Signal conversion as tumor micro environment (TME) specifically activated cytokine.

Targeted cytokine delivery has been gaining popularity in cancer immunotherapy since systemic recombinant cytokine treatment has not been successful due to low response rate and systemic toxicities in the clinical studies. In order to address these issues, we propose a new concept that cytokine signal is specifically activated at tumor-micro-environment (TME) by delivering two protein subunits of heterodimeric cytokine fused with a tumor targeting antibody respectively to TME and by bridging the two subunits into active heterodimeric form.Interleukin-12 (IL-12) is one of the major cytokines which can induce immune activation. IL-12 consists of two protein subunits which are p35 and p40. IL-12 signaling is initiated when it forms as the heterodimeric protein and binds to IL-12 receptor complex. We made fusion proteins of both IL-12p35 and IL-12p40 targeting specific tumor associated antigens (TAAs) and demonstrated the formation of bioactive IL12p70 with TME targeting antibody toward both p35 and p40 to form as the active molecule. We describe our concept validation in an in vitro based functional assay.

Fc-independent functions of anti-CTLA-4 antibodies contribute to anti-tumor efficacy.

Ipilimumab, a monoclonal antibody that recognizes cytotoxic T-lymphocyte associated protein 4 (CTLA-4), was the first immune checkpoint inhibitor approved by the FDA to treat metastatic melanoma patients. Multiple preclinical studies have proposed that Fc effector functions of anti-CTLA-4 therapy are required for anti-tumor efficacy, in part, through the depletion of intratumoral regulatory T cells (Tregs). However, the contribution of the Fc-independent functions of anti-CTLA-4 antibodies to the observed efficacy is not fully understood. H11, a non-Fc-containing single-domain antibody (VHH) against CTLA-4, has previously been demonstrated to block CTLA-4-ligand interaction. However, in vivo studies demonstrated lack of anti-tumor efficacy with H11 treatment. Here, we show that a half-life extended H11 (H11-HLE), despite the lack of Fc effector functions, induced potent anti-tumor efficacy in mouse syngeneic tumor models. In addition, a non-Fc receptor binding version of ipilimumab (Ipi-LALAPG) also demonstrated anti-tumor activity in the absence of Treg depletion. Thus, we demonstrate that Fc-independent functions of anti-CTLA-4 antibodies contributed to anti-tumor efficacy, which may indicate that non-Treg depleting activity of anti-CTLA-4 therapy could benefit cancer patients in the clinic.

Quasiparticle Trapping at Vortices Producing Josephson Supercurrent Enhancement.

The Josephson junction of a strong spin-orbit material under a magnetic field is a promising Majorana fermion candidate. Supercurrent enhancement by a magnetic field has been observed in the InAs nanowire Josephson junctions and assigned to a topological transition. In this work we observe a similar phenomenon but discuss the nontopological origin by considering the trapping of quasiparticles by vortices that penetrate the superconductor under a finite magnetic field. This assignment is supported by the observed hysteresis of the switching current when sweeping up and down the magnetic field. Our experiment shows the importance of quasiparticles in superconducting devices with a magnetic field, which can provide important insights for the design of qubits using superconductors.

Evaluation of a carbapenem antimicrobial stewardship program and clinical outcomes in a Japanese hospital.

INTRODUCTION: Microorganisms can evolve and become resistant to antimicrobials, and this is known as antimicrobial resistance (AMR). Inappropriate use of antibiotics contributes to AMR, and antimicrobial stewardship programs have been developed to mitigate AMR. The Appropriate Use of Carbapenems Program was implemented in March 2019 in a university hospital and its effect was evaluated. METHODS: We conducted a prospective audit and feedback on carbapenems at the time of prescription daily. Additionally, we compared a monthly survey of the total days of therapy (DOTs) per 1000 patient-days for carbapenems, piperacillin/tazobactam, and fluoroquinolones. The susceptibility of Pseudomonas aeruginosa to meropenem, piperacillin/tazobactam, and levofloxacin was tested before (January 2018 to February 2019) and after (March 2019 to December 2020) the intervention. RESULTS: The monthly median DOTs of carbapenem usage decreased after the intervention; carbapenem use immediately declined during the intervention period. The monthly median DOTs of piperacillin/tazobactam and fluoroquinolones also decreased and continued to decline significantly after the intervention. Susceptibility of P. aeruginosa to meropenem, piperacillin/tazobactam, and levofloxacin did not change significantly during the study. CONCLUSION: The implementation of the Appropriate Use of Carbapenems Program was effective in reducing the use of broad-spectrum antibiotics and maintaining the antibiotic susceptibility of P. aeruginosa.

Synthesis and Properties of Spiro-double Sila[7]helicene: The LUMO Spiro-conjugation.

A double helicene with a spiro-Si linker (4) was synthesized by four successive nucleophilic substitutions on SiCl4 . Its (P,P), (M,M) and (P,M) isomers were isolated and characterized by single crystal X-ray analysis. Due to the central spirosilabi[fluorene] moiety, the two helicene units in 4 are symmetrically and nearly perpendicularly arranged. (P,P)-4 and (M,M)-4 exhibit unique optical properties attributable to the LUMO spiro-conjugation between the two sila[7]helicene units.

Tumor-immune profiling of CT-26 and Colon 26 syngeneic mouse models reveals mechanism of anti-PD-1 response.

BACKGROUND: Immune checkpoint blockade (ICB) therapies have changed the paradigm of cancer therapies. However, anti-tumor response of the ICB is insufficient for many patients and limited to specific tumor types. Despite many preclinical and clinical studies to understand the mechanism of anti-tumor efficacy of ICB, the mechanism is not completely understood. Harnessing preclinical tumor models is one way to understand the mechanism of treatment response. METHODS: In order to delineate the mechanisms of anti-tumor activity of ICB in preclinical syngeneic tumor models, we selected two syngeneic murine colorectal cancer models based on in vivo screening for sensitivity with anti-PD-1 therapy. We performed tumor-immune profiling of the two models to identify the potential mechanism for anti-PD-1 response. RESULTS: We performed in vivo screening for anti-PD-1 therapy across 23 syngeneic tumor models and found that CT-26 and Colon 26, which are murine colorectal carcinoma derived from BALB/c mice, showed different sensitivity to anti-PD-1. CT-26 tumor mice were more sensitive to the anti-PD-1 antibody than Colon 26, while both models show similarly sensitivity to anti-CTLA4 antibody. Immune-profiling showed that CT-26 tumor tissue was infiltrated with more immune cells than Colon 26. Genomic/transcriptomic analyses highlighted thatWnt pathway was one of the potential differences between CT-26 and Colon 26, showing Wnt activity was higher in Colon 26 than CT-26. . CONCLUSIONS: CT-26 and Colon 26 syngeneic tumor models showed different sensitivity to anti-PD-1 therapy, although both tumor cells are murine colorectal carcinoma cell lines from BALB/c strain. By characterizing the mouse cells lines and tumor-immune context in the tumor tissues with comprehensive analysis approaches, we found that CT-26 showed "hot tumor" profile with more infiltrated immune cells than Colon 26. Further pathway analyses enable us to propose a hypothesis that Wnt pathway could be one of the major factors to differentiate CT-26 from Colon 26 model and link to anti-PD-1 response. Our approach to focus on preclinical tumor models with similar genetic background but different sensitivity to anti-PD-1 therapy would contribute to illustrating the potential mechanism of anti-PD-1 response and to generating a novel concept to synergize current anti-PD-1 therapies for cancer patients.

[Impact of Aperture Shape Controller on Volumetric Modulated Arc Therapy Treatment Planning for Nasopharyngeal Cancer].

PURPOSE: The aperture shape controller (ASC) decreases the complexity of the multi-leaf collimator (MLC) aperture for volumetric modulated arc therapy (VMAT). The purpose of this study was to evaluate the effect of ASC settings on the VMAT plan quality. METHOD: First, VMAT plans were created (ASC=off) for three test patterns of The American Association of Physicists in Medicine (AAPM) Task Group 119 (TG-119) and 20 cases of nasopharyngeal cancer. Next, for these VMAT plans, only the ASC settings were changed from very low (complexity reduction: low) to very high (complexity reduction: high) in five steps, and VMAT plans were created respectively. To evaluate the created VMAT plans per each ASC settings, we analyzed the modulation complexity score (MCSV) and dosimetric parameters for the planning target volume (PTV) and organ at risk (OAR). RESULT: In three test patterns, there were no major dosimetric differences between the VMAT plans. In nasopharyngeal cancer, the mean MCSV were 0.413, 0.325, 0.320, 0.307, 0.303, and 0.272 for very high, high, moderate, low, very low, off settings, respectively. Therefore, the most complex MLC aperture was off, followed by very low, low, moderate, high, and very high. In terms of dosimetric parameters, the VMAT plans created using the very high setting showed an increase of D2% in the PTV and worse OAR sparing than that using other ASC settings. On the other hand, the dosimetric results for the very low to moderate setting obtained similar results to those for the off setting, respectively. CONCLUSION: The ASC was able to decrease the complexity of the MLC aperture according to the setting level. From very low to moderate settings, a plan equivalent to the off setting could be created in terms of dose parameters.

Capillary electrophoretic reactor for estimation of spontaneous dissociation rate of Trypsin-Aprotinin complex.

A capillary electrophoretic reactor was used to analyze the dissociation kinetics of an enzyme-inhibitor complex in a homogeneous solution without immobilization. The complex consisting of trypsin (Try) and aprotinin (Apr) was used as the model. Capillary electrophoresis provided a reaction field for Try-Apr complex to dissociate through the steady removal of free Try and Apr from the Try-Apr zone. By analyzing the dependence of peak height of Try-Apr on separation time, the dissociation rate kdH was obtained as 2.73 × 10-4 s-1 (298 K) at pH 2.46. The dependence of kdH on the proton concentration (pH = 2.09-3.12) revealed a first-order dependence of kdH on [H+]; kdH = kd + k1[H+], where kd is the spontaneous dissociation rate and was 5.65 × 10-5 s-1, and k1 is the second-order rate constant and was 5.07 × 10-2 M-1 s-1. From the kd value, the half-life of the Try-Apr complex at physiological pH was determined as 3.4 h. The presence of the proton-assisted dissociation can be explained by the protonation of -COO- of the Asp residue in Try, which breaks the salt bridge with the -NH3+ group of Lys in Apr.

Low entropy of interictal gamma oscillations is a biomarker of the seizure onset zone in focal cortical dysplasia type II.

OBJECTIVE: Dynamic changes in the regularity of interictal gamma oscillations (GOs, 30-70 Hz) on intracranial electroencephalography (EEG) reflect focal ictogenesis with epileptogenic neuronal synchronization in focal cortical dysplasia (FCD). We investigated whether the regularity of interictal GOs is a biomarker of the seizure onset zone (SOZ) using multiscale entropy analysis. METHODS: We quantified the regularity of interictal GOs using intracranial EEG data from 1164 electrodes in 13 patients with FCD who were seizure-free postoperatively. The regularity of interictal GOs was quantified as entropy values. Low entropy represents high regularity. We standardized entropy values using Z values for each SOZ, resection area (RA), and the region outside the RA. The cutoff Z values, sensitivity, and specificity for detecting each area were calculated using area under the receiver operating characteristics curves (AUCs). RESULTS: Low Z values represent higher regularity of GOs. The cutoff Z value of ≤-2.09 for the SOZ had a sensitivity of 100% and specificity of 97.1% (AUC = 0.992 ±â€¯0.002). The cutoff Z value of ≤-0.12 for the RA had a sensitivity of 54.2% and specificity of 73.8% (AUC = 0.673 ±â€¯0.019). The cutoff Z value of ≥-0.11 for the region outside the RA had a sensitivity of 73.8% and specificity of 54.2% (AUC = 0.673 ±â€¯0.019). CONCLUSIONS: Low entropy of interictal GOs was a reliable biomarker for the SOZ. Maintained high entropy of interictal GOs may be an auxiliary biomarker for nonepileptogenic regions. SIGNIFICANCE: Low entropy of interictal GOs may be a biomarker for the SOZ in FCD type II.

[Influence of Respiratory Phase during Image Acquisition on Prescribed Dose in Image Guided Radiation Therapy Using Implant Marker for Prostate Cancer].

In image guided radiation therapy (IGRT) using implanted fiducial marker by two-dimensional radiography for prostate cancer, temporal positional relationship during treatment between the isocenter and the prostate is changed by respiratory phase at the time of image acquisition. We examined influence of the respiratory phase in the IGRT on dose variation by interplay effect. Intra-fractional prostate motions of patients who were implanted fiducial marker were measured using fluoroscopy, then we reconstructed plans considering for the respiratory phase in IGRT and the respiratory motion during volumetric modulated arc therapy. Averages of the intra-fractional prostate motion in left-right, anterior-posterior and superior-inferior direction were 0.039, 0.49 and 1.6 mm respectively. There was a patient whose intra-fractional prostate motion was larger than 4 mm that was planning target volume margin. By changing the respiratory phase like inspiration, exhalation and dispersing respiratory phase in each fraction, dose variation from original plan became smaller in order of the inspiration, exhalation and dispersion. The largest variations of dose indices in clinical target volume, bladder and rectum were 8.0%, 4.5% and 9.1% respectively when IGRT was done in inspiration. When the IGRT is performed by the same respiratory phase in each fraction, systematic dose variations may occur even if the respiratory phase at the timing of irradiation is changed. By dispersing the respiratory phase in each fraction, the variations in all dose indices were<1% from original plan. We realized that dispersing the respiratory phase in IGRT by each fraction is effective to reduce the dose variation caused by the respiratory phase in IGRT.

Outbreak of Trichinella T9 Infections Associated with Consumption of Bear Meat, Japan.

An outbreak of trichinellosis occurred in Japan in December 2016. All case-patients had eaten undercooked bear meat, from which Trichinella larvae were subsequently isolated. DNA sequencing analysis of the mitochondrial genes cytochrome c-oxidase subunit 1 and internal transcribed spacer 2 confirmed that Trichinella T9 had caused the outbreak.

A study on the plasticity of soda-lime silica glass via molecular dynamics simulations.

Molecular dynamics (MD) simulations were applied to construct a plasticity model, which enables one to simulate deformations of soda-lime silica glass (SLSG) by using continuum methods. To model the plasticity, stress induced by uniaxial and a variety of biaxial deformations was measured by MD simulations. We found that the surfaces of yield and maximum stresses, which are evaluated from the equivalent stress-strain curves, are reasonably represented by the Mohr-Coulomb ellipsoid. Comparing a finite element model using the constructed plasticity model to a large scale atomistic model on a nanoindentation simulation of SLSG reveals that the empirical method is accurate enough to evaluate the SLSG mechanical responses. Furthermore, the effect of ion-exchange on the SLSG plasticity was examined by using MD simulations. As a result, it was demonstrated that the effects of the initial compressive stress on the yield and maximum stresses are anisotropic contrary to our expectations.

Successful Resection of a Growing Distal Medial Lenticulostriate Artery Pseudoaneurysm Presenting with Isolated Intraventricular Hemorrhage.

INTRODUCTION: Distal medial lenticulostriate artery (LSA) aneurysms associated with isolated intraventricular hemorrhage (IVH) are extremely rare. We report a very rare case of the isolated IVH due to the rupture of the distal medial LSA pseudoaneurysm that was not visible at the initial angiography but later emerged and grew. CASE REPORT: A 61-year-old woman with a history of hypertension had sudden onset of severe headache and mild consciousness disturbance. The computed tomography scan revealed the IVH, but the initial angiographies showed no evidence of aneurysm. The follow-up magnetic resonance imaging revealed that an intraventricular mass, arising from the right distal medial LSA, emerged and grew into the right anterior horn. Considering the risk of rebleeding, we resected the mass lesion via the transsulcal transventricular approach. The postoperative imaging showed complete obliteration of the mass lesion. Histopathological analysis indicated the pseudoaneurysm. The patient was discharged without any neurological deficit. CONCLUSIONS: The careful and repetitive follow-up imaging should be done in the cases with isolated IVH even if the initial image evaluations are unrevealing. The transsulcal transventricular approach can be the most minimally invasive surgical option for intraventricular lesion.

Palladium-Catalyzed Asymmetric Synthesis of Silicon-Stereogenic 5,10-Dihydrophenazasilines via Enantioselective 1,5-Palladium Migration.

A palladium-catalyzed asymmetric synthesis of silicon-stereogenic 5,10-dihydrophenazasilines was developed that proceeds via an unprecedented enantioselective 1,5-palladium migration. High enantioselectivity was achieved by employing 4,4'-bis(trimethylsilyl) (R)-Binap as the chiral ligand, and a series of mechanistic investigations were carried out to probe the catalytic cycle of this process.

Increased subcortical oligodendroglia-like cells in pharmacoresistant focal epilepsy in children correlate with extensive epileptogenic zones.

OBJECTIVE: Cortical resections in epilepsy surgery tend to involve multiple lobes in children, compared to adults, partly due to underlying pathology. Oligodendroglia-like cells (OLCs) have been observed in surgical specimens from children with pharmacoresistant epilepsy. We hypothesize that OLCs recruit multiple-lobe epileptogenic zones in pediatric pharmacoresistant focal epilepsy. METHODS: We examined the surgical specimens from 30 children who underwent epilepsy surgery (1.8- to 16.9-years-old; mean age 9.7 years). Immunohistochemical assays of OLCs were performed using Olig2, which is a marker of OLC. OLC populations in three sites (gray matter, gray-white matter junction, and white matter) were counted. We also performed immunohistochemical staining with neuronal nuclear antigen (NeuN) and glial fibrillary acidic protein (GFAP) for neuronal and astroglial markers, respectively. NeuN- and GFAP-positive cells were distinguished from OLCs. OLC results were compared with seizure types, scalp and intracranial video-electroencephalography (EEG), magnetic resonance imaging (MRI), surgical resection area, histopathologic diagnosis, and seizure outcome. RESULTS: Histopathologic diagnosis consisted of 14 cases of focal cortical dysplasia (FCD; type I; 4, type II; 9, type III; one); 6 cases of oligodendrogliosis; 6 cases of astrocytic gliosis; 2 cases of hyaline protoplasmic astrocytopathy; and 2 cases of tuberous sclerosis. Fifteen children (50%) underwent multiple-lobe resections after intracranial video-EEG. There was a positive correlation between the number of resected electrodes and the OLC population in the white matter (correlation coefficient 0.581, p = 0.001) and at the gray-white matter junction- (correlation coefficient 0.426, p = 0.027). OLC populations in both areas were increased significantly in nine children with epileptic spasms (ES) (gray-white matter junction [p = 0.021] and white matter [p = 0.025]), and nine nonfocal ictal scalp EEG findings (gray-white matter junction [p = 0.04] and white matter [p = 0.042]). The OLC population in white matter was significantly increased in children with 11 nonfocal interictal scalp EEG findings (p = 0.01), with 15 multiple-lobe resections (p = 0.028). SIGNIFICANCE: Pharmacoresistant epilepsy in children with increased OLCs presented with nonfocal epileptiform discharges on scalp EEG and ES, and they required multiple-lobe resections. We found increased populations of subcortical OLCs in the extensive epileptogenic zone.

Remote MEG dipoles in focal cortical dysplasia at bottom of sulcus.

OBJECTIVE: To investigate whether the magnetoencephalography (MEG) single moving dipole (SMD) method could delineate the epileptic zone of focal cortical dysplasia (FCD) at the bottom of sulcus (FCDB). METHODS: We retrospectively analyzed 17 children (11 male; mean age 8.8 years, range 3-17 years) with FCD type II who underwent epilepsy surgery. We compared spatial congruence between the following: (1) MEG cluster and FCDB and (2) MEG cluster and FCD at the brain surface (FCDS). We measured the volume and depth of magnetic resonance imaging (MRI)-visible lesions to investigate whether they affect spatial congruence between MEG cluster and MRI-visible lesion. RESULTS: Eight children had FCDB and the other nine children had FCDS. The volume of MRI-visible lesions for FCDB ranged from 1,632 to 4,707 mm(3) (mean ± standard deviation [SD] 3,095 ± 1,211 mm(3) ). The depth of FCDB ranged from 19 to 33 mm (mean ± SD 26 ± 4 mm). The volume of MRI-visible lesion for FCDS ranged from 2,375 to 57,331 mm(3) (15,470 ± 18,455 mm(3) ). There was a tendency for a smaller volume of MRI-visible lesion for FCDB, relative to FCDS(p = 0.079). In FCDB, six children showed clusters of MEG dipoles and two children showed scattered MEG dipoles for interictal spikes. The spatial congruence between the MEG result and FCDB was partially overlapping in four children and discordant in another four children. In FCDS, eight children had MEG cluster and one child had MEG scatter alone. The spatial congruence between MEG result and FCDS was overlapping in eight of nine children (fully two; partially six) and discordant in one of nine children. Fifteen children (88%; FCDB eight; FCDS seven) became seizure-free after resective surgery. MEG spike dipole resection ratio in the cluster ranged from 4-100% (mean 67%) in 6 FCDB and 23-99% (mean 77%) in 8 FCDS. SIGNIFICANCE: The SMD method may drift MEG spike dipoles for FCDB. Lesionectomy can control seizures for four of eight patients in FCDB despite the remote MEG dipoles. The FCDB or FCDS partially overlapped with MEG cluster may have an extending/invisible epileptogenic zone consecutive to the MRI-visible lesion.

Prospective evaluation of the safety of transrectal ultrasound-guided transperineal prostate biopsy based on adverse events.

BACKGROUND: Although transperineal (TP) prostate biopsy is growing in popularity, its safety has not been evaluated based on extensive studies. We prospectively assessed the adverse events associated with transrectal ultrasound (TRUS)-guided TP 16-core prostate biopsy at a single institution. PATIENTS AND METHODS: We enrolled 2,086 males who underwent first-time TRUS-guided TP prostate biopsy under lumbar spinal anesthesia at Chiba Cancer Center between 2009 and 2013. Eight adverse events were assessed prospectively using a purpose-designed questionnaire. The prevalence and duration of all adverse events were evaluated. We performed subgroup analyses for hematuria and urinary retention in relation to clinical factors. RESULTS: Questionnaires were collected from 1,663 cases (79.7 %). The cancer detection rate was 53.5 % in all patients. The prevalence and duration of complications were as follows: hematuria, 73.4 % and 4.51 ± 2.88 days; perineal bleeding, 7.1 % and 2.20 ± 2.24 days; hematospermia 14.4 %; dysuria, 15.7 % and 3.12 ± 2.71 days; urinary tract pain, 49.5 % and 2.43 ± 2.08 days; perineal pain, 35.5 % and 3.53 ± 2.59 days; fever ≥37 °C, 1.7 % and 1.79 ± 1.72 days; and headache, 22.1 % and 3.40 ± 2.10 days. Seventeen patients (1.1 %) required indwelling urethral catheterization for grade 2 urinary retention. Pre-biopsy International Prostate Symptom Score (p = 0.014) was an independent related factor for hematuria. Prostate volume (p = 0.001) was an independent related factor for grade 2 urinary retention. CONCLUSIONS: TRUS-guided TP prostate biopsy under lumbar spinal anesthesia can be performed safely with only minor adverse events.

Preictal surrender of post-spike slow waves to spike-related high-frequency oscillations (80-200 Hz) is associated with seizure initiation.

OBJECTIVE: Spike and slow waves consist of a "spike" including high-frequency oscillations (HFOs), which are linked to epileptogenicity and a "post-spike slow wave (PSS)" related to inhibitory activity. The aim of this study was to elucidate the spatiotemporal relationship between spike-related HFOs and PSS in patients with focal cortical dysplasia (FCD) type II. METHODS: We studied 10 pediatric patients with FCD type II, who underwent extraoperative video-electroencephalography (EEG). We selected spike and slow waves, which included HFOs (80-200 Hz), and performed spike peak-locked averaging 10 times during both 30 s interictal (>1 h apart from seizures) and 30 s preictal periods. We calculated the power of spike-related HFOs and PSS during both periods for the following three areas: (1) inside the seizure-onset zone (SOZ), (2) inside the resection area (RA) but outside SOZ (RA-SOZ), and (3) outside the RA. Between the interictal and preictal periods we performed correlation (Spearman's coefficient) and simple linear regression analyses comparing HFO and PSS power within each area. RESULTS: A total of 1,614 averaged spike and slow waves were analyzed during both periods. During the interictal periods, there were significant positive correlations between HFO and PSS power in all areas (inside SOZ, r = 0.568; RA-SOZ, r = 0.700; outside RA, r = 0.320). During the preictal periods, the correlation became weaker inside SOZ (r = 0.149) and remained unchanged both inside the RA-SOZ (r = 0.704) and outside RA (r = 0.346). From the interictal to preictal period, the slope (ΔPSS power/ΔHFO power) of the simple regression line decreased inside SOZ (0.349 to 0.051) but increased in RA-SOZ (0.534 to 0.734) and outside RA (0.267 to 0.435). SIGNIFICANCE: Relative power reduction of PSS to spike-related HFOs in SOZ is relevant for seizure initiation. Our analysis will contribute to future studies of seizure prediction and distinction between pathologic and physiologic HFOs. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Efficacy of traditional and alternative sunitinib treatment schedules in Japanese patients with metastatic renal cell carcinoma.

We report the adverse events and efficacy of traditional (4 weeks on 2 weeks off) and alternative sunitinib treatment schedules for Japanese patients with metastatic renal cell carcinoma. We retrospectively investigated 54 patients who received sunitinib for metastatic renal cell carcinoma between May 2006 and June 2012: 32 received a traditional treatment schedule and 22 received an alternative schedule. According to the Memorial Sloan-Kettering Cancer Center risk classification, five patients had favorable prognoses, 42 had intermediate prognoses and seven had poor prognoses. The mean observation periods were 16.3 and 20 months for the traditional and alternative schedule groups, respectively. Adverse events were significantly less common in the alternative schedule group, including most high-grade events. In the traditional and alternative schedule groups, median times to failure were 4.1 and 11.6 months (P = 0.040), median progression-free survival times were 4.1 and 11.3 months (P = 0.031), and median overall survival times were 12.0 and 32.1 months (P = 0.018), respectively. Each of these measures was better in the group of patients who received an alternative treatment schedule, suggesting that individualized changes to the sunitinib administration schedule can be effective.

Effectiveness of perampanel for focal seizures determined by interictal gamma oscillation regularity analysis.

Although perampanel (PER) has received approval as an antiseizure medication, reports quantifying its antiseizure effects using electroencephalography (EEG) remain scarce. In a previous study, we demonstrated that the interictal high gamma oscillation regularity (GOR) on scalp EEG is an excellent marker of epileptogenicity. Herein, we investigated whether the antiseizure effect of PER could be quantified through interictal GOR analysis of scalp EEG data. To investigate this, we examined the interictal GOR from 20 s of scalp EEG data before and after PER administration collected from five patients with epilepsy with focal seizures. Prior to PER administration, each patient presented with localized areas with high GOR consistent with brain lesions or seizure semiology. In all patients, the seizures improved following PER administration, and the localized high GOR, which is considered an epileptogenic focus, disappeared. These results indicate that interictal GOR analysis may be a useful tool for the quantitative assessments of the antiseizure effects of PER in focal epilepsy. PLAIN LANGUAGE SUMMARY: This study explored whether perampanel (PER)'s antiseizure effects can be quantified using interictal high gamma oscillation regularity (GOR) analysis from scalp EEG data. Analyzing 20-second EEG segments before and after PER administration in five patients with focal epilepsy, we found that high GOR areas, indicative of epileptogenic foci, disappeared following PER administration. The results suggest that interictal GOR analysis could effectively quantify the antiseizure effects of PER.