Abstract Aim To re-audit the compliance of departmental practice to the antimicrobial guidelines for elective laparoscopic cholecystectomies. A Cochrane review found no evidence to support the use of antibiotic prophylaxis in elective cases. Method A retrospective study looking at all the elective laparoscopic cholecystectomies for the period between 1st June 2023 to 30th September 2023 using local Bluespier theatre software. Electronic operation notes were reviewed to identify cases where antibiotics were given. The main indications were bile spillage, conversion to open and cholecystitis amongst others. Total number of cholecystectomies carried out over the period was 92. At present gentamicin and metronidazole as a single dose was the choice. Results Antibiotic use during laparoscopic cholecystectomy is between 39% and 63% due to many cases not documenting the use of antibiotics. Adherence to guidelines reduced from 36% (2019) to 3% in 2023. Patients who received correct antibiotics allergic to penicillin was 75% (2019) and 100% in 2023. Continued lack of antibiotic documentation, use and indication in operation notes. Continued overuse of co-amoxiclav 60% (2019) and 87% in 2023. Conclusions Antibiotic prophylaxis in elective cholecystectomies was only performed correctly in 3% of cases. This can have a major impact on patient safety and also the financial aspect to the trust. Understanding why surgeons have failed to adopt the local guidelines may benefit in changing practice. We suggested an education session from the microbiology team to help better understand the importance of antibiotic stewardship and using laminated guidelines in theatre to ensure this is followed closely.
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.
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.
<p>Supporting Video S4. Video S3 with MR, without CT. Horizontal PET(red)/MR(grey) projection showing dynamic, CED delivery of [18F]-1. PET is overexposed to emphasize gastrointestinal clearance. Major quantities of [18F]-1 are delivered to glioma. Time on video is vs. PET scan start. CED was started 17 min into the PET scan. (Video of Fig.4Aii and iii)</p>
<p>Supporting Video S7. Video S6 with MR, without CT. Horizontal PET(red)/MR(grey) projection showing dynamic, systemic (tail-vein) delivery of [18F]-1. PET is overexposed in attempts to capture drug presence at glioma. Very minor quantities of [18F]-1 are delivered to glioma. (Video of Fig.4Aiv and v)</p>
Abstract Introduction: Diffuse intrinsic pontine glioma (DIPG) is the most common pediatric brainstem tumor, but its prognosis is dismal, with a median survival time of less than one year. Prior studies have implicated amplifications in the receptor tyrosine kinase (RTK)-PI3K/AKT/mTOR signaling pathway in DIPG gliomagenesis, and platelet-derived growth factor receptor (PDGFR) is the most commonly over-expressed RTK. One treatment strategy is thus to inhibit kinases in this pathway with drugs such as dasatinib (PDGFR inhibitor), perifosine (AKT inhibitor), and everolimus (mTOR inhibitor). In this study, we aim to show that combinatorial therapy with dasatinib, perifosine, and everolimus is more effective in impeding tumor cell growth than each drug individually. Methods: Mouse brainstem glioma cells (mBSG) were derived from a transgenic mouse model of DIPG driven by PDGFB overexpression and p53 loss. Cells were treated for 72 hours with dasatinib, perifosine, and everolimus individually and in combination, and cell viability was assayed with MTS. Western blot with cleaved-caspase 3 antibody was used to assess apoptosis. Cell cycle analysis was performed by propidium iodide flow cytometry. Results: GI50 concentrations of each individual drug were as follows: 50 nM dasatinib, 50 μM perifosine, and 10 μM everolimus. With combined dasatinib and perifosine treatment, 31.6% of cells survived (p = 0.016 vs. dasatinib alone). The addition of everolimus to dasatinib and perifosine further reduced cell survival to 27.0% (p = 0.011 vs. combinatorial treatment with dasatinib and perifosine). Cell cycle analysis revealed that dasatinib treatment alone prominently arrested cells in G0/G1 phase while both 2-drug combinatorial treatment with dasatinib and perifosine and 3-drug combinatorial treatment with dasatinib, perifosine, and everolimus caused substantial cell cycle arrest in the G0/G1 and G2/M phases. However, Western blot analysis found that no drug treatment group effectively induced apoptosis. Conclusion: Three-drug combinatorial therapy with dasatinib, perifosine, and everolimus was more effective in reducing DIPG cell viability than dasatinib alone, primarily through the induction of cell cycle arrest at G0/G1 and G2/M. This effect and the lack of apoptosis is consistent with previous observations that inhibition of the PI3K/AKT/mTOR signaling pathway is cytostatic rather than cytotoxic. Moreover, mutations in p53 are seen in up to 50% of patients with DIPG, which allow tumor cells to evade apoptosis despite treatment with chemotherapeutic agents. Taken together, targeting the PI3K/AKT/mTOR pathway alone appears to be insufficient. Ongoing studies aim to understand resistance mechanisms to inhibitors of this pathway and to improve therapeutic efficacy in DIPG by identifying potential synergistic drug combinations targeting alternate survival pathways. Citation Format: Yue Linda Wu, Uday Bhanu Maachani, Melanie Schweitzer, Oren J. Becher, Melinda Wang, Ranjodh Singh, Zhiping Zhou, Mark M. Souweidane. Targeting multiple nodes in the RTK- PI3K/AKT/mTOR signaling pathway in a p53-/- mouse model of DIPG induces G2/M phase cell cycle arrest. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2986.
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