Immediately sequential bilateral cataract surgery: advantages and disadvantages.

PURPOSE OF REVIEW: The number of cataract surgeries performed globally will continue to rise to meet the needs of an aging population. This increased demand will require healthcare systems and providers to find new surgical efficiencies while maintaining excellent surgical outcomes. Immediately sequential bilateral cataract surgery (ISBCS) has been proposed as a solution and is increasingly being performed worldwide. The purpose of this review is to discuss the advantages and disadvantages of ISBCS. RECENT FINDINGS: When appropriate patient selection occurs and guidelines are followed, ISBCS is comparable with delayed sequential bilateral cataract surgery in long-term patient satisfaction, visual acuity and complication rates. In addition, the risk of bilateral postoperative endophthalmitis and concerns of poorer refractive outcomes have not been supported by the literature. ISBCS is cost-effective for the patient, healthcare payors and society, but current reimbursement models in many countries create significant financial barriers for facilities and surgeons. SUMMARY: As demand for cataract surgery rises worldwide, ISBCS will become increasingly important as an alternative to delayed sequential bilateral cataract surgery. Advantages include potentially decreased wait times for surgery, patient convenience and cost savings for healthcare payors. Although they are comparable in visual acuity and complication rates, hurdles that prevent wide adoption include liability concerns as ISBCS is not an established standard of care, economic constraints for facilities and surgeons and inability to fine-tune intraocular lens selection in the second eye. Given these considerations, an open discussion regarding the advantages and disadvantages of ISBCS is important for appropriate patient selection.

Apparent diffusion coefficient changes predict survival after intra-arterial bevacizumab treatment in recurrent glioblastoma.

PURPOSE: Superselective intra-arterial cerebral infusion (SIACI) of bevacizumab (BV) has emerged as a novel therapy in the treatment of recurrent glioblastoma (GB). This study assessed the use of apparent diffusion coefficient (ADC) in predicting length of survival after SIACI BV and overall survival in patients with recurrent GB. METHODS: Sixty-five patients from a cohort enrolled in a phase I/II trial of SIACI BV for treatment of recurrent GB were retrospectively included in this analysis. MR imaging with a diffusion-weighted (DWI) sequence was performed before and after treatment. ROIs were manually delineated on ADC maps corresponding to the enhancing and non-enhancing portions of the tumor. Cox and logistic regression analyses were performed to determine which ADC values best predicted survival. RESULTS: The change in minimum ADC in the enhancing portion of the tumor after SIACI BV therapy was associated with an increased risk of death (hazard ratio = 2.0, 95% confidence interval(CI) [1.04-3.79], p = 0.038), adjusting for age, tumor size, BV dose, and prior IV BV treatments. Similarly, the change in ADC after SIACI BV therapy was associated with greater likelihood of surviving less than 1 year after therapy (odds ratio = 7.0, 95% CI [1.08-45.7], p = 0.04). Having previously received IV BV was associated with increased risk of death (OR 18, 95% CI [1.8-180.0], p = 0.014). CONCLUSION: In patients with recurrent GB treated with SIACI BV, the change in ADC value after treatment is predictive of overall survival.

Glioblastoma spheroids produce infiltrative gliomas in the rat brainstem.

PURPOSE: Diffuse intrinsic pontine glioma (DIPG) is universally fatal without proven therapy other than radiation therapy for palliation. Representative animal models will play an essential role in the preclinical stage of future therapy development. To address the shortage of representative models, we created a novel infiltrative brainstem glioma model in rats based on glioblastoma spheroids. METHODS: Cells dissociated from glioblastoma spheroids grown from surgical specimens were implanted into the brainstem of NIH nude rats. Animals were serially assessed clinically and radiographically with magnetic resonance imaging (MRI). Tumors were further characterized using histology, immunohistochemistry, and cytogenetics. RESULTS: Tumor generation was successful in all animals receiving glioblastoma spheroid cells. The rats survived 17-25 weeks before severe symptoms developed. The tumors showed as diffuse hyperintense lesions on T2-weighted images. Histologically, they demonstrated cellular heterogeneity, and infiltrative and invasive features, with cells engorging vascular structures. The tumors were shown to comprise immature human origin glial tumor cells, with human epidermal growth factor receptor (EGFR) gene amplification and gain. CONCLUSIONS: This study showed that cells from glioblastoma spheroids produced infiltrative gliomas in rat brainstem. The rat brainstem gliomas are radiographically and histologically accurate compared to DIPG. These tumors develop over several months that would allow sequential clinical and radiographic assessments of therapeutic interventions. This study demonstrated in principle the feasibility of developing patient-specific animal models based on putative cancer stem cells from biopsy or resection samples.

Three-dimensional volumetric measurements in defining endoscope-guided giant adenoma surgery outcomes.

PURPOSE: Maximum two-dimensional (2D) diameter has been used to define giant pituitary adenoma (GPA) surgery outcomes as has volume using an ellipsoid approximation of volumetrics. Cross sectional length can be measured in several different planes. We sought to compare the accuracy of different 2D cross sectional measurements with the 3D volumetric measurements for predicting GPA surgery outcomes. METHODS: Retrospective analysis was performed on a prospectively collected database. Tumors with >3 cm diameter were identified and classified based on maximal cross sectional measurements in three separate co-axial planes, i.e. transverse (TV), antero-posterior (AP) and cranio-caudal (CC). Volume was calculated using both MRI-guided volumetrics and an ellipsoid approximation (TV × AP × CC/2). Univariate and multivariate analysis was used to evaluate the relationship between cross sectional and volumetric data and extent of resection (EOR). RESULTS: In 62 subjects, median tumor volume using 3D volumetrics was 13.74 cm(3), which was overestimated by 16 % by the ellipsoid calculation (p = 0.0029), particularly for tumors >20 cm(3). Gross total resection (GTR) was 46.7 % and median EOR was 99.57 %. At 22-month follow-up, visual and anterior pituitary functions were stable (90 %) or improved (87 %). Pre-operative tumor volume >10 cm(3) (p = 0.02) and Knosp grade 3-4 (p = 0.04) were independent predictors of EOR. Knosp grade 3-4 (p < 0.0001), TV measurement >4 cm (p = 0.007) and maximum cross sectional length >4 cm (p = 0.04) were predictors of not achieving GTR. Only TV measurement (p = 0.02) predicted permanent diabetes insipidis. The smallest significant thresholds for predicting decreased GTR were TV measurement >25 mm, AP measurement >35 mm and volume >19 cm(3). CONCLUSION: We propose a new volumetric threshold of 20 cm(3) as most accurate for predicting GTR in the EEA era. CC measurement is the least useful predictor. Cavernous sinus invasion remains the best predictor of incomplete resection.

Eccrine Porocarcinoma Presenting as a Hand Cyst.

Eccrine porocarcinoma is a rare tumor that arises from the epithelium of the eccrine ducts, with a tendency for metastatic spread and a high rate of local recurrence after excision. It was first described in 1963 by Pinkus and Mehregan and can present clinically as a nodule, erosive plaque or a polypoid growth that may ulcerate. The variable clinical appearance of these lesions can make diagnosis challenging and could delay appropriate treatment. If metastasis occurs the prognosis is poor, with a reported mortality rate of up to 80%. We report an uncommon presentation of porocarcinoma as a cyst on the dorsum of the right hand in a 37-year-old man. Only 8% of porocarcinomas occur in the upper extremity and only 3% are on the hand. Furthermore, the tumor is more common in females and mean age at diagnosis is 67 years. Treatment is with wide local excision with free tumor borders confirmed by biopsy, which has been shown to be curative in 70% to 80% of patients.

Knitting up 2,7-disubstituted carbazole based oligomers through supramolecular interactions for their application in organic thin film transistors.

For the design and development of organic electronic devices, the main focus is particularly on the synthesis of new organic semiconductors and dielectric materials. Molecular engineering is another effective strategy, in this direction which has been explored successfully in this study through synthesis of a π-conjugated oligomer CbzTPAU2, with Mw = 2169. This bow shaped oligomer has its core unit made of 2,7-disubstituted carbazole which further has been connected to its end-terminal unit TPAU2 by 1,4-bis(decyloxy)-2,5-diethynylbenzene. The presence of a uracil moiety on end terminals of CbzTPAU2 has triggered the self-assembly of CbzTPAU2 molecules through knitting up of each of these single units through four Uracil-Uracil intermolecular hydrogen bonds (UU) per CbzTPAU2 unit. An Atomic Force Microscope (AFM) study was employed to explore the directionality of hydrogen bonding. Further, the effect of solvent polarity on the stability of UU bonding in CbzTPAU2 oligomers has also been reported here in this study. The potential of these self-assembled CbzTPAU2 oligomers when explored as charge transporting layers in OTFTs has shown p-type behaviour. The OTFT device bottom-gate, top-contact when fabricated on the heavily doped n-type Si wafer with SiO2 as a gate dielectric (200 nm) has shown a good on/off ratio 3.43 × 10(3) and with an average hole mobility of 0.167 cm(2) V(-1) s(-1).

Toxicity evaluation of prolonged convection-enhanced delivery of small-molecule kinase inhibitors in naïve rat brainstem.

PURPOSE: Convection-enhanced delivery (CED), a local drug delivery technique, is typically performed as a single session and drug concentrations therefore decline quickly post CED. Prolonged CED (pCED) overcomes this problem by performing a long-term infusion to maintain effective drug concentrations for an extended period. The purpose of the current study was to assess the toxicity of using pCED to deliver single and multi-drug therapy in naïve rat brainstem. METHODS: Sixteen rats underwent pCED of three small-molecule kinase inhibitors in the pons. Single and multi-drug combinations were delivered continuously for 7 days using ALZET mini-osmotic pumps (model 2001, rate of 1 µl/h). Rats were monitored daily for neurological signs of toxicity. Rats were sacrificed 10 days post completion of infusion, and appropriate tissue sections were analyzed for histological signs of toxicity. RESULTS: Two rats exhibited signs of neurological deficits, which corresponded with diffuse inflammation, necrosis, and parenchymal damage on histological analysis. The remaining rats showed no neurological or histological signs of toxicity. CONCLUSION: The neurological deficits in the two rats were likely due to injury from physical force, such as cannula movement post insertion and subsequent encephalitis. The remaining rats showed no toxicity and therefore brainstem targeting using pCED to infuse single and multi-drug therapy was well tolerated in these rats.

Toxicity evaluation of convection-enhanced delivery of small-molecule kinase inhibitors in naïve mouse brainstem.

PURPOSE: Diffuse intrinsic pontine gliomas (DIPGs) are inoperable and lethal high-grade gliomas lacking definitive therapy. Platelet-derived growth factor receptor (PDGFR) and its downstream signaling molecules are the most commonly overexpressed oncogenes in DIPG. This study tested the effective concentration of PDGFR pathway inhibitors in cell culture and then toxicity of these small-molecule kinase inhibitors delivered to the mouse brainstem via convection-enhanced delivery (CED) for potential clinical application. METHODS: Effective concentrations of small-molecule kinase inhibitors were first established in cell culture from a mouse brainstem glioma model. Sixteen mice underwent CED, a local drug delivery technique, of saline or of single and multidrug combinations of dasatinib (2 M), everolimus (20 M), and perifosine (0.63 mM) in the pons. Animals were kept alive for 3 days following the completion of infusion. RESULTS: No animals displayed any immediate or delayed neurological deficits postoperatively. Histological analysis revealed edema, microgliosis, acute inflammation, and/or axonal injury in the experimental animals consistent with mild acute drug toxicity. CONCLUSIONS: Brainstem CED of small-molecule kinase inhibitors in the mouse did not cause serious acute toxicities. Future studies will be necessary to evaluate longer-term safety to prepare for potential clinical application.

Benefit of a single dose of preoperative antibiotic on surgical site infection in varicose vein surgery.

BACKGROUND: Ligation and division of the saphenofemoral junction (L/D SFJ) can protect against the danger of venous thromboembolism (VTE) associated with greater saphenous vein (GSV) radiofrequency ablation (RFA). Although this procedure is regarded as clean from an infection standpoint, surgical site infection (SSI) can offset its thromboembolic benefit. We questioned whether SSI associated with L/D SFJ could be minimized by a single preoperative dose of antibiotic. METHODS: A retrospective cohort study was performed on 902 ambulatory surgery patients who underwent 953 consecutive RFAs of the GSV in combination with L/D SFJ. A single dose of preoperative antibiotic was administered 1 hour before incision to some patients (n = 449 extremities), with all other patients receiving no antibiotic (n = 504). Primary outcome measure was SSI categorized based on type of therapy required (1: oral antibiotic, 2: hospitalization for intravenous antibiotic and/or wound debridement), with a secondary outcome measure of VTE. RESULTS: VTE occurred in 10 patients (1%) and included three pulmonary emboli. The majority of VTE were calf deep vein thromboses (n = 7). SSI developed in 78 patients (8.2%) with groin, thigh, and calf distributions of 47%, 8%, and 45%, respectively. All category 2 infections (n = 8, 10%) occurred in control subjects, and the majority were located in the groin. Body mass index significantly increased risk for both overall (odds ratio [OR]: 1.09, 95% confidence interval [CI]: 1.05-1.14, P < 0.0001) and groin (OR: 1.08, 95% CI: 1.02-1.14, P = 0.01) SSI as well as VTE (OR: 1.17, 95% CI: 1.08-1.30, P = 0.003). Diabetes was a significant risk for groin SSI (OR: 5.13, 95% CI: 1.44-18.26, P = 0.01). Antibiotic was associated with a significantly reduced risk for both overall (OR: 0.54, 95% CI: 0.37-0.89, P = 0.02) and groin (OR: 0.34, 95% CI: 0.16-0.73, P = 0.01) SSI. Furthermore, prophylaxis eliminated category 2 infections (P = 0.008) and was associated with a significantly lower risk of VTE (OR: 0.11, 95% CI: 0.01-0.85, P = 0.01). Although SSI was noted more commonly in extremities with thromboembolic complications (20% [n = 2] vs. 8.1% [n = 76] in those without), this trend was not significant and could not account for the antibiotic effect on VTE. CONCLUSIONS: L/D SFJ combined with RFA of the GSV, when treated as a clean procedure and not prophylaxed with antibiotic, carries a significant risk of SSI. While diabetes and high body mass index are patient-associated SSI risk factors, a single dose of preoperative antibiotic significantly reduces the rate of all infection, eliminates the danger of serious infection, and is associated with minimal VTE.

Successful Osteopathic Manipulative Treatment of Foot Drop.

This case report presents a 63-year-old male patient with chronic left foot drop. The etiology for his condition most likely involved lateral lumbar stenosis and/or sacroiliac joint dysfunction resulting in radiculopathy and subsequent symptoms. The patient was previously recommended a surgical approach for his condition. After an extensive osteopathic examination and application of a high-amplitude low-velocity technique, the patient reported a significant improvement in his pain and resolution of his foot drop. To the best of the author's knowledge, this is the first reported case of the use of osteopathic medicine in the successful treatment and management of left foot drop most likely secondary lumbar stenosis and/or sacroiliac joint dysfunction. The aim of this case report is to discuss the possible mechanisms by which the condition may have been resolved and the role that osteopathic treatment played in it.

Volume of distribution and clearance of peptide-based nanofiber after convection-enhanced delivery.

OBJECTIVE Drug clearance may be a limiting factor in the clinical application of convection-enhanced delivery (CED). Peptide-based nanofibers (NFPs) have a high aspect ratio, and NFPs loaded with drugs could potentially maintain effective drug concentrations for an extended period sufficient for cancer therapy. The objective of this study was to assess the volume of distribution (Vd) and clearance of variable lengths of NFPs when administered using CED. METHODS NFPs composed of multiple methoxypolyethylene glycol (mPEG)-conjugated constructs (mPEG2000-KLDLKLDLKLDL-K( FITC)-CONH2, for which FITC is fluorescein isothiocyanate) were assembled in an aqueous buffer. The NFPs were approximately 5 nm in width and were formulated into different lengths: 100 nm (NFP-100), 400 nm (NFP-400), and 1000 nm (NFP-1000). The NFP surface was covalently conjugated with multiple Cy5.5 fluorophores as the optical reporters to track the post-CED distribution. Forty-two 6- to 8-week-old Ntv-a;p53fl/fl mice underwent CED to the striatum. Animals were killed immediately, 24 hours or 72 hours after CED. The brains were extracted and sectioned for assessing NFP Vd to volume of infusion (Vi) ratio, and clearance using fluorescence microscopy. RESULTS CED of NFPs was well tolerated by all the animals. The average Vd/Vi ratios for NFP-100, NFP-400, NFP-1000, and unconjugated positive control (free Cy5.5) were 1.87, 2.47, 1.07, and 3.0, respectively, which were statistically different (p = 0.003). The percentages remaining of the original infusion volume at 24 hours for NFP-100, -400, and -1000 were 40%, 90%, and 74%, respectively. The percentages remaining at 72 hours for NFP-100, -400, and -1000 were 15%, 30%, and 46%, respectively. Unconjugated Cy5.5 was not detected at 24 or 72 hours after CED. CONCLUSIONS CED of NFPs is feasible with Vd/Vi ratios and clearance rates comparable to other nanocarriers. Of the 3 NFPs, NFP-400 appears to provide the best distribution and slowest clearance after 24 hours. NFP provides a dynamic theranostic platform, with the potential to deliver clinically efficacious drug payload to brain tumor after CED.

Predictors of Treatment Response and Survival Outcomes in Meningioma Recurrence with Atypical or Anaplastic Histology.

BACKGROUND: Recurrence rates for atypical and anaplastic meningiomas range between 9% and 50% after gross total resection and between 36% and 83% after subtotal resection. Optimal treatment of recurrent meningiomas exhibiting atypical/anaplastic histology is complicated because they are often refractory to both surgery and radiation. OBJECTIVE: To evaluate clinical determinants of recurrence and treatment-specific outcomes in patients with recurrent meningiomas exhibiting atypical/anaplastic histology at our institution. METHODS: A cohort study was conducted using clinical data of all patients treated for meningiomas with atypical/anaplastic histology at first recurrence between January 1985 and July 2014 at a tertiary cancer center. Predictors of second recurrence were analyzed using competing risks regression models. RESULTS: Nine hundred eighteen patients with meningioma were screened, of whom 60 (55% female) had recurrent disease with atypical/anaplastic histology at a median age of 58.1 yr at diagnosis. The median follow-up from the time of first recurrence was 36.7 mo, with 32 (53%) patients alive at last follow-up. There was no effect of extent of resection at first recurrence on time to a subsequent recurrence. Inclusion of radiation as primary or adjuvant therapy at first recurrence reduced the risk of progression or subsequent recurrence compared to surgery alone (P = .07). CONCLUSION: Treatment of recurrent meningiomas with atypical/anaplastic histology remains challenging. Our data, from one of the largest cohorts, suggest better tumor control with the addition of radiation and challenges the importance of extent of resection at first recurrence. A multicenter effort is needed to confirm these findings and propose treatment guidelines.

Telemedical Diagnosis of Stage 4 and Stage 5 Retinopathy of Prematurity.

PURPOSE: To determine the accuracy of image-based diagnosis for stage 4 or worse retinopathy of prematurity (ROP) disease. DESIGN: Prospective cohort study. PARTICIPANTS: We prospectively obtained data, from 8 major ROP centers, for 1220 eye examinations from 230 infants. METHODS: An ophthalmologist at each center provided a clinical diagnosis using indirect ophthalmoscopy. Wide-angle retinal images (RetCam; Clarity Medical Systems, Pleasanton, CA) were then obtained, and these were independently read by 2 ROP experts using a web-based system for an image-based diagnosis. MAIN OUTCOME MEASURES: Sensitivity and specificity of image-based diagnosis from the ROP experts were calculated using the clinical diagnosis as the reference standard. RESULTS: Of 1220 examinations, 28 (2%) had a clinical diagnosis of stage 4 or worse. Sensitivity and specificity for stage 4 or worse disease were 75% and 99% for expert 1, and 86% and 99% for expert 2. Sensitivity and specificity for the detection of stage 5 disease were 69% and 99% for both experts. CONCLUSIONS: There are inconsistencies in the accuracy of image-based diagnosis of stage 4 and stage 5 ROP when compared with the clinical diagnosis.

A direct tissue-grafting approach to increasing endogenous brown fat.

There is widespread evidence that increasing functional mass of brown adipose tissue (BAT) via browning of white adipose tissue (WAT) could potentially counter obesity and diabetes. However, most current approaches focus on administration of pharmacological compounds which expose patients to highly undesirable side effects. Here, we describe a simple and direct tissue-grafting approach to increase BAT mass through ex vivo browning of subcutaneous WAT, followed by re-implantation into the host; this cell-therapy approach could potentially act synergistically with existing pharmacological approaches. With this process, entitled "exBAT", we identified conditions, in both mouse and human tissue, that convert whole fragments of WAT to BAT via a single step and without unwanted off-target pharmacological effects. We show that ex vivo, exBAT exhibited UCP1 immunostaining, lipid droplet formation, and mitochondrial metabolic activity consistent with native BAT. In mice, exBAT exhibited a highly durable phenotype for at least 8 weeks. Overall, these results enable a simple and scalable tissue-grafting strategy, rather than pharmacological approaches, for increasing endogenous BAT and studying its effect on host weight and metabolism.

Pre-transplant optimization by Molecular Adsorbent Recirculating System in patients with severely decompensated chronic liver disease.

BACKGROUND: The outcome of liver transplantation (LT) is influenced by the recipient's clinical condition. In a retrospective observational study, we evaluated the role of pre-LT Molecular Adsorbent Recirculating System (MARS) treatment in improving the clinical status and thereby the outcome of patients with chronic liver disease and severe hepatic decompensation. METHODS: Between March 2002 and September 2006, 70 patients with end-stage chronic liver disease underwent living-donor LT (LDLT). Of these, 9 (13%) patients with severely decompensated liver function (serum bilirubin> 350 micromol/L [20 mg/dL] and/or hepatic encephalopathy > or = grade 2) received pre-LT MARS treatment. RESULTS: The median MELD score was 33 (range, 26-47). A median of 2 (range, 1-6) sessions (8 hour/session) of MARS dialysis was performed per patient. MARS treatment was associated with reduction in serum bilirubin, creatinine and ammonia levels and no procedure-related complications. CONCLUSION: Pre-LT MARS is well tolerated and results in reduction of jaundice and improvement in renal function and may be useful in the management of patients with severe hepatic decompensation.

Adult living donor liver transplantation in Singapore: the Asian centre for liver diseases and transplantation experience.

INTRODUCTION: Living donor liver transplantation (LDLT) has progressed dramatically in Asia due to the scarcity of cadaver donors and is increasingly performed in Singapore. The authors present their experience with adult LDLT. MATERIALS AND METHODS: Adult LDLTs performed at the Asian Centre for Liver Diseases and Transplantation, Singapore from 20 April 2002 until 20 March 2006 were reviewed. All patients received right lobe grafts and were managed by the same team throughout this period. Data were obtained by chart review. This study presents both recipient and donor outcomes in a single centre. RESULTS: A total of 65 patients underwent LDLT. Forty-three were genetically related while 22 were from emotionally-related donors. The majority were chronic liver failure while 14% were acute. The most common indication for LDLT was end-stage liver disease due to hepatitis B virus. A total of 22 patients with hepatoma were transplanted and overall 1-year disease specific survival was 94.4%. The mean model for end-stage liver disease (MELD) score was 17.4 +/- 9.4 (range, 6 to 40). Six patients had preoperative molecular adsorbent recycling system (MARS) dialysis with 83% transplant success rate. The mean follow-up was 479.2 days with a median of 356 days. One-year overall survival was 80.5%. There was 1 donor mortality and morbidity rate was 17%. Our series is in its early stage with good perioperative survival outcome with 1-month and 3-month actuarial survival rates of 95.4% and 87.3% respectively. CONCLUSION: The study demonstrates that LDLT can be done safely with good results for a variety of liver diseases. However, with dynamically evolving criteria and management strategies, further studies are needed to maximise treatment outcome.

Convection-Enhanced Delivery for Diffuse Intrinsic Pontine Glioma Treatment.

Convection-enhanced delivery (CED) is a technique designed to deliver drugs directly into the brain or tumors. Its ability to bypass the blood-brain barrier (BBB), one of the major hurdles in delivering drugs to the brain, has made it a promising drug delivery method for the treatment of primary brain tumors. A number of clinical trials utilizing CED of various therapeutic agents have been conducted to treat patients with supratentorial high-grade gliomas. Significant responses have been observed in certain patients in all of these trials. However, the insufficient ability to monitor drug distribution and pharmacokinetics hampers CED from achieving its potentials on a larger scale. Brainstem CED for diffuse intrinsic pontine glioma (DIPG) treatment is appealing because this tumor is compact and has no definitive treatment. The safety of brainstem CED has been established in small and large animals, and recently in early stage clinical trials. There are a few current clinical trials of brainstem CED in treating DIPG patients using targeted macromolecules such as antibodies and immunotoxins. Future advances for CED in DIPG treatment will come from several directions including: choosing the right agents for infusion; developing better agents and regimen for DIPG infusion; improving instruments and technique for easier and accurate surgical targeting and for allowing multisession or prolonged infusion to implement optimal time sequence; and better understanding and control of drug distribution, clearance and time sequence. CED-based therapies for DIPG will continue to evolve with new understanding of the technique and the disease.

Dual Inhibition of PI3K/AKT and MEK/ERK Pathways Induces Synergistic Antitumor Effects in Diffuse Intrinsic Pontine Glioma Cells.

Diffuse intrinsic pontine glioma (DIPG) is a devastating disease with an extremely poor prognosis. Recent studies have shown that platelet-derived growth factor receptor (PDGFR) and its downstream effector pathway, PI3K/AKT/mTOR, are frequently amplified in DIPG, and potential therapies targeting this pathway have emerged. However, the addition of targeted single agents has not been found to improve clinical outcomes in DIPG, and targeting this pathway alone has produced insufficient clinical responses in multiple malignancies investigated, including lung, endometrial, and bladder cancers. Acquired resistance also seems inevitable. Activation of the Ras/Raf/MEK/ERK pathway, which shares many nodes of cross talk with the PI3K/AKT pathway, has been implicated in the development of resistance. In the present study, perifosine, a PI3K/AKT pathway inhibitor, and trametinib, a MEK inhibitor, were combined, and their therapeutic efficacy on DIPG cells was assessed. Growth delay assays were performed with each drug individually or in combination. Here, we show that dual inhibition of PI3K/AKT and MEK/ERK pathways synergistically reduced cell viability. We also reveal that trametinib induced AKT phosphorylation in DIPG cells that could not be effectively attenuated by the addition of perifosine, likely due to the activation of other compensatory mechanisms. The synergistic reduction in cell viability was through the pronounced induction of apoptosis, with some effect from cell cycle arrest. We conclude that the concurrent inhibition of the PI3K/AKT and MEK/ERK pathways may be a potential therapeutic strategy for DIPG.

Eco-Friendly and Biodegradable Biopolymer Chitosan/Y2O3 Composite Materials in Flexible Organic Thin-Film Transistors.

The waste from semiconductor manufacturing processes causes serious pollution to the environment. In this work, a non-toxic material was developed under room temperature conditions for the fabrication of green electronics. Flexible organic thin-film transistors (OTFTs) on plastic substrates are increasingly in demand due to their high visible transmission and small size for use as displays and wearable devices. This work investigates and analyzes the structured formation of aqueous solutions of the non-toxic and biodegradable biopolymer, chitosan, blended with high-k-value, non-toxic, and biocompatible Y2O3 nanoparticles. Chitosan thin films blended with Y2O3 nanoparticles were adopted as the gate dielectric thin film in OTFTs, and an improvement in the dielectric properties and pinholes was observed. Meanwhile, the on/off current ratio was increased by 100 times, and a low leakage current was observed. In general, the blended chitosan/Y2O3 thin films used as the gate dielectric of OTFTs are non-toxic, environmentally friendly, and operate at low voltages. These OTFTs can be used on surfaces with different curvature radii because of their flexibility.

Traumatic brain injury and gene knockout animal models: an up-to-date review.

Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Identification of endogenous neuroprotective mechanisms after TBI and the development of therapeutic targets to improve TBI outcomes are areas of intense scientific research. In this review, we summarize genetically modified TBI mouse models and highlight the recent scientific findings from using such models, including mediators of inflammation, programmed cell death and metabolism, modulators of vascular tone and membrane channel proteins. A deeper understanding of the complex biochemical processes and genetic pathways in TBI could offer personalized genomic-based therapies for and improve clinical outcomes in TBI patients.