Heart of England: HEFT Repository
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Oral 11β-HSD1 inhibitor AZD4017 improves wound healing and skin integrity in adults with type 2 diabetes mellitus: a pilot randomized controlled trial.
No full textBackground
Chronic wounds (e.g. diabetic foot ulcers) reduce the quality of life, yet treatments remain limited. Glucocorticoids (activated by the enzyme 11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1) impair wound healing.
Objectives
Efficacy, safety, and feasibility of 11β-HSD1 inhibition for skin function and wound healing.
Design
Investigator-initiated, double-blind, randomized, placebo-controlled, parallel-group phase 2b pilot trial.
Methods
Single-center secondary care setting. Adults with type 2 diabetes mellitus without foot ulcers were administered 400 mg oral 11β-HSD1 inhibitor AZD4017 (n = 14) or placebo (n = 14) bi-daily for 35 days. Participants underwent 3-mm full-thickness punch skin biopsies at baseline and on day 28; wound healing was monitored after 2 and 7 days. Computer-generated 1:1 randomization was pharmacy-administered. Analysis was descriptive and focused on CI estimation. Of the 36 participants screened, 28 were randomized.
Results
Exploratory proof-of-concept efficacy analysis suggested AZD4017 did not inhibit 24-h ex vivoskin 11β-HSD1 activity (primary outcome; difference in percentage conversion per 24 h 1.1% (90% CI: -3.4 to 5.5) but reduced systemic 11β-HSD1 activity by 87% (69-104%). Wound diameter was 34% (7-63%) smaller with AZD4017 at day 2, and 48% (12-85%) smaller after repeat wounding at day 30. AZD4017 improved epidermal integrity but modestly impaired barrier function. Minimal adverse events were comparable to placebo. Recruitment rate, retention, and data completeness were 2.9/month, 27/28, and 95.3%, respectively.
Conclusion
A phase 2 trial is feasible, and preliminary proof-of-concept data suggests AZD4017 warrants further investigation in conditions of delayed healing, for example in diabetic foot ulcers.
Significance statement
Stress hormone activation by the enzyme 11β-HSD type 1 impairs skin function (e.g. integrity) and delays wound healing in animal models of diabetes, but effects in human skin were previously unknown. Skin function was evaluated in response to treatment with a 11β-HSD type 1 inhibitor (AZD4017), or placebo, in people with type 2 diabetes. Importantly, AZD4017 was safe and well tolerated. This first-in-human randomized, controlled, clinical trial found novel evidence that 11β-HSD type 1 regulates skin function in humans, including improved wound healing, epidermal integrity, and increased water loss. Results warrant further studies in conditions of impaired wound healing, for example, diabetic foot ulcers to evaluate 11β-HSD type 1 as a novel therapeutic target forchronic wounds
Acetabular reconstruction using a composite layer of impacted cancellous allograft bone and cement: minimum 5-year follow-up study.
No full textBACKGROUND
Revision total hip arthroplasty (rTHA) is often complex and has a less reliable outcome than primary total hip arthroplasty. Acetabular reconstruction remains a challenge because of the variable amount of bone loss. This study describes and evaluates a novel technique of acetabular reconstruction using composite bone grafting.
PATIENTS AND METHODS
Between June 2005 and January 2012, 108 consecutive patients underwent revision hip arthroplasty in which the acetabular component was revised using composite bone grafting. Of these, 24 were lost to follow-up leaving 84 in the study with a minimum 5-year follow-up. There were 54 women and 30 men with a mean age of 70.1 (31-91) years. All patients were assessed clinically and radiologically after a minimum of 5 years. The primary outcome measures were rate of re-revision, patient-reported outcomes and radiological evidence of loosening.
RESULTS
The mean follow-up after revision surgery was 6.9 years (5-10). At operation, 60 patients had an acetabular defect of AAOS stage 3 or more. There was no evidence of loosening in 69 revision acetabular components; 12 showed evidence of non-progressive loosening and 3 patients underwent a re-revision procedure (2 for infection, 1 recurrent dislocation).The mean postoperative Hip Disability and Osteoarthritis Outcome Score (HOOS) was 89.11/100 (95% CI, 87.8-90.5). Scores were significantly improved in patients with a more extensive preoperative defect ( 0.006). The overall patient satisfaction rate at final follow-up was very high.
CONCLUSIONS
Composite impaction grafting using a layered cement and bone graft technique can give satisfactory clinical and radiological outcomes in the medium- to long-term
Esophagectomy or Total Gastrectomy for Siewert 2 Gastroesophageal Junction (GEJ) Adenocarcinoma: An Ongoing Debate.
No full textSurface guided radiation therapy: An international survey on current clinical practice.
No full textIntroduction
Surface Guided Radiation Therapy (SGRT) is being increasingly implemented into clinical practice across a number of techniques and irradiation-sites. This technology, which is provided by different vendors, can be used with most simulation- and delivery-systems. However, limited guidelines and the complexity of clinical settings have led to diverse patterns of operation. With the aim to understand current clinical practice a survey was designed focusing on specifics of the clinical implementation and usage.
Materials and methods
A 32-question survey covered: type and number of systems, quality assurance (QA), clinical workflows, and identification of strengths/limitations. Respondents from different professional groups and countries were invited to participate. The survey was distributed internationally via ESTRO-membership, social media and vendors.
Results
Of the 278 institutions responding, 172 had at least one SGRT-system and 136 use SGRT clinically. Implementation and QA were primarily based on the vendors' recommendations and phantoms. SGRT was mainly implemented in breast RT (116/136), with strong but diverse representation of other sites. Many (58/135) reported at least partial elimination of skin-marks and a third (43/126) used open-masks. The most common imaging protocol reported included the combination of radiographic imaging with SGRT. Patient positioning (115/136), motion management (104/136) and DIBH (99/136) were the main applications.Main barriers to broader application were cost, system integration issues and lack of demonstrated clinical value. A lack of guidelines in terms of QA of the system was highlighted.
Conclusions
This overview of the SGRT status has the potential to support users, vendors and organisations in the development of practices, products and guidelines
The use of obinutuzumab and ofatumumab in the treatment of immune thrombotic thrombocytopenic purpura.
No full textRituximab, an anti-CD20 monoclonal antibody, can be used to treat immune thrombotic thrombocytopenic purpura (iTTP) during acute presentation or disease relapse. Undesirable side-effects include severe hypersensitivity reactions, particularly anaphylaxis and rituximab-induced serum sickness, with a minority not maintaining a response to treatment. Alternative humanised anti-CD20 treatments, obinutuzumab and ofatumumab, have been used. A review of the UK TTP Registry showed 15 patients received these drugs over 26 treatment episodes (eight obinutuzumab and 18 ofatumumab). Indications for alternative anti-CD20 treatment were severe infusion-related reactions, acute rituximab-induced serum sickness and a short duration of disease remission. All patients achieved disease remission (ADAMTS13 [A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13] activity ≥30 iu/dl) after a median 15 days and 92% of episodes achieved complete remission (≥60 iu/dl). Seven patients required further treatment for disease relapse with a median relapse-free survival of 17.4 months. All patients continued to respond to re-treatment with the preceding drug when relapse occurred. There were four adverse events in 26 treatment episodes (15%) - two infections and two infusion reactions. These results suggest that obinutuzumab and ofatumumab may be considered as an alternative option to rituximab in the treatment of iTTP with a comparable safety profile, absence of significant hypersensitivity reactions and sustained normalisation of ADAMTS13
Prophylactic embolization of large spontaneous portosystemic shunts with TIPS: A panacea for post TIPS hepatic encephalopathy?
No full textLenalidomide induced secondary Acute Lymphoblastic Leukemia in a Multiple Myeloma patient: A case-report.
No full textLenalidomide mechanism of action has been shown to modulate the different components of the immune system. A 68-year-old lady presented to us with severe backache and was then diagnosed with MM. Lenalidomide started as per protocol along with dexamethasone. Later, she presented with complaints of generalized weakness and her workup showed significant blast cells with Pan-B-cell markers consistent with secondary B-ALL. The reported incidence of secondary Acute Lymphocytic Leukemia is 2.3%. The development of more aggressive neoplasm in a patient with prior malignancy dictates a poor outcome and hence such patients should be enrolled in a clinical trial whenever available
Association between anesthesia modality and clinical outcomes following endovascular stroke treatment in the extended time window.
No full textBACKGROUND
There is a paucity of data on anesthesia-related outcomes for endovascular treatment (EVT) in the extended window (>6 hours from ischemic stroke onset). We compared functional and safety outcomes between local anesthesia (LA) without sedation, conscious sedation (CS) and general anesthesia (GA).
METHODS
Patients who underwent EVT in the early (<6 hours) and extended time windows using LA, CS, or GA between October 2015 and March 2020 were included from a UK national stroke registry. Multivariable analyses were performed, adjusted for age, sex, baseline stroke severity, pre-stroke disability, EVT technique, center, procedural time and IV thrombolysis.
RESULTS
A total of 4337 patients were included, 3193 in the early window (1135 LA, 446 CS, 1612 GA) and 1144 in the extended window (357 LA, 134 CS, 653 GA). Compared with GA, patients treated under LA alone had increased odds of an improved modified Rankin Scale (mRS) score at discharge (early: adjusted common (ac) OR=1.50, 95% CI 1.29 to 1.74, p=0.001; extended: acOR=1.29, 95% CI 1.01 to 1.66, p=0.043). Similar mRS scores at discharge were found in the LA and CS cohorts in the early and extended windows (p=0.21). Compared with CS, use of GA was associated with a worse mRS score at discharge in the early window (acOR=0.73, 95% CI 0.45 to 0.96, p=0.017) but not in the extended window (p=0.55). There were no significant differences in the rates of symptomatic intracranial hemorrhage or in-hospital mortality across the anesthesia modalities in the extended window.
CONCLUSION
LA without sedation during EVT was associated with improved functional outcomes compared with GA, but not CS, within and beyond 6 hours from stroke onset. Prospective studies assessing anesthesia-related outcomes in the extended time window are warranted