% CI 19.9-51.6 months; p = 0.03). Supratotal or gross total resection was correlated with better PFS in IDH-mutant type of diffuse astrocytomas and anaplastic astrocytomas (n = 19; MS, not reached vs. n = 35; MS, 40.6 months; 95% CI 22.3-59.0 months; p = 0.02). By contrast, supratotal or gross total resection was not associated with longer PFS rates in patients with IDH-wild type of diffuse astrocytomas and anaplastic astrocytomas. CONCLUSIONS: The present study demonstrates a significant association between tumor EOR and survival in patients with GII/III gliomas. The EOR cut-off value for 5-year PFS was ≥ 85.3%. It is noteworthy that supratotal or gross total resection significantly correlated with better PFS in IDH-mutant type of WHO grade II and III astrocytic tumors. In light of our finding that EOR did not correlate with PFS in patients with aggressive IDH-wild type of diffuse astrocytomas and anaplastic astrocytomas, we suggest treatments that are more intensive will be needed for the control of these tumors.

Discrepancy between CARTO and Rhythmia maps for defining the left atrial low-voltage areas in atrial fibrillation ablation.

Reported mapping procedures of left atrial (LA) low-voltage areas (LVAs) vary widely. This study aimed to compare the PentaRay®/CARTO®3 (PentaRay map) and Orion™/Rhythmia™ (Orion map) systems for LA voltage mapping. This study included 15 patients who underwent successful pulmonary vein isolation (PVI) for atrial fibrillation. After PVI, PentaRay and Orion maps created for all patients were compared. LVAs were defined as sites with ≥ 3 adjacent low-voltage points < 0.5 mV. LVAs were indicated in 8 (53%) among 15 patients, and the average values of the measured LVAs was comparable between the systems (PentaRay map = 5.4 ± 8.7 cm2; Orion map = 4.3 ± 6.4 cm2, p = 0.69). However, in 2 of 8 patients with LVAs, the Orion map indicated LVAs at the septum and posterolateral sites of the LA, respectively, whereas the PentaRay map indicated no LVAs. In those patients, sharp electrograms of > 0.5 mV were properly recorded at the septum and posterolateral sites during appropriate beats in the PentaRay map. The PentaRay map had a shorter procedure time than the Orion map (12 ± 3 min vs. 23 ± 8 min, respectively; p < 0.01). Our study results showed a discrepancy in the LVA evaluation between the PentaRay and Orion maps. In 2 of 15 patients, the Orion map indicated LVAs at the sites where > 0.5-mV electrograms were properly recorded in the PentaRay map.

Cardiac rehabilitation after catheter ablation of atrial fibrillation in patients with left ventricular dysfunction.

Few studies have examined the efficacy and safety of cardiac rehabilitation in patients with atrial fibrillation (AF) who underwent AF ablation. We explored the feasibility of additional cardiac rehabilitation after AF ablation in patients with a reduced left ventricular ejection fraction (LVEF). Fifty-four patients with heart failure (HF) and a reduced LVEF (HFrEF) (LVEF < 50%; 67.1 ± 11.6 years; 43 men) who underwent initial AF ablation procedures were included. Fourteen (25.9%) patients underwent cardiac rehabilitation (rehabilitation-group) and the remaining 40 (74.1%) did not (non-rehabilitation-group) after the procedure. The rehabilitation-group patients were relatively older, more likely female (p = 0.024), and had more likely a history of an HF hospitalization (p < 0.01) and cardiac device implantation (p = 0.041). The baseline LVEF was significantly lower (p = 0.043) and brain natriuretic peptide (BNP) (p < 0.01) and C-reactive protein (CRP) (p < 0.01) values were significantly higher in the rehabilitation-group. The 6-min walk distance significantly improved after 21.4 ± 11.5 days of cardiac rehabilitation during hospitalization (226.1 ± 155.9 vs. 398.1 ± 77.5 m, p = 0.016) without any adverse events. During an 18.9 ± 6.3 month follow-up period, the freedom from AF recurrence (p = 0.52) and re-hospitalizations due to HF (p = 0.63) were similar between the 2 groups. No death or strokes were observed. During the follow-up period, the LVEF significantly improved similarly in both groups, and the change in the BNP and CRP values significantly decreased in the rehabilitation-group. Despite the rehabilitation-group patients having a more severe HF status, the clinical outcomes and AF freedom were similar between the 2 groups, suggesting the favorable impact of cardiac rehabilitation after AF ablation in HFrEF patients.

Relationship between single-leg stance test with light touch and hip muscle strength in healthy young adults.

[Purpose] This study investigated the relationship between the single-leg stance test with light touch and hip rotator muscle strength. [Participants and Methods] Thirty-one healthy young adults participated in the study. A single leg stance test with light touch was performed to evaluate the participants' static balance ability. The duration that an individual could successfully perform the single leg stance test with light touch in the eyes open was measured. The participants were instructed to slightly touch their right index fingertip on the digital scale. The hip muscle strength of the internal rotators and external rotators were measured by the isometric peak torque. The internal/external rotator strength ratio was calculated by dividing the strength of the internal rotator by that of the external rotator. [Results] The hip external rotator muscle strength was higher in males than in females. Moreover, there was a significant correlation between the single-leg stance test with light touch and hip external rotator muscle strength in males and between the single leg stance test with light touch and hip internal rotator muscle strength in females. Furthermore, a significant positive correlation was found between the single leg stance test with light touch and hip internal rotator/external rotator ratio in males. [Conclusion] We concluded that the single leg stance test with light touch is a useful tool to evaluate static hip muscle strength.

Feasibility of Uninterrupted Direct Oral Anticoagulants with Temporary Switching to Dabigatran ("Dabigatran Bridge") for Catheter Ablation of Atrial Fibrillation.

Uninterrupted anticoagulation therapy during atrial fibrillation (AF) ablation minimizes the risk of periprocedural thromboembolic events. Although the use of direct oral anticoagulants (DOACs) has rapidly developed in patients undergoing AF ablation, no antidote is available for factor Xa inhibitors. We sought to investigate the feasibility of an uninterrupted DOAC protocol with temporary switching to dabigatran ("dabigatran bridge") for AF ablation.The study consisted of consecutive 137 patients in whom DOACs were interrupted on the procedural day with heparin bridging (interrupted group) and 135 in whom DOACs were uninterrupted with temporary switching to dabigatran during the periprocedural hospitalization period ("dabigatran bridge" group). The coagulation markers were measured just before and after the ablation procedure. The adverse events during and up to 8 weeks after the procedure were compared according to the definition of the International Society on Thrombosis and Hemostasis.The patients were significantly older in the "dabigatran bridge" group; however, the other baseline patient characteristics were similar between the two groups. The incidence of all adverse events was comparable between the two groups (8/137 versus 8/135, P = 0.96); however, one patient from the interrupted group experienced stroke, and another from the "dabigatran bridge" group experienced cardiac tamponade, which was safely managed with an antidote. In the "dabigatran bridge" group, the activated partial thromboplastin time was significantly longer, and coagulation markers (soluble fibrin monomer and thrombin-antithrombin complexes) were significantly lower than in the interrupted group before ablation.The "dabigatran bridge" seems to be a reasonable anticoagulation protocol to minimize the thromboembolic risk while ensuring safety in patients undergoing AF ablation and taking factor Xa inhibitors.

Next Generation Sequencing-Based Transcriptome Predicts Bevacizumab Efficacy in Combination with Temozolomide in Glioblastoma.

Glioblastoma (GBM), the most common and malignant brain tumor, is classified according to its isocitrate dehydrogenase (IDH) mutation status in the 2016 World Health Organization (WHO) brain tumor classification scheme. The standard treatment for GBM is maximal resection, radiotherapy, and Temozolomide (TMZ). Recently, Bevacizumab (Bev) has been added to basic therapy for newly diagnosed GBM, and monotherapy for recurrent GBM. However, the effect of IDH1 mutation on the combination of Bev and TMZ is unknown. In this study, we performed transcriptomic analysis by RNA sequencing with next generation sequencing (NGS), a newly developed powerful method that enables the quantification of the expression level of genome-wide genes. Extracellular matrix and immune cell migration genes were mainly upregulated whereas cell cycle genes were downregulated in IDH1-mutant U87 cells but not in IDH1-wildtype U87 cells after adding Bev to TMZ. In vitro and in vivo studies were conducted for further investigations to verify these results, and the addition of Bev to TMZ showed a significant antitumor effect only in the IDH1-mutant GBM xenograft model. Further studies of gene expression profiling in IDH1 mutation gliomas using NGS will provide more genetic information and will lead to new treatments for this refractory disease.

Endoscopic approach via the interhemispheric fissure: the role of an endoscope in a surgical case of multiple falcine lesions.

BACKGROUND: For treating a patient with multiple falcine and parasagittal lesions, we believe that it is beneficial to resect the maximum possible number of lesions during one operation, even if some lesions are asymptomatic. This practice can potentially reduce the total number of operations during a patient's lifetime. METHODS: We provide an introduction of a concurrent endoscopic approach via the interhemispheric fissure. CONCLUSIONS: Applying this endoscopic approach concurrently with conventional microscopic surgery can enable the safe resection of as many lesions as possible during one operation.

A novel deletion in the splice donor site of MLH1 exon 6 in a Japanese colon cancer patient with Lynch syndrome.

Lynch syndrome is an autosomal dominantly inherited disease that is characterized by a predisposition to cancers, mainly colorectal cancer. Germline mutations of DNA mismatch repair genes such as MLH1, MSH2, MSH6 and PMS2 have been described in patients with Lynch syndrome. Here, we report deletion of 2 bp in the splice donor site of the MLH1 exon 6 (c.545+4_545+5delCA) in a 48-year-old Japanese woman with Lynch syndrome. RT-PCR direct sequencing analysis revealed that this mutation led to an increase in the level of an MLH1 transcript in which exon 6 was skipped, and may cause a frameshift (p.E153FfsX8). Therefore, this mutation appears to be pathogenic and is responsible for Lynch syndrome. Additionally, analysis of the patient's tumor cells indicated microsatellite instability high phenotype and loss of the MLH1 and PMS2 proteins. To our knowledge, this is a germline splice site mutation of MLH1 that has not been reported previously.

A case of early onset rectal cancer of Lynch syndrome with a novel deleterious PMS2 mutation.

Heterozygous deleterious mutation of the PMS2 gene is a cause of Lynch syndrome, an autosomal dominant cancer disease. However, the frequency of PMS2 mutation is rare compared with that of the other causative genes; MSH2, MLH1 and MSH6. PMS2 mutation has so far only been reported once from a Japanese facility. Detection of PMS2 mutation is relatively complicated due to the existence of 15 highly homologous pseudogenes, and its gene conversion event with the pseudogene PMS2CL. Therefore, for PMS2 mutation analysis, it is crucial to clearly distinguish PMS2 from its pseudogenes. We report here a novel deleterious 11 bp deletion mutation of exon 11 of PMS2 distinguished from PMS2CL in a 34-year-old Japanese female with rectal cancer. PMS2 mutated at c.1492del11 results in a truncated 500 amino acid protein rather than the wild-type protein of 862 amino acids. This is supported by the fact that, although there is usually concordance between MLH1 and PMS2 expression, cells were immunohistochemically positive for MLH1, whereas PMS2 could not be immunohistochemically stained using an anti-C-terminal PMS2 antibody, or effective PMS2 mRNA degradation with NMD caused by the frameshift mutation.

Identification of coding exon 3 duplication in the BMPR1A gene in a patient with juvenile polyposis syndrome.

Juvenile polyposis syndrome is an autosomal dominant inherited disorder characterized by multiple juvenile polyps arising in the gastrointestinal tract and an increased risk of gastrointestinal cancers, specifically colon cancer. BMPR1A and SMAD4 germline mutations have been found in patients with juvenile polyposis syndrome. We identified a BMPR1A mutation, which involves a duplication of coding exon 3 (c.230+452_333+441dup1995), on multiple ligation dependent probe amplification in a patient with juvenile polyposis syndrome. The mutation causes a frameshift, producing a truncated protein (p.D112NfsX2). Therefore, the mutation is believed to be pathogenic. We also identified a duplication breakpoint in which Alu sequences are located. These results suggest that the duplication event resulted from recombination between Alu sequences. To our knowledge, partial duplication in the BMPR1A gene has not been reported previously. This is the first case report to document coding exon 3 duplication in the BMPR1A gene in a patient with juvenile polyposis syndrome.

Obstructive Hydrocephalus Due to Aggressive Posterior Fossa Tumor Exhibiting Histological Characteristics of Pilocytic Astrocytoma in Two Adult Neurofibromatosis Type 1 (NF1) Cases.

Neurofibromatosis type 1 (NF1) is an autosomal dominant syndrome caused by germline alteration of the NF1gene. Among various NF1-related manifestations, obstructive hydrocephalus especially in adult NF1 cases is less frequently found. We report two adult NF1 cases exhibiting obstructive hydrocephalus due to an aggressive posterior fossa tumor exhibiting pathological characteristics of pilocytic astrocytoma as NF1-related manifestations. In these two cases, we performed endoscopic third ventriculostomy (ETV) and tumor biopsy as an initial treatment. The initial pathological diagnosis of the tumor is conventional pilocytic astrocytoma. After biopsy both cases revealed rapid tumor growth, therefore, we performed tumor removal, chemotherapy, and radiation therapy during an aggressive clinical course. However, both cases revealed dismal prognosis due to the progression of the tumor in spite of successful management of hydrocephalus by an initial ETV. DNA methylation analysis revealed that the tumor of one case matched high-grade astrocytoma with piloid features (HGAP). Most central nervous system tumors developed in NF1 are less aggressive such as pilocytic astrocytoma; however, recently a few studies revealed that HGAP, which has been a newly introduced malignant tumor in the World Health Organization Classification of Tumors of the Central Nervous System, 5th edition (WHO CNS 5), rarely develops in NF1 cases. These findings suggested that HGAP might be one of the important causes of obstructive hydrocephalus in adult NF1 cases.