Network Meta-analysis of Randomised Controlled Trials Comparing the Outcomes of Different Endovascular Revascularisation Treatments for Infra-inguinal Peripheral Arterial Disease Causing Chronic Limb Threatening Ischaemia.

OBJECTIVE: The aim of this study was to compare the efficacy of different endovascular revascularisation procedures for treating chronic limb threatening ischaemia (CLTI) using network meta-analysis (NMA). DATA SOURCES: The databases PubMed and Cochrane Central Register for Controlled Trials were searched on 14 March 2023. REVIEW METHODS: A NMA of randomised controlled trials (RCTs) reporting the efficacy of different endovascular revascularisation techniques for treating CLTI was performed according to PRISMA guidelines. The primary and secondary outcomes were major amputation and mortality, respectively. Random effects models were developed and the results were presented using surface under the cumulative ranking curve plots and forest plots. A p value of ≤ .050 was considered statistically significant. The Cochrane collaborative tool was used to assess risk of bias. RESULTS: A total of 2 655 participants of whom 94.8% had CLTI were included. Eleven trials compared plain balloon angioplasty (PBA) vs. drug coated balloon (DCB) angioplasty (n = 1 771), five trials compared bare metal stent (BMS) vs. drug coated stent (DCS) (n = 466), three trials compared atherectomy vs. DCB (n = 194), two trials compared PBA vs. BMS (n = 70), one trial compared PBA vs. atherectomy (n = 50), and one trial compared BMS vs. DCB (n = 104). None of the revascularisation strategies significantly reduced the risk of major amputation or mortality compared with PBA. Using the network estimates, GRADE certainty of evidence for improvement in major amputation outcomes for DCB was moderate, for atherectomy and BMS was low, and for DCS was very low compared with PBA. Risk of bias was low in 16 trials, some concerns in six trials, and high in 1 trial, respectively. CONCLUSION: There is no current evidence from RCTs to reliably conclude that BMS, DCB, DCS, or atherectomy are superior to PBA in preventing major amputation and mortality in patients with CLTI. Larger comparative RCTs are needed to identify the best endovascular revascularisation strategy.

Impact of Reirradiation Utilizing Fractionated Stereotactic Radiotherapy for Recurrent Glioblastoma.

BACKGROUND: Patients with recurrent glioblastoma (GBM) have limited treatment options. This study determined whether patients with recurrent GBM treated with initial radiation/temozolomide (TMZ) and reirradiation using fractionated stereotactic radiotherapy (FSRT) had improved outcomes. MATERIALS AND METHODS: We identified 95 patients with recurrent GBM, 50 of whom underwent FSRT at recurrence and 45 who had systemic treatment only (control). The median total FSRT dose at the time of GBM recurrence was 30 Gy in five fractions of the gadolinium-enhanced tumor only. RESULTS: With a median follow-up of 18 months, the progression-free survival (PFS) and overall survival (OS) following initial GBM diagnosis were longer in the reirradiation group compared to the control group (13.5 vs. 7.5 months [p=0.001] and 24.6 vs. 12.6 months [p<0.001], respectively). For patients who underwent reirradiation, the median time interval between the end of the initial radiation and reirradiation was 15.2 months. The median OS after GBM recurrence was longer in the reirradiation group versus the control group (9.9 vs. 3.5 months [p<0.001]), with a one-year OS survival rate of 22%. The hazard ratio for death of patients in the reirradiation group was 0.31 [0.19-0.50]. The reirradiation group had a higher percentage of patients who received bevacizumab (BEV, 62.0% vs. 28.9%, p=0.002) and a lower percentage of patients whose TMZ was discontinued due to toxicity (8.0% vs. 28.9%, p=0.017) compared to the control group. CONCLUSIONS: Reirradiation utilizing FSRT was associated with improved PFS and OS after GBM recurrence compared to the control group who did not receive additional irradiation.

Aqueous Humor TGF-ß2 and Its Association With Intraocular Pressure in a Naturally Occurring Large Animal Model of Glaucoma.

Purpose: Transforming growth factor (TGF)-ß2 has been widely implicated in human glaucoma pathology. The purpose of this study was to determine the source of TGF-ß2 in aqueous humor (AH) and its relationship with intraocular pressure (IOP) in an inherited large animal model of glaucoma. Methods: Sixty-six glaucomatous cats homozygous for LTBP2 mutation, and 42 normal cats were studied. IOP was measured weekly by rebound tonometry. AH was collected by anterior chamber paracentesis from each eye under general anesthesia, and serum samples collected from venous blood concurrently. Concentrations of total, active and latent TGF-ß2 in AH and serum samples were measured by quantitative sandwich immunoassay. For comparisons between groups, unpaired t-test or Mann Whitney test were used, with P < 0.05 considered significant. The relationships between TGF-ß2 concentrations and IOP values were examined by Pearson's correlation coefficient and generalized estimating equation. Results: IOP and AH TGF-ß2 concentrations were significantly higher in glaucomatous than in normal cats. AH TGF-ß2 showed a significant, robust positive correlation with IOP in glaucomatous cats (r = 0.83, R2 = 0.70, P < 0.0001). Serum TGF-ß2 did not correlate with AH TGF-ß2 and was not significantly different between groups. TGF-ß2 mRNA and protein expression were significantly increased in local ocular tissues in glaucomatous cats. Conclusions: Enhanced, local ocular production of TGF-ß2 with a robust positive association with IOP was identified in this spontaneous feline glaucoma model, providing a foundation for preclinical testing of novel therapeutics to limit disease-associated AH TGF-ß2 elevation and signaling in glaucoma.

Efficacy of laser interstitial thermal therapy for biopsy-proven radiation necrosis in radiographically recurrent brain metastases.

Background: Laser interstitial thermal therapy (LITT) in the setting of post-SRS radiation necrosis (RN) for patients with brain metastases has growing evidence for efficacy. However, questions remain regarding hospitalization, local control, symptom control, and concurrent use of therapies. Methods: Demographics, intraprocedural data, safety, Karnofsky performance status (KPS), and survival data were prospectively collected and then analyzed on patients who consented between 2016-2020 and who were undergoing LITT for biopsy-proven RN at one of 14 US centers. Data were monitored for accuracy. Statistical analysis included individual variable summaries, multivariable Fine and Gray analysis, and Kaplan-Meier estimated survival. Results: Ninety patients met the inclusion criteria. Four patients underwent 2 ablations on the same day. Median hospitalization time was 32.5 hours. The median time to corticosteroid cessation after LITT was 13.0 days (0.0, 1229.0) and cumulative incidence of lesional progression was 19% at 1 year. Median post-procedure overall survival was 2.55 years [1.66, infinity] and 77.1% at one year as estimated by KaplanMeier. Median KPS remained at 80 through 2-year follow-up. Seizure prevalence was 12% within 1-month post-LITT and 7.9% at 3 months; down from 34.4% within 60-day prior to procedure. Conclusions: LITT for RN was not only again found to be safe with low patient morbidity but was also a highly effective treatment for RN for both local control and symptom management (including seizures). In addition to averting expected neurological death, LITT facilitates ongoing systemic therapy (in particular immunotherapy) by enabling the rapid cessation of steroids, thereby facilitating maximal possible survival for these patients.

Safety for cervical corpectomy and diskectomy: univariate and multivariate analysis on predictors for prolonged ICU stay after anterior spinal fusion.

AIM: Cervical anterior spinal fusion (ASF) with corpectomy has risks of catastrophic acute complications such as airway obstruction requiring re-intubation. Our team has adopted a management plan for all cervical corpectomy patients to be admitted to the intensive care unit (ICU) after the operations for overnight observation. Some of these patients were kept intubated after the operations and transferred to the ICU. This study aims to review the outcome of this practice and to identify independent predictors associated with a prolonged ICU stay. METHODS: We reviewed consecutive patients with cervical ASF from January 2010 to June 2018. The primary outcome was the ICU length of stay. Univariate and multivariate analyses were conducted to identify independent risk factors associated with a prolonged ICU stay. In total, 103 patients had ASF during the study period. ICU length of stay for elective ASF was 1.01 day (SD 0.373 days) and was significantly shorter than that for emergency ASF (13.29 days, SD 12.57 days) (p < 0.001). 79.6% (82/103) of the ASF patients were extubated in the operating theatre after surgery. Significantly more corpectomy patients (33.3%) versus ACDF patients (15.1%) were kept intubated to the ICU after the operation (p = 0.037). None required reintubation in the ICU. 90.9% (80/88) of the elective ASF can be discharged from the ICU within 24 hours and only 3.41% (3/88) of the elective ASF had prolonged post-operative stay in the ICU (≥48 hours). RESULTS: For prolonged postoperative ICU stay (≥48 hours), ICU admission airway status of ASF patients who were either extubated in the OT or kept intubated to ICU had no significant association (p = 0.903). Univariate and multivariate analysis had identified emergency admissions (p = 0.043) and the presence of postoperative neurological deficits (p = 0.031) as independent predictors associated with a prolonged postoperative ICU stay. CONCLUSION: In conclusion, cervical corpectomy and ASF were safe with minimal acute complications.

Multifocal intradural extramedullary ependymoma, MYCN amplified: illustrative case.

BACKGROUND: Ependymomas are the most frequent tumors of the adult spinal cord, representing 1.9% of all central nervous system tumors and 60% of spinal cord tumors. Spinal ependymomas are usually solitary, intramedullary lesions. While intradural extramedullary (IDEM) ependymomas are infrequent, multifocal IDEM ependymomas are exceptionally rare. OBSERVATIONS: The authors reported the first case in the literature of a patient diagnosed with multifocal IDEM ependymomas who was treated with tumor resection and brain and spinal radiotherapy. The patient presented with a 10-day history of bilateral leg numbness extending to the umbilicus and gait instability. Magnetic resonance imaging (MRI) studies revealed multiple enhancing nodular nodules throughout the entire spinal canal. Brain MRI revealed no abnormal lesions. A World Health Organization grade II ependymoma was confirmed histologically. At 31 months postoperatively, the patient remained clinically asymptomatic. Although cervical and thoracic MRI revealed stable intradural nodules and several areas of leptomeningeal enhancement, no malignant cells were seen in the cerebrospinal fluid (CSF). He underwent genetic testing to determine the appropriate chemotherapeutic agent if activation of the tumor should arise. LESSONS: Because complete resection of multifocal IDEM ependymomas is not feasible, continued monitoring with brain and spine MRI is warranted to detect potential tumor dissemination in the CSF.

Efficacy of laser interstitial thermal therapy (LITT) for newly diagnosed and recurrent IDH wild-type glioblastoma.

Background: Treatment options for unresectable new and recurrent glioblastoma remain limited. Laser ablation has demonstrated safety as a surgical approach to treating primary brain tumors. The LAANTERN prospective multicenter registry (NCT02392078) data were analyzed to determine clinical outcomes for patients with new and recurrent IDH wild-type glioblastoma. Methods: Demographics, intraprocedural data, adverse events, KPS, health economics, and survival data were prospectively collected and then analyzed on IDH wild-type newly diagnosed and recurrent glioblastoma patients who were treated with laser ablation at 14 US centers between January 2016 and May 2019. Data were monitored for accuracy. Statistical analysis included individual variable summaries, multivariable differences in survival, and median survival numbers. Results: A total of 29 new and 60 recurrent IDH wild-type WHO grade 4 glioblastoma patients were treated. Positive MGMT promoter methylation status was present in 5/29 of new and 23/60 of recurrent patients. Median physician-estimated extent of ablation was 91%-99%. Median overall survival (OS) was 9.73 months (95% confidence interval: 5.16, 15.91) for newly diagnosed patients and median post-procedure survival was 8.97 months (6.94, 12.36) for recurrent patients. Median OS for newly diagnosed patients receiving post-LITT chemo/radiation was 16.14 months (6.11, not reached). Factors associated with improved survival were MGMT promoter methylation, adjuvant chemotherapy within 12 weeks, and tumor volume <3 cc. Conclusions: Laser ablation is a viable option for patients with new and recurrent glioblastoma. Median OS for IDH wild-type newly diagnosed glioblastoma is comparable to outcomes observed in other tumor resection studies when those patients undergo radiation and chemotherapy following LITT.

A prospective multicenter study of laser ablation for drug resistant epilepsy - One year outcomes.

OBJECTIVE: To report one-year seizure outcomes, procedural data, and quality of life scores following laser interstitial thermal therapy (LITT) of epileptogenic foci. METHODS: Data from an ongoing prospective, multi-center registry were assessed. Procedural information, Engel seizure outcomes, and quality of life (QoL) scores were analyzed. A responder analysis was performed to better understand potential clinical characteristics that could influence seizure outcome. RESULTS: Sixty patients have been enrolled into LAANTERN (Laser Ablation of Abnormal Neurological Tissue Using Robotic NeuroBlate System) specifically for epilepsy treatment, of which 42 reached one year follow up. Engel I outcome was achieved in 64.3 % at one year follow up. Patients with mesial temporal lobe epilepsy (MTLE) comprised 56.7 % of this cohort of multiple epilepsy types. Other significant etiologies included focal cortical dysplasia, hypothalamic hamartoma, cavernoma, heterotopias, and tuberous sclerosis. Median length of stay was 32.7 h. At discharge, head pain score averaged 1.4 ± 2.1 on a scale from 1 to 10. Five adverse events were reported, one categorized as serious. Seizure worry and social functioning scores improved significantly in quality of life measures. SIGNIFICANCE: Surgical treatment with LITT for epileptic foci is a safe and effective treatment option for people with drug resistant epilepsy. Our multicenter prospective seizure outcomes continue to expand published LITT experience in MTLE as well as non-MTLE epilepsies. The minimally invasive nature allows for short hospitalizations with minimal reported pain and discomfort.

Novel regulation of PKC-induced inflammation by Akt and protein phosphatase 2A in ovarian granulosa cells.

PKC-mediated inflammation is important in ovarian physiology. The roles of Akt and protein phosphatase 2A (PP2A) in PKC-mediated inflammation in ovarian granulosa cells (GCs) remain mostly unclear. PKC activator phorbol 12-myristate 13-acetate induced the Akt phosphorylation in rat primary GCs but reduced the Akt phosphorylation in KGN human GCs. In rat GCs, an inhibitory effect of PI3K inhibitor wortmannin and a stimulatory effect of Akt activator SC79 on PKC-induced cyclooxygenase-2 (COX-2)/PGE2production were noted; wortmannin and SC79 acted oppositely in human GCs. In rat GCs, PP2A inhibitor okadaic acid further enhanced the PKC-mediated promoter activation and elevation of mRNA and protein levels of the COX-2 gene, whereas PP2A activator sodium selenate attenuated the PKC-mediated COX-2 expression and promoter activation. PKC activation did not affect PP2A phosphorylation, but okadaic acid indeed augmented the PKC-induced NF-κB nuclear translocation. Thus, PP2A appears to act as a negative modulator in PKC-mediated cellular inflammation in rat GCs, at least in part due to its attenuating effect on the PKC-induced NF-κB activation.

Glucosamine regulation of fibroblast growth factor 21 expression in liver and adipose tissues.

Obesity is associated with metabolic disorders. Fibroblast growth factor 21 (FGF21) has been recognized as important in metabolism. Glucosamine (GLN) has been demonstrated to perform diverse beneficial functions. This study aimed to reveal whether and how GLN would modulate FGF21 production in relation to metabolism. With in vivo model of normal diet (ND) and high-fat diet (HFD) mice receiving GLN injection and in vitro model of mouse AML12 liver cells and differentiated 3T3L1 adipocytes challenged with GLN, GLN appeared to improve the glucose metabolism in HFD and ND mice and to elevate FGF21 protein expression in HFD liver and to increase both FGF21 protein and mRNA levels in WAT from HFD and ND mice and it also upregulated FGF21 expression in both AML12 and differentiated 3T3L1 cells. By using inhibitors against various signaling pathways, p38, Akt, NF-κB, and PKA appeared potentially involved in GLN-mediated FGF21 production in AML12 cells; GLN was able to mediate activation of NF-κB, p38 or PKA/CREB signaling. Our accumulated findings suggest that GLN may potentially improve the metabolic performance by inducing FGF21 production in liver and adipose tissues and such induction in liver cells may act in part due to GLN induction of the NF-κB, p38 and PKA pathways.

In Kinematically Aligned Total Knee Arthroplasty, Failure to Recreate Native Tibial Alignment Is Associated With Early Revision.

BACKGROUND: The goal of kinematically aligned (KA) total knee arthroplasty (TKA) is to restore native knee anatomy. However, there are concerns about patellofemoral tracking problems with this technique that lead to early revision. We measured the differences between preoperative anatomic alignment and postoperative component alignment in a consecutive series of KA TKA and evaluated the association between alignment changes and the likelihood of early revision. METHODS: The charts of 219 patients who underwent 275 KA TKA procedures were reviewed. Preoperative anatomic alignment and postoperative tibial and femoral component alignment were measured radiographically. The difference in component alignment compared with preoperative anatomic alignment was compared between patients who underwent aseptic revision and those who did not at a minimum of 12 months of follow-up. Receiver operating characteristic curves were created for statistically significant variables, and the Youden index was used to determine optimal alignment thresholds with regard to likelihood of revision surgery. RESULTS: Change in tibial component alignment compared with native alignment was greater (P = .005) in the revision group (5.0° ± 3.7° of increased varus compared with preoperative anatomic tibial angle) than in the nonrevision group (1.3° ± 4.2° of increased varus). The Youden index indicated that increasing tibial varus by >2.2° or more is associated with increased likelihood of revision. Preoperative anatomic alignment and change in femoral alignment and overall joint alignment (ie, Q angle) were not associated with increased likelihood of revision. CONCLUSION: Small increases in tibial component varus compared with native alignment are associated with early aseptic revision in patients undergoing KA TKA.

Heuristic evaluation and simulated use testing of infusion pumps to inform pump selection.

BACKGROUND: Poorly designed infusion pumps can lead to user errors and adverse incidents. Therefore, assessments of their usability and performance that can inform managerial decisions about the selection of appropriate medical devices are essential. OBJECTIVE: This study aimed to identify design deficiencies and evaluate the usability and performance of four infusion pump models and thus inform decisions about infusion pump selection. METHODS: Four evaluators evaluated the interface designs of the pumps according to a series of design principles in a heuristic evaluation in order to identify pump design deficiencies. Additionally, 60 registered nurses participated in simulated use testing to perform a series of tasks using the pumps in order to examine the pump performances. Outcome measures included task completion time, frequency of deviations, frequency of requests for assistance, and nurses' perceptions. RESULTS: Design issues identified included system status visibility, information access, and error prevention. The results of simulated use testing favored some pumps over others, depending on which outcome measures were considered. CONCLUSIONS: Heuristic evaluations and simulated use testing can provide information about the basic usability of medical devices and related operational issues. However, practitioners should select appropriate evaluation principles, testing tasks, and outcome measures based on the tested medical devices and contexts.

NCF1 (p47phox)-deficient chronic granulomatous disease: comprehensive genetic and flow cytometric analysis.

Mutations in NCF1 (p47phox) cause autosomal recessive chronic granulomatous disease (CGD) with abnormal dihydrorhodamine (DHR) assay and absent p47phox protein. Genetic identification of NCF1 mutations is complicated by adjacent highly conserved (>98%) pseudogenes (NCF1B and NCF1C). NCF1 has GTGT at the start of exon 2, whereas the pseudogenes each delete 1 GT (ΔGT). In p47phox CGD, the most common mutation is ΔGT in NCF1 (c.75_76delGT; p.Tyr26fsX26). Sequence homology between NCF1 and its pseudogenes precludes reliable use of standard Sanger sequencing for NCF1 mutations and for confirming carrier status. We first established by flow cytometry that neutrophils from p47phox CGD patients had negligible p47phox expression, whereas those from p47phox CGD carriers had ∼60% of normal p47phox expression, independent of the specific mutation in NCF1 We developed a droplet digital polymerase chain reaction (ddPCR) with 2 distinct probes, recognizing either the wild-type GTGT sequence or the ΔGT sequence. A second ddPCR established copy number by comparison with the single-copy telomerase reverse transcriptase gene, TERT We showed that 84% of p47phox CGD patients were homozygous for ΔGT NCF1 The ddPCR assay also enabled determination of carrier status of relatives. Furthermore, only 79.2% of normal volunteers had 2 copies of GTGT per 6 total (NCF1/NCF1B/NCF1C) copies, designated 2/6; 14.7% had 3/6, and 1.6% had 4/6 GTGT copies. In summary, flow cytometry for p47phox expression quickly identifies patients and carriers of p47phox CGD, and genomic ddPCR identifies patients and carriers of ΔGT NCF1, the most common mutation in p47phox CGD.

Regulation of the regulator of G protein signaling 2 expression and cellular localization by PKA and PKC pathways in mouse granulosa cells.

G protein-coupled receptor (GPCR) activation-mediated PKA and PKC pathways have been recognized to be important in ovarian physiology. Expression of regulator of G-protein signaling 2 (RGS2) has been reported in ovarian granulosa cells. The detailed mechanisms in PKA- and PKC-regulated RGS2 expression and cellular translocation in granulosa cells remain mostly unclear. PKA activator 8-bromo-cAMP and PKC activator phorbol-12, 13-didecanoate appeared to rapidly elevate both protein and mRNA levels and promoter activation of RGS2 gene. Two consensus Sp1 elements within the shortest 78 bp fragment of RGS2 promoter sequence were essential for the full responsiveness to PKA and PKC. PKC activation appeared to increase the RGS2 translocation from nucleus to cytosol. PKA- and PKC-mediated RGS2 transcription in a Sp-1-dependent manner and a PKC-mediated RGS2 intracellular translocation were noted in granulosa cells.

Binding of smoothelin-like 1 to tropomyosin and calmodulin is mutually exclusive and regulated by phosphorylation.

BACKGROUND: The smoothelin-like 1 protein (SMTNL1) can associate with tropomyosin (Tpm) and calmodulin (CaM), two proteins essential to the smooth muscle contractile process. SMTNL1 is phosphorylated at Ser301 by protein kinase A during calcium desensitization in smooth muscle, yet the effect of SMTNL1 phosphorylation on Tpm- and CaM-binding has yet to be investigated. RESULTS: Using pull down studies with Tpm-Sepharose and CaM-Sepharose, we examined the interplay between Tpm binding, CaM binding, phosphorylation of SMTNL1 and calcium concentration. Phosphorylation greatly enhanced the ability of SMTNL1 to associate with Tpm in vitro; surface plasmon resonance yielded a 10-fold enhancement in K D value with phosphorylation. The effect on CaM binding is more complex and varies with the availability of calcium. CONCLUSIONS: Combining both CaM and Tpm with SMTNL1 shows that the binding to both is mutually exclusive.

Novel augmentation by bufalin of protein kinase C-induced cyclooxygenase-2 and IL-8 production in human breast cancer cells.

Cyclooxygenase-2 (COX-2) and IL-8 are two inflammatory mediators induced by protein kinase C (PKC) via various stimuli. Both contribute significantly to cancer progression. Bufalin, a major active component of the traditional Chinese medicine Chan Su, is known to induce apoptosis in various cancer cells. This study clarifies the role and mechanism of bufalin action during PKC regulation of COX-2/IL-8 expression and investigates the associated impact on breast cancer. Using MB-231 breast cancer cells, bufalin augments PKC induction of COX-2/IL-8 at both the protein and mRNA levels, and the production of prostaglandin E2 (PGE2) and IL-8. The MAPK and NF-κB pathways are involved in both the PKC-mediated and bufalin-promoted PKC regulation of COX-2/IL-8 production. Bufalin increases PKC-induced MAPKs phosphorylation and NF-κB nuclear translocation. PGE2 stimulates the proliferation/migration of breast cancer cells. Furthermore, PKC-induced matrix metalloproteinase 3 expression is enhanced by bufalin. Bufalin significantly enhances breast cancer xenograft growth, which is accompanied by an elevation in COX-2/IL-8 expression. In conclusion, bufalin seems to promote the inflammatory response in vitro and in vivo, and this occurs, at least in part, by targeting the MAPK and NF-κB pathways, which then enhances the growth of breast cancer cells.

Growth Hormone Releasing Peptide-2 Attenuation of Protein Kinase C-Induced Inflammation in Human Ovarian Granulosa Cells.

Cyclooxygenase-2 (COX-2) and interleukin-8 (IL-8) are two important inflammatory mediators in ovulation. Ghrelin may modulate inflammatory signaling via growth hormone secretagogue receptors. We investigated the role of ghrelin in KGN human ovarian granulosa cells using protein kinase C (PKC) activator phorbol 12, 13-didecanoate (PDD) and synthetic ghrelin analog growth hormone releasing peptide-2 (GHRP-2). GHRP-2 attenuated PDD-induced expression of protein and mRNA, the promoter activity of COX-2 and IL-8 genes, and the secretion of prostaglandin E2 (PGE2) and IL-8. GHRP-2 promoted the degradation of PDD-induced COX-2 and IL-8 proteins with the involvement of proteasomal and lysosomal pathways. PDD-mediated COX-2 production acts via the p38, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways; PDD-mediated IL-8 production acts via the p38, JNK and ERK pathways. GHRP-2 reduced the PDD-induced phosphorylation of p38 and JNK and activator protein 1 (AP-1) reporter activation and PDD-induced NF-κB nuclear translocation and reporter activation. The inhibitors of mitogen-activated protein kinase phosphatase-1 (MKP-1) and protein phosphatase 2 (PP2A) reduced the inhibitory effect of GHRP-2 on PDD-induced COX-2 and IL-8 expression. Our findings demonstrate an anti-inflammatory role for ghrelin (GHRP-2) in PKC-mediated inflammation of granulosa cells, at least in part, due to its inhibitory effect on PKC-induced activation of p38, JNK and NF-κB, possibly by targeting to MKP-1 and PP2A.

Phase I-II Clinical Trial Assessing Safety and Efficacy of Umbilical Cord Blood Mononuclear Cell Transplant Therapy of Chronic Complete Spinal Cord Injury.

Umbilical cord blood-derived mononuclear cell (UCB-MNC) transplants improve recovery in animal spinal cord injury (SCI) models. We transplanted UCB-MNCs into 28 patients with chronic complete SCI in Hong Kong (HK) and Kunming (KM). Stemcyte Inc. donated UCB-MNCs isolated from human leukocyte antigen (HLA ≥4:6)-matched UCB units. In HK, four patients received four 4-µl injections (1.6 million cells) into dorsal entry zones above and below the injury site, and another four received 8-µl injections (3.2 million cells). The eight patients were an average of 13 years after C5-T10 SCI. Magnetic resonance diffusion tensor imaging of five patients showed white matter gaps at the injury site before treatment. Two patients had fiber bundles growing across the injury site by 12 months, and the rest had narrower white matter gaps. Motor, walking index of SCI (WISCI), and spinal cord independence measure (SCIM) scores did not change. In KM, five groups of four patients received four 4-µl (1.6 million cells), 8-µl (3.2 million cells), 16-µl injections (6.4 million cells), 6.4 million cells plus 30 mg/kg methylprednisolone (MP), or 6.4 million cells plus MP and a 6-week course of oral lithium carbonate (750 mg/day). KM patients averaged 7 years after C3-T11 SCI and received 3-6 months of intensive locomotor training. Before surgery, only two patients walked 10 m with assistance and did not need assistance for bladder or bowel management before surgery. The rest could not walk or do their bladder and bowel management without assistance. At about a year (41-87 weeks), WISCI and SCIM scores improved: 15/20 patients walked 10 m ( p = 0.001) and 12/20 did not need assistance for bladder management ( p = 0.001) or bowel management ( p = 0.002). Five patients converted from complete to incomplete (two sensory, three motor; p = 0.038) SCI. We conclude that UCB-MNC transplants and locomotor training improved WISCI and SCIM scores. We propose further clinical trials.

Dexamethasone administration during definitive radiation and temozolomide renders a poor prognosis in a retrospective analysis of newly diagnosed glioblastoma patients.

BACKGROUND: Dexamethasone (DXM) is commonly used in the management of cerebral edema in patients diagnosed with glioblastoma multiforme (GBM). Bevacizumab (BEV) is FDA-approved for the progression or recurrence of GBM but has not been shown to improve survival when given for newly diagnosed patients concurrently with radiation (RT) and temozolomide (TMZ). Both DXM and BEV reduce cerebral edema, however, DXM has been shown to induce cytokine cascades which could interfere with cytotoxic therapy. We investigated whether DXM would reduce survival of GBM patients in the setting of concurrent TMZ and BEV administration. METHODS: We reviewed the treatment of all 73 patients with GBM who received definitive therapy at our institution from 2005 to 2013 with RT (60 Gy) delivered with concurrent daily TMZ (75 mg/m(2)). Of these, 34 patients also were treated with concurrent BEV (10 mg/kg every two weeks). Patients received adjuvant therapy (TMZ or TMZ/Bev) until either progression, discontinuation due to toxicity, or 12 months after radiation completion. All patients who had GBM progression with TMZ were offered BEV for salvage therapy, with 19 (56 %) receiving BEV. RESULTS: With a median follow-up of 15.6 months, 67 (91.8 %) patients were deceased. The OS for the entire cohort was 15.9 months, while the PFS was 7.7 months. The extent of resection was a prognostic indicator for OS (p = .0044). The median survival following gross tumor resection (GTR) was 22.5 months, subtotal resection (STR) was 14.9 months, and biopsy was 12.1 months. The addition of BEV to TMZ with RT was borderline significantly associated with increased PFS (9.4 vs. 5.1 months, p = 0.0574) although was not significantly associated with OS (18.1 vs. 15.3 months respectively, p = 0.3064). In patients receiving TMZ, DXM use concurrent with RT was a poor prognostic indicator of both OS (12.7 vs. 22.6 months, p = 0.003) and PFS (3.6 vs. 8.4 months, p <0.0001). DXM did not reduce OS in patients who received TMZ and BEV concurrently with RT (22.9 vs 22.8 months, p = 0.4818). On multivariable analysis, DXM use predicted an unfavorable OS hazard ratio (HR) = 1.72, p = 0.045). CONCLUSIONS: Our results with TMZ, BEV, and RT are similar to previous studies in terms of PFS and OS. DXM use during RT with concurrent TMZ correlated with reduced OS and PFS unless BEV was administered.

Heterogeneity correction for intensity-modulated frameless SRS in pituitary and cavernous sinus tumors: a retrospective study.

BACKGROUND: Frameless immobilization allows for planning and quality assurance of intensity-modulated radiosurgery (IM-SRS) plans. We tested the hypothesis that IM-SRS planning with uniform tissue density corrections results in dose inaccuracy compared to heterogeneity-corrected algorithms. METHODS: Fifteen patients with tumors of the pituitary or cavernous sinus underwent frameless IM-SRS. Treatment planning CT and MRI scans were obtained and fused to delineate the tumor, optic nerves, chiasm, and brainstem. The plan was developed with static gantry IM-SRS fields using a pencil beam (PB), analytical anisotropic (AAA), and Acuros XB (AXB) algorithms. We evaluated measures of target coverage as well as doses to organs at risk (OAR) for each algorithm. We compared the results of each algorithm in the cases where PTV overlapped OAR (n = 10) to cases without overlapping OAR with PTV (n = 5). Utilizing film dosimetry, we measured the dose distribution for each algorithm through a uniform density target to a rando phantom with non-uniform density of air, tissue, and bone. RESULTS: There was no difference in target coverage measured by DMaxPTV, DMinPTV, D95%PTV, or the isodose surface (IDS) covering 95% of the PTV regardless of algorithm. However, there were differences in dose to OAR. PB predicted higher (p < 0.05) Dmax for the brainstem, chiasm, right optic nerve, and left optic nerve. In cases of PTV overlapping an optic nerve (n = 7), PB was unable to limit dose to 8 Gy while achieving PTV coverage (PB 855 cGy vs. AAA 769 cGy, p = 0.05 vs. AXB 658 cGy, p = 0.03). Within the rando phantom, the PB and AAA algorithms over-estimated the dose delivered in the bone-tissue-air interface of the sinus (+17%), while the AXB algorithm closely predicted the actual dose delivered through the inhomogeneous tissue (+/- 1 % max, p < 0.05). CONCLUSIONS: Patients undergoing frameless SRS benefit from heterogeneity corrected dose plans when the lesion lies in areas of widely varying tissue density and near critical normal structures such as the skull base. Film dosimetry confirms that the AXB dose calculation algorithm more accurately predicts actual dose delivered though tissues of varying densities than PB or AAA dose calculation algorithms.