RTL1/PEG11 imprinted in human and mouse brain mediates anxiety-like and social behaviors and regulates neuronal excitability in the locus coeruleus.

RTL1/PEG11, which has been associated with anxiety disorders, is a retrotransposon-derived imprinted gene in the placenta. However, imprinting patterns and functions of RTL1 in the brain have not been well-investigated. We found Rtl1 was paternally, but not maternally, expressed in brain stem, thalamus, and hypothalamus of mice, and imprinting status of RTL1 was maintained in human brain. Paternal Rtl1 knockout (Rtl1m+/p-) mice had higher neonatal death rates due to impaired suckling, and low body weights beginning on embryonic day 16.5. High paternal expression of Rtl1 was detected in the locus coeruleus (LC) and Rtl1m+/p- mice showed an increased delay in time of onset for action potentials and inward currents with decreased neuronal excitability of LC neurons. Importantly, Rtl1m+/p- mice exhibited behaviors associated with anxiety, depression, fear-related learning and memory, social dominance, and low locomotor activity. Taken together, our findings demonstrate RTL1 is imprinted in brain, mediates emotional and social behaviors, and regulates excitability in LC neurons.

A phase 1 study of biweekly nab-paclitaxel/oxaliplatin/S-1/LV for advanced upper gastrointestinal cancers: TCOG T1216 study.

BACKGROUND: Oxaliplatin- and fluoropyrimidine-based triplet regimens have demonstrated feasibility and efficacy in the treatment of upper gastrointestinal (UGI) cancers. Herein, we evaluate the feasibility and preliminary efficacy of biweekly nab-paclitaxel plus oxaliplatin and S-1/leucovorin (SOLAR) in chemonaïve UGI cancers. METHODS: A 3 + 3 phase 1 study was conducted to determine the maximal tolerated dose (MTD) of oxaliplatin in SOLAR (nab-paclitaxel [150 mg/m2 in D1], oxaliplatin [60, 75, or 85 mg/m2 in D1], and oral S-1/leucovorin [35 mg/m2 and 30 mg bid from D1 to D7]). The secondary endpoints were overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Thirteen and 6 accruals were in the dose-escalation and MTD expansion cohorts, respectively. One of 6 patients at level III experienced dose-limiting toxicity (grade 3 diarrhea), which revealed that the MTD of oxaliplatin was 85 mg/m2. After a mean of 15.9 cycles of treatment, the most common treatment-related grade 3/4 toxicities were neutropenia (57.9%) and diarrhea (21.1%). The ORR was 63.2%. The median PFS and OS were 12.5 and 24.7 months, respectively. CONCLUSION: The current study revealed the MTD of oxaliplatin and demonstrated the preliminary efficacy of SOLAR in UGI cancers, which deserves further investigation. CLINICALTRIALS.GOV IDENTIFIER: NCT03162510.

Impact of previous S-1 treatment on efficacy of liposomal irinotecan plus 5-fluorouracil and leucovorin in patients with metastatic pancreatic cancer.

BACKGROUND/OBJECTIVES: Liposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI + 5-FU/LV) provides survival benefits for metastatic pancreatic adenocarcinoma (mPDAC) refractory to gemcitabine-based treatment, mainly gemcitabine plus nab-paclitaxel (GA), in current practice. Gemcitabine plus S-1 (GS) is another commonly administered first-line regimen before nab-paclitaxel reimbursement; however, the efficacy and safety of nal-IRI + 5-FU/LV for mPDAC after failed GS treatment has not been reported and was therefore explored in this study. METHODS: In total, 177 patients with mPDAC received first-line GS or GA treatment, followed by second-line nal-IRI + 5-FU/LV treatment (identified from a multicenter retrospective cohort in Taiwan from 2018 to 2020); 85 and 92 patients were allocated to the GS and GA groups, respectively. Overall survival (OS), time-to-treatment failure (TTF), and adverse events were compared between the two groups. RESULTS: The baseline characteristics of the two groups were generally similar; however, a higher median age (67 versus 62 years, p < 0.001) and fewer liver metastases (52% versus 78%, p < 0.001) were observed in the GS versus GA group. The median OS was 15.0 and 15.9 months in the GS and GA groups, respectively (p = 0.58). The TTF (3.1 versus 2.8 months, p = 0.36) and OS (7.6 versus 6.7 months, p = 0.83) after nal-IRI treatment were similar between the two groups. More patients in the GS group developed mucositis during nal-IRI treatment (15% versus 4%, p = 0.02). CONCLUSIONS: The efficacy of second-line nal-IRI +5-FU/LV treatment was unaffected by prior S-1 exposure. GS followed by nal-IRI treatment is an alternative treatment sequence for patients with mPDAC.

Perfluorooctanesulfonic Acid Alters the Plant's Phosphate Transport Gene Network and Exhibits Antagonistic Effects on the Phosphate Uptake.

Per- and polyfluoroalkyl substances (PFASs), with significant health risks to humans and wildlife, bioaccumulate in plants. However, the mechanisms underlying plant uptake remain poorly understood. This study deployed transcriptomic analysis coupled with genetic and physiological studies using Arabidopsis to investigate how plants respond to perfluorooctanesulfonic acid (PFOS), a long-chain PFAS. We observed increased expressions of genes involved in plant uptake and transport of phosphorus, an essential plant nutrient, suggesting intertwined uptake and transport processes of phosphorus and PFOS. Furthermore, PFOS-altered response differed from the phosphorus deficiency response, disrupting phosphorus metabolism to increase phosphate transporter (PHT) transcript. Interestingly, pht1;2 and pht1;8 mutants showed reduced sensitivity to PFOS compared to that of the wild type, implying an important role of phosphate transporters in PFOS sensing. Furthermore, PFOS accumulated less in the shoots of the pht1;8 mutant, indicating the involvement of PHT1;8 protein in translocating PFOS from roots to shoots. Supplementing phosphate improved plant's tolerance to PFOS and reduced PFOS uptake, suggesting that manipulating the phosphate source in PFOS-contaminated soils may be a promising strategy for minimizing PFOS uptake by edible crops or promoting PFOS uptake during phytoremediation. This study highlighted the critical role of phosphate sensing and transport system in the uptake and translocation of PFOS in plants.

Contemporary Management of Pediatric Brainstem Tumors.

Brain tumors are the second most common malignancy in childhood. Around 15-20% of pediatric brain tumors occur in the brainstem. The most common type of brainstem tumor are diffuse tumors in the ventral pons, whereas focal tumors tend to arise from the midbrain, medulla, and dorsal pons. Glioma is the most common pathological entity. Contemporary management consists of surgery, radiotherapy, chemotherapy, and other adjuvant treatment. Surgical options range from biopsy to radical excision. Biopsy can be performed for diagnostic and prognostic purposes, or in the setting of clinical trials, mainly for diffuse intrinsic pontine gliomas. For focal tumors, surgeons need to carefully balance clinical outcomes against possible neurological sequelae in order to achieve maximal safe resection. Radiotherapy is essential for control of high-grade tumors and may be applied to residual or recurrent low-grade tumors. Proton therapy may provide similar efficacy and less neurotoxicity in comparison to conventional photon therapy. Oncological treatment continues to evolve from conventional chemotherapy to targeted therapy, immunotherapy, and other novel treatment methods and holds great potential as adjuvant therapy for pediatric brainstem tumors.

Prognostic implications of distinctive imaging characteristics in primary intracranial germ cell tumors: A retrospective analysis.

PURPOSE: Primary central nervous system (CNS) germ cell tumors (GCTs) are rare brain tumors that encompass two subtypes: germinomas and non-germinomatous germ cell tumors (NGGCTs), NGGCTs have less favorable outcome and require multi-modality treatment. Biopsy is recommended for disease diagnosis, the specimen may not adequately reflect the entire tumor. This study aimed to assess distinct imaging characteristics to differentiate between GCT subgroups and to identify possible initial image and subgroup features that influence survival. METHOD: This retrospective study, conducted from January 2006 to March 2023, analyzed patient data and MRI findings of primary CNS GCTs. It evaluated tumor characteristics including cysts, seeding, multifocality, and hemorrhage. Tumor volumes and apparent diffusion coefficient (ADC) values of both tumoral and normal-appearing contralateral white matter were measured. These factors were correlated with overall and 5-year survival rates. RESULTS: This study included 51 participants with CGTs, comprising 19 germinoma and 32 NGGCTs cases. GCTs with hemorrhage had worse overall (P = 0.03) and 5-year (P = 0.01) survival rates. No survival difference between germinoma and non-hemorrhagic NGGCT. NGGCTs were more likely to bleed (P < 0.001) than germ cell tumor, especially those with choriocarcinoma or yolk sac tumor components (P = 0.001). The ADC ratios of germinomas were significantly lower than those of NGGCTs (P = 0.03 for whole tumor; P < 0.01 or solid part), The ADC ratios of choriocarcinoma were also lower than mixed tumor (P = 0.01; P = 0.02). CONCLUSION: Hemorrhage indicates worse prognosis. Intratumoral hemorrhage and ADC ratios differentiate germinoma from NGGCTs. Larger cohorts and advanced MR techniques are needed for future study.

A phase II randomised trial of induction chemotherapy followed by concurrent chemoradiotherapy in locally advanced pancreatic cancer: the Taiwan Cooperative Oncology Group T2212 study.

BACKGROUND: The objective of this study was to evaluate the efficacy and safety of induction chemotherapy (ICT), GOFL (gemcitabine, oxaliplatin plus fluorouracil (5-FU)/leucovorin) versus modified FOLFIRINOX (irinotecan, oxaliplatin plus 5-FU/leucovorin), followed by concurrent chemoradiotherapy (CCRT) in locally advanced pancreatic adenocarcinoma (LAPC). METHODS: Chemo-naive patients with measurable LAPC were eligible and randomly assigned to receive biweekly ICT with either mFOLFIRINOX or GOFL for 3 months. Patients without systemic progression would have 5-FU- or gemcitabine-based CCRT (5040 cGy/28 fractions) and were then subjected to surgery or continuation of chemotherapy until treatment failure. The primary endpoint was 9-month progression-free survival (PFS) rate. RESULTS: Between July 2013 and January 2019, 55 patients were enrolled. After ICT, 21 (77.8%) of 27 patients who received mFOLFIRINOX and 17 (60.7%) of 28 patients who received GOFL completed CCRT. Of them, one and five had per-protocol R0/R1 resection. On intent-to-treat analysis, the 9-month PFS rate, median PFS and overall survival in mFOLFIRINOX and GOFL arms were 30.5% versus 35.9%, 6.6 (95% confidence interval: 5.9-12.5) versus 7.6 months (3.9-12.3) and 19.6 (13.4-22.9) versus 17.9 months (13.4-23.9), respectively. Grade 3-4 neutropenia and diarrhoea during induction mFOLFIRINOX and GOFL were 37.0% versus 21.4% and 14.8% versus 3.6%, respectively. CONCLUSION: Induction GOFL and mFOLFIRINOX followed by CCRT provided similar clinical outcomes in LAPC patients. GOV IDENTIFIER: NCT01867892.

Integration of immunohistochemistry, RNA sequencing, and multiplex ligation-dependent probe amplification for molecular classification of pediatric medulloblastoma.

BACKGROUND: Medulloblastoma (MB) is commonly classified into four molecular groups, that is, WNT, SHH, group 3, and group 4, for prognostic and therapeutic purposes. METHODS: Here we applied immunohistochemistry (IHC) and RNA sequencing (RNA-seq) for the molecular classification of MB, and utilized multiplex ligation-dependent probe amplification (MLPA) to determine chromosomal alterations and specific gene amplifications. RESULTS: We retrospectively enrolled 37 pediatric MB patients. Twenty-three had genomic material available for gene/RNA analysis. For IHC, ß-catenin, GAB1, and YAP were the biomarkers to segregate MB into three subgroups, WNT (1/23), SHH (5/23), and non-WNT/non-SHH (17/23). However, four cases (17.3%) were found to be misclassified after analysis by RNA-seq. The result of MLPA revealed two group 3 tumors carrying MYC amplification, and three SHH tumors harboring MYCN amplification. While IHC provided rapid subgroup stratification, it might result in incorrect subgrouping. Thus, validation of the IHC result with genomic data analysis by RNA-seq or other tools would be preferred. In addition, MLPA can detect important genetic alterations and is helpful for the identifications of high-risk patients. CONCLUSIONS: Our study revealed that integration of these diagnostic tools can provide a precise and timely classification of MB, optimizing an individualized, risk-directed postoperative adjuvant therapy for these patients. This workflow can be applied in a countrywide fashion to guide future clinical trials for patients with MB.

Fate and Transformation of 6:2 Fluorotelomer Sulfonic Acid Affected by Plant, Nutrient, Bioaugmentation, and Soil Microbiome Interactions.

6:2 Fluorotelomer sulfonic acid (6:2 FTSA) is a dominant per- and poly-fluoroalkyl substance (PFAS) in aqueous film-forming foam (AFFF)-impacted soil. While its biotransformation mechanisms have been studied, the complex effects from plants, nutrients, and soil microbiome interactions on the fate and removal of 6:2 FTSA are poorly understood. This study systematically investigated the potential of phytoremediation for 6:2 FTSA byArabidopsis thalianacoupled with bioaugmentation ofRhodococcus jostiiRHA1 (designated as RHA1 hereafter) under different nutrient and microbiome conditions. Hyperaccumulation of 6:2 FTSA, defined as tissue/soil concentration > 10 and high translocation factor > 3, was observed in plants. However, biotransformation of 6:2 FTSA only occurred under sulfur-limited conditions. Spiking RHA1 not only enhanced the biotransformation of 6:2 FTSA in soil but also promoted plant growth. Soil microbiome analysis uncovered Rhodococcus as one of the dominant species in all RHA1-spiked soil. Different nutrients such as sulfur and carbon, bioaugmentation, and amendment of 6:2 FTSA caused significant changes in - microbial community structure. This study revealed the synergistic effects of phytoremediation and bioaugmentation on 6:2 FTSA removal. and highlighted that the fate of 6:2 FTSA was highly influced by the complex interactions of plants, nutrients, and soil microbiome.

Long-term outcomes of moyamoya disease following indirect revascularization in middle adulthood: A prospective, quantitative study.

BACKGROUND/PURPOSE: Our previous study demonstrated that indirect revascularization is effective in the treatment of adult moyamoya patients. This prospective study aims to evaluate the long-term effectiveness of indirect revascularization in moyamoya patients in middle adulthood. METHODS: From January 2013 to June 2019, moyamoya patients more than 40 years of age underwent indirect revascularizations were studied. The hypoperfusion area of brains was revascularized. The cerebral angiography and time-to-peak (TTP) scoring (ranged 0-14) of the magnetic resonance perfusion study were used to evaluate the revascularization effect. RESULTS: During the study period, 50 consecutive adult moyamoya patients underwent indirect revascularization. Seventeen patients (27 cerebral hemispheres) more than 40 years of age were included. The mean age was 47.9 ± 6.4 years, and 13 patients were female. The pre-operative Suzuki stages were I, II, III, IV, V, and VI in 1, 1, 9, 13, 0, and 3 hemispheres, respectively. After a mean follow-up period of 52.5 ± 20.6 months, all patients had improvement or stabilization of their clinical conditions. Available post-operative angiography demonstrated Matsushima grading A in 18 of 20 hemispheres. The mean TTP score of all 27 hemispheres improved from 5.0 ± 3.3 pre-operatively to 12.0 ± 2.1 after surgery (p < 0.001). The post-operative mean TTP score of the 7 hemispheres without angiographic follow-up was 10.4 ± 1.8. One patient had persistent mild motor weakness after 56-month follow-up. Transient complications with full recovery occurred in 3 patients. CONCLUSION: Indirect revascularization is a safe method with satisfactory long-term results in moyamoya patient in middle adulthood.

Surgical application of endoscopic-assisted minimally-invasive neurosurgery to traumatic brain injury: Case series and review of literature.

BACKGROUND/PURPOSE: Adequate decompression is the primary goal during surgical management of patients with traumatic brain injury (TBI). Therefore, it may seem counterintuitive to use minimally-invasive strategies to treat these patients. However, recent studies show that endoscopic-assisted minimally-invasive neurosurgery (MIN) can provide both adequate decompression (which is critical for preserving viable brain tissue) and maximize neurological recovery for patients with TBI. Hence, we reviewed the pertinent literature and shared our experiences on the use of MIN. METHODS: This was a retrospective multi-center study. We collected data of 22 TBI patients receiving endoscopic-assisted MIN within 72 hours after the onset, with Glasgow Coma Scale (GCS) scores of 6-14 and whose hemorrhage volume ranging from 30 to 70 mL. RESULTS: We have applied MIN techniques to a group of 22 patients with traumatic ICH (TICH), epidural hematoma (EDH), and subdural hematoma (SDH). The mean pre-operative GCS score was 7.5 (median 7), and mean hemorrhage volume was 57.14 cm3 Surgery time was shortened with MIN approaches to a mean of 59.6 min. At 6-month follow-up, the mean GCS score had improved to 12.3 (median 15). By preserving more normal brain tissue, MIN for patients with TBI can result in beneficial effects on recoveries and neurological outcomes. CONCLUSION: Endoscopic-assisted MIN in TBI is safe and effective in a carefully selected group of patients.

Contribution of nuclear BCL10 expression to tumor progression and poor prognosis of advanced and/or metastatic pancreatic ductal adenocarcinoma by activating NF-κB-related signaling.

BACKGROUND: We previously demonstrated that nuclear BCL10 translocation participates in the instigation of NF-κB in breast cancer and lymphoma cell lines. In this study, we assessed whether nuclear BCL10 translocation is clinically significant in advanced and metastatic pancreatic ductal adenocarcinoma (PDAC). METHOD AND MATERIALS: We analyzed the expression of BCL10-, cell cycle-, and NF-κB- related signaling molecules, and the DNA-binding activity of NF-κB in three PDAC cell lines (mutant KRAS lines: PANC-1 and AsPC-1; wild-type KRAS line: BxPC-3) using BCL10 short hairpin RNA (shBCL10). To assess the anti-tumor effect of BCL10 knockdown in PDAC xenograft model, PANC-1 cells treated with or without shBCL10 transfection were inoculated into the flanks of mice. We assessed the expression patterns of BCL10 and NF-κB in tumor cells in 136 patients with recurrent, advanced, and metastatic PDAC using immunohistochemical staining. RESULTS: We revealed that shBCL10 transfection caused cytoplasmic translocation of BCL10 from the nuclei, inhibited cell viability, and enhanced the cytotoxicities of gemcitabine and oxaliplatin in three PDAC cell lines. Inhibition of BCL10 differentially blocked cell cycle progression in PDAC cell lines. Arrest at G1 phase was noted in wild-type KRAS cell lines; and arrest at G2/M phase was noted in mutant KRAS cell lines. Furthermore, shBCL10 transfection downregulated the expression of phospho-CDC2, phospho-CDC25C, Cyclin B1 (PANC-1), Cyclins A, D1, and E, CDK2, and CDK4 (BxPC-3), p-IκBα, nuclear expression of BCL10, BCL3, and NF-κB (p65), and attenuated the NF-κB pathway activation and its downstream molecule, c-Myc, while inhibition of BCL10 upregulated expression of p21, and p27 in both PANC-1 and BxPC-3 cells. In a PANC-1-xenograft mouse model, inhibition of BCL10 expression also attenuated the tumor growth of PDAC. In clinical samples, nuclear BCL10 expression was closely associated with nuclear NF-κB expression (p < 0.001), and patients with nuclear BCL10 expression had the worse median overall survival than those without nuclear BCL10 expression (6.90 months versus 9.53 months, p = 0.019). CONCLUSION: Nuclear BCL10 translocation activates NF-κB signaling and contributes to tumor progression and poor prognosis of advanced/metastatic PDAC.

Preoperative 2-[18F]FDG PET-CT aids in the prognostic stratification for patients with primary ampullary carcinoma.

OBJECTIVES: We sought to investigate whether preoperative dual-phase 2-[18F]FDG PET-CT identify predictors for poor survival in patients with ampullary carcinoma receiving pancreaticoduodenectomy. METHODS: The preoperative PET-CT images of patients with resected ampullary carcinoma from June 2007 to July 2017 were analyzed. Survival curves were analyzed using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazard model was used to identify potential prognostic factors associated with disease-free survival (DFS) and overall survival (OS). RESULTS: Fifty-four subjects (26 men, 28 women) were enrolled with a median tumor size of 20 mm. All patients were followed for a median period of 36.9 months with 3- and 5-year DFS of 50.3% and 44.2%, and OS of 77.0% and 68.2%, respectively. Parameters associated with DFS in multivariate analysis were lymphovascular invasion (hazard ratio [HR]: 9.45, p < 0.001), involved margin in pathology (HR: 7.67, p < 0.001), and tumor retention index (RI) from the dual-phase PET (HR: 2.41, p = 0.03), whereas involved margin (HR: 13.14, p < 0.001), post-recurrence chemotherapy (HR: 0.10, p < 0.001), and metabolic tumor volume (MTV) (HR: 4.62, p = 0.009) emerged as independent prognostic factors for OS. CONCLUSIONS: Preoperative 2-[18F]FDG PET-CT offered independent prognostic biomarkers in patients with ampullary carcinoma receiving standard surgical resection. KEY POINTS: • 2-[18F]FDG PET-CT offers good survival prediction before operation in primary malignant neoplasms at ampulla of Vater. • Dual-phase PET scan with bowel distention can better delineate Ampulla of Vater and characterize tumor physiology. • Preoperative risk stratification might aid in better treatment planning.

A Dynamic Interbody Cage Improves Bone Formation in Anterior Cervical Surgery: A Porcine Biomechanical Study.

BACKGROUND: Anterior cervical discectomy and fusion (ACDF) with a rigid interbody spacer is commonly used in the treatment of cervical degenerative disc disease. Although ACDF relieves clinical symptoms, it is associated with several complications such as pseudoarthrosis and adjacent segment degeneration. The concept of dynamic fusion has been proposed to enhance fusion and reduce implant subsidence rate and post-fusion stiffness; this pilot preclinical animal study was conducted to begin to compare rigid and dynamic fusion in ACDF. QUESTIONS/PURPOSES: Using a pig model, we asked, is there (1) decreased subsidence, (2) reduced axial stiffness in compression, and (3) improved likelihood of bone growth with a dynamic interbody cage compared with a rigid interbody cage in ACDF? METHODS: ACDF was performed at two levels, C3/4 and C5/6, in 10 pigs weighing 48 to 55 kg at the age of 14 to 18 months (the pigs were skeletally mature). One level was implanted with a conventional rigid interbody cage, and the other level was implanted with a dynamic interbody cage. The conventional rigid interbody cage was implanted in the upper level in the first five pigs and in the lower level in the next five pigs. Both types of interbody cages were implanted with artificial hydroxyapatite and tricalcium phosphate bone grafts. To assess subsidence, we took radiographs at 0, 7, and 14 weeks postoperatively. Subsidence less than 10% of the disc height was considered as no radiologic abnormality. The animals were euthanized at 14 weeks, and each operated-on motion segment was harvested. Five specimens from each group were biomechanically tested under axial compression loading to determine stiffness. The other five specimens from each group were used for microCT evaluation of bone ingrowth and ongrowth and histologic investigation of bone formation. Sample size was determined based on 80% power and an α of 0.05 to detect a between-group difference of successful bone formation of 15%. RESULTS: With the numbers available, there was no difference in subsidence between the two groups. Seven of 10 operated-on levels with rigid cages had subsidence on a follow-up radiograph at 14 weeks, and subsidence occurred in two of 10 operated-on levels with dynamic cages (Fisher exact test; p = 0.07). The stiffness of the unimplanted rigid interbody cages was higher than the unimplanted dynamic interbody cages. After harvesting, the median (range) stiffness of the motion segments fused with dynamic interbody cages (531 N/mm [372 to 802]) was less than that of motion segments fused with rigid interbody cages (1042 N/mm [905 to 1249]; p = 0.002). Via microCT, we observed bone trabecular formation in both groups. The median (range) proportions of specimens showing bone ongrowth (88% [85% to 92%]) and bone volume fraction (87% [72% to 100%]) were higher in the dynamic interbody cage group than bone ongrowth (79% [71% to 81%]; p < 0.001) and bone volume fraction (66% [51% to 78%]; p < 0.001) in the rigid interbody cage group. The percentage of the cage with bone ingrowth was higher in the dynamic interbody cage group (74% [64% to 90%]) than in the rigid interbody cage group (56% [32% to 63%]; p < 0.001), and the residual bone graft percentage was lower (6% [5% to 8%] versus 13% [10% to 20%]; p < 0.001). In the dynamic interbody cage group, more bone formation was qualitatively observed inside the cages than in the rigid interbody cage group, with a smaller area of fibrotic tissue under histologic investigation. CONCLUSION: The dynamic interbody cage provided satisfactory stabilization and percentage of bone ongrowth in this in vivo model of ACDF in pigs, with lower stiffness after bone ongrowth and no difference in subsidence. CLINICAL RELEVANCE: The dynamic interbody cage appears to be worthy of further investigation. An animal study with larger numbers, with longer observation time, with multilevel surgery, and perhaps in the lumbar spine should be considered.

Selection of Essential Neural Activity Timesteps for Intracortical Brain-Computer Interface Based on Recurrent Neural Network.

Intracortical brain-computer interfaces (iBCIs) translate neural activity into control commands, thereby allowing paralyzed persons to control devices via their brain signals. Recurrent neural networks (RNNs) are widely used as neural decoders because they can learn neural response dynamics from continuous neural activity. Nevertheless, excessively long or short input neural activity for an RNN may decrease its decoding performance. Based on the temporal attention module exploiting relations in features over time, we propose a temporal attention-aware timestep selection (TTS) method that improves the interpretability of the salience of each timestep in an input neural activity. Furthermore, TTS determines the appropriate input neural activity length for accurate neural decoding. Experimental results show that the proposed TTS efficiently selects 28 essential timesteps for RNN-based neural decoders, outperforming state-of-the-art neural decoders on two nonhuman primate datasets (R2=0.76±0.05 for monkey Indy and CC=0.91±0.01 for monkey N). In addition, it reduces the computation time for offline training (reducing 5-12%) and online prediction (reducing 16-18%). When visualizing the attention mechanism in TTS, the preparatory neural activity is consecutively highlighted during arm movement, and the most recent neural activity is highlighted during the resting state in nonhuman primates. Selecting only a few essential timesteps for an RNN-based neural decoder provides sufficient decoding performance and requires only a short computation time.

Multicentre, phase II study of gemcitabine and S-1 in patients with advanced biliary tract cancer: TG1308 study.

BACKGROUND & AIMS: Gemcitabine plus cisplatin (GC) remains the standard, frontline therapy for advanced biliary tract cancer (ABTC). The JCOG1113 study suggested that gemcitabine plus S-1 (GS) had noninferior median overall survival and comparable incidence of significant neutropenia as compared to GC treatments. This study evaluates the efficacy and safety of a modified GS regimen. METHODS: The eligible patients with chemonaive, measurable ABTC received 800 mg/m2 of gemcitabine on day 1 and 80 mg/m2 /day of S-1 (80/100/120 mg for patients with body surface <1.25/ ≥1.25 and <1.5/ ≥1.5 m2 respectively). The primary endpoint was the 12-week disease control rate (12-week DCR: objective response and stable disease ≥ 12 weeks). Per the p0 = 40% and p1 = 60% (α/ß = 0.05/0.2) assumption, Simon's optimal two-stage design indicated 12-week DCR in ≥ 24 of 46 evaluable patients for significant activity. Tumour responses were assessed every 6 weeks. RESULTS: Fifty-one patients were enrolled and most of them had intrahepatic cholangiocarcinoma (64.7%), metastatic disease (84.3%) and disease-related symptoms (82.4%). On intention-to-treat analysis, 11 (21.6%) patients showed partial response, whereas 21 (41.2%) showed stable disease ≥ 12 weeks. The progression-free and overall survival were 5.4 months (95% confidence interval [CI]: 3.5-7.0), and 12.7 months (95% CI: 6.1-15.6) respectively. The study met its primary endpoint with a 12-week DCR of 69.6% in 46 evaluable patients. Grade 3/4 treatment-related adverse eventsoccurred in < 6% of patients of all individual items. The mean dose intensities of S-1 and gemcitabine were 87.1% and 92.5% respectively. CONCLUSIONS: Modified GS showed moderate efficacy with a favourable safety profile in ABTC patients, thus mandating further assessment. ClinicalTrials.gov number: NCT02425137.

Contemporary management of pediatric spinal tumors: a single institute's experience in Taiwan in the modern era.

INTRODUCTION: Pediatric spinal tumors are unique pathologies treated by pediatric neurosurgeons. Special attention is required for the preservation of neural function and bony alignment. We reported our experience in the management of these challenging lesions. METHODS: A total of 75 pediatric patients with spinal tumors treated at the National Taiwan University Hospital from 1998 to 2018 were identified retrospectively. Clinical data, radiographic image, and pathological report were reviewed for analysis. RESULTS: There were 37 females and 38 males. The median age was 9 years. Thirty-eight tumors (50.6%) were extradural, 20 (26.7%) intradural extramedullary, and 17 (22.6%) intramedullary. The most common pathologies were glioma, ependymoma, and neuroblastoma. The rate of total and subtotal resection was 45.3% and 21.3%. Thirty-four patients (45.3%) required post-operative adjuvant therapy. Eight patients (10.6%) with spinal deformity had simultaneous tumor excision and spinal fusion surgery. Additional six (8%) patients had subsequent spinal fixation and fusion for deformity after primary tumor operation. Eighty-four percent of patients were ambulatory 3 years after operation. For patients with intradural extramedullary and intramedullary tumors, worse survival outcome was associated with tumor derived from CSF seeding and cranial involvement of spinal tumor, while poorer functional outcome was correlated with cranial involvement and adjuvant therapy with chemotherapy or radiotherapy. CONCLUSIONS: Pediatric spinal tumor surgery carries low surgical morbidity and mortality under current standard of neurosurgical practice. Post-operative adjuvant therapy is required for nearly half of the cases. Spinal deformity requires special attention and sometimes surgical correction. Contemporary management of pediatric spinal tumors enables effective ablation of the lesion and delivers favorable outcome for the majority of patients.

Postoperative change of neuropsychological function after indirect revascularization in childhood moyamoya disease: a correlation with cerebral perfusion study.

PURPOSE: The relationships between postoperative functional improvement in various cognitive domains and regional hemodynamic change have not been sufficiently studied in childhood moyamoya disease (MMD). The present study aimed to examine the cognitive benefit of indirect revascularization, the underlying biological mechanism, and factors affecting surgical outcome in childhood MMD. METHODS: Twenty-three patients with MMD aged under 20 years received neuropsychological examinations before and after indirect revascularization surgery, evaluating intellectual function, verbal and visual memory, and executive function. Among them, 13 patients had magnetic resonance perfusion (MRP) studies, in which regional cerebral perfusion was rated. RESULTS: Postoperative improvement was observed in verbal memory performances (p = 0.02-0.03) and in cerebral perfusion at all 26 cerebral hemispheres (p = 0.003-0.005), especially in the middle cerebral artery (MCA) territories (p = 0.001-0.003). Hemodynamic improvement in the left MCA territories was significantly correlated with improvement of both verbal new learning (p = 0.01) and intellectual function (p = 0.004). Postoperative cognitive improvement of immediate recall and verbal intellectual function was associated with female sex (r = - 0.42) and symptom duration (p = - 0.03), respectively. Hemodynamic improvement in the MCA territories was related to longer follow-up intervals (p = 0.02). CONCLUSION: The findings revealed that the selective postoperative cognitive improvement was associated with increased regional perfusion in the MCA territories, and indicate the importance of early intervention and the potential of indirect revascularization regarding long-term outcome.

Low-dose nab-paclitaxel-based combination chemotherapy in heavily pretreated pancreatic cancer patients.

BACKGROUND: Heavily pretreated pancreatic cancer patients have a grave prognosis. In this case series study, we evaluated the safety and efficacy of nab-paclitaxel-based chemotherapy for such patients. METHODS: The data of pancreatic adenocarcinoma patients (n = 40) treated with nab-paclitaxel after the failure of gemcitabine or fluoropyrimidines at our institution in 2013-2015 were reviewed. RESULTS: The median number of prior chemotherapy regimens was two (range, 1-6). Eighteen patients had an Eastern Cooperative Oncology Group performance status of ≥2. The regimens comprised nab-paclitaxel combined with the following drugs: gemcitabine (n = 28), gemcitabine and fluoropyrimidine (n = 3), platinum and fluoropyrimidine (n = 4), fluoropyrimidine (n = 4), and irinotecan and fluoropyrimidine (n = 1). The median dose of nab-paclitaxel was 63 (range, 51-72) mg/m2/dose, with the schedule of D1/15, D1/8, and D1/8/15 followed in 23, 14, and 3 patients, respectively. The median overall survival was 5.1 (95% CI, 4.6-5.7) months. Among 32 evaluable patients, two partial responses and six stable diseases were observed. The median progression-free survival was 2.6 (95% CI, 1.9-3.2) months. Grade 3/4 leucopenia or neutropenia was observed in three and two patients, respectively. Grade 3/4 anemia was observed in four patients. Other significant (grade 3 or more) nonhematological toxicities were not frequent, except for sepsis/infection (n = 7). However, more severe anemia or sepsis/infection was significantly associated with disease control. CONCLUSION: In heavily pretreated pancreatic adenocarcinoma patients, low-dose nab-paclitaxel-based chemotherapy was fairly tolerable with modest efficacy.

The role of sacral laminoplasty in the management of spina bifida and sacral cystic lesions: case series.

OBJECTIVE: Although laminae are not viewed as essential structures for spinal integrity, in the sacrum the anatomical weakness and gravity makes it a vulnerable area for CSF accumulation and expansion. The congenital or postoperative defects of sacral laminae, such as in patients with spina bifida, make this area more susceptible to forming progressive dural ectasia, pseudomeningocele, or expansile arachnoid cyst (Tarlov cyst). In addition, adhesions between the dura and surrounding soft tissue after laminectomy can cause some local symptoms, which are difficult to relieve. The authors propose that sacral laminoplasty with titanium mesh can provide a rigid support and barrier to resolve these sacral lesions and local symptoms. METHODS: From January 2016 to December 2017, patients with progressive CSF-containing lesions in the sacral area and defective sacral laminae were included in the study. After repair of the lesion, the authors performed sacral laminoplasty with titanium mesh in each patient. Subsequently, the soft tissue and skin were closed primarily. RESULTS: A total of 6 patients were included. Four patients with repaired myelomeningocele had progressive dural ectasia. One patient with lipomyelomeningocele previously underwent detethering surgery and developed postoperative pseudomeningocele. One patient had a symptomatic Tarlov cyst. Four of these 6 cases presented with low-back pain and local tenderness. During follow-up, ranging from 13 to 37 months, all 6 patients experienced no recurrence of dural ectasia or pseudomeningocele and were free from local symptoms. CONCLUSIONS: Sacral laminoplasty with titanium mesh is a safe and effective procedure for treating progressive sacral dural ectasia and refractory pseudomeningocele, preventing CSF leakage as well as relieving local symptoms that may occur years after previous surgery for spina bifida.