Narrative review-diagnosing and managing malignant epidural spinal cord compression: an evidence-based approach.

Background and Objective: Malignant spinal cord compression (MSCC) is a medical emergency. Clinical deterioration can occur quickly and irreversibly. MSCC is caused predominantly by metastatic cancer spread to the epidural space by epithelial or haematological malignancies. The primary diagnostic test is full-spine magnetic resonance imaging (MRI) since it has excellent soft tissue spatial resolution, and MSCC is multi-level in around one-third of cases. The modalities of therapy for MSCC are steroids, radiotherapy, and surgery. Radiotherapy is a mainstay of treatment since indications for surgery are limited. Recently randomised clinical trials exploring long course vs. short course radiotherapy have been undertaken as well as novel incorporation of stereotactic ablative radiotherapy (SABR). This review summarises these recent trials and identifies and discusses published data for novel treatment paradigms of MSCC. Methods: Multiple medical databases were searched through January 7th, 2023 and identified relevant studies that examined the use of radiotherapy with or without surgery in the management of MSCC. Key Content and Findings: In addition to a detailed overview of the pathophysiology and diagnosis of cord compression, we also examine all recent phase III clinical trials to date on the use of conventional radiotherapy in managing MSCC. Our review also provides a comprehensive summary and discussion of the novel approaches to the management of cord compression, including the role of SABR and a non-traditional surgical approach as well. Conclusions: Shorter courses of radiotherapy can be considered for poor prognosis patients. For favourable prognosis patients, longer courses of treatment provide more durable local control. An emerging treatment paradigm is a hybrid approach of surgery and SABR, however this has not been studied prospectively.

A narrative review of combined stereotactic ablative radiotherapy and immunotherapy in metastatic non-small cell lung cancer.

Immune checkpoint inhibitors (ICIs) have significantly improved overall survival (OS) in metastatic non-small cell lung cancer (m-NSCLC). However, not all patients with m-NSCLC benefit from ICIs, and resistance to ICIs is an emerging challenge. The tumour microenvironment (TME) is immunosuppressive, and provides a myriad of mechanisms to facilitate escape of cancer cells from immune surveillance. The TME may also dampen the response to ICIs by inhibiting T cell effector responses. The poor prognosis of m-NSCLC has led to investigation of ICIs combined with other treatments with the intention of modulating the TME and sensitizing tumours to the effects of ICIs. Stereotactic ablative radiotherapy (SABR) in combination with ICIs is an area of intense interest. SABR is thought to evoke a pro-immunogenic response in the TME, with the capacity to turn a "cold", unresponsive tumour to "hot" and receptive to ICI. In addition to improved local response, SABR is postulated to produce a heightened systemic immune response when compared to conventional radiotherapy (RT). Preclinical studies have demonstrated a synergistic effect of SABR + ICIs, and clinical studies in m-NSCLC showed safety and promising efficacy compared to systemic therapies alone. To optimize ICI + SABR, ICI choice, combinations, dosing and length of treatment, as well as sequencing of ICI + SABR all require further investigation. Appropriate sequencing may depend on the ICI(s) being utilized, with differing sites of metastases possibly eliciting differing immune responses. Single versus multisite radiation is controversial, whilst effects of irradiated tumour volume and nodal irradiation are increasingly recognized. Taken together, there is strong preclinical and biological rationale, with emerging clinical evidence, supporting the strategy of combining SABR + ICIs in m-NSCLC.

Post-operative stereotactic radiosurgery following excision of brain metastases: A systematic review and meta-analysis.

BACKGROUND: Following the resection of brain metastases, Stereotactic Radiosurgery (SRS) to the post-operative surgical cavity has increasingly replaced Whole Brain Radiotherapy (WBRT) as the standard of practice. There is however tremendous variation in the way SRS can be delivered and outcomes of SRS are yet to be systemically characterized. METHODS: Pubmed, Medline, Embase, and Cochrane databases were searched through June 2019 to identify papers that examined post-operative SRS after resection of brain metastases. An aggregate data analysis was performed to estimate the pooled rate of local control at 12 months (LC12), radiation necrosis, and leptomengingeal disease dissemination as binary outcomes. We pre-specified a random effects model using the method of DerSimonian and Laird with the Mantel-Haenszel weighting scheme and a fixed continuity correction of 0.5. Heterogeneity was assessed using the I2 statistic. RESULTS: Fifty studies involving 3458 patients were included for analysis. LC12 across all studies was found to be 83.7%. Patients treated with fractionated SRS had better local control than patients treated with single fraction SRS (LC12 87.3% vs 80.0%, p = 0.021) in a univariate analysis. There was no improved LC12 with the addition of a margin (LC12 of 84.3% vs 83.1% with no margin, p = 0.71). Radiation necrosis was rare at 6.9% across all reported studies and leptomeningeal disease was found to be 13% across all reported studies. One year distant brain control was found to be 52.8%. CONCLUSION: Our review supports the use of post-operative SRS to the resection cavity as a safe and efficacious treatment option. Fractionated SRS appears to be beneficial and warrants further exploration.

Current review-The rise of bacteriophage as a unique therapeutic platform in treating peri-prosthetic joint infections.

Peri-prosthetic joint infection (PJI) is one of the most serious and dreaded complications after total joint replacement (TJR). Due to an aging population and the constant rise in demand for TJR, the incidence of PJI is also increasing. Successful treatment of PJI is challenging and is associated with high failure rates. One of the main causes for treatment failure is bacterial biofilm formation on implant surfaces and the adherence of biofilm bacteria on tissue and bone next to the implant. Biofilms are protective shields to bacterial cells and possess many unique properties that leads to antibiotic resistance. New therapeutic platforms are currently being explored to breakdown biofilm matrix in order to enhance the efficacy of antibiotics. Bacteriophages (phages) is one of these unique therapeutic platforms that can degrade biofilms as well as target the killing of bacterial cells. Preclinical studies of biofilm-mediated infections have demonstrated the ability of phage to eradicate biofilms and clear infections by working synergistically with antibiotics. There is strong preclinical evidence that phage can reduce the concentration of antibiotics required to treat an infection. These findings support a promising role for phages as a future clinical adjunct to antibiotics. In addition, phage therapy can be personalized to target a specific bacterial strain. Clinical studies using phage therapy are limited in Western literature; but phase I studies have established good safety profile with no adverse outcomes reported. In order to translate phage therapy to treat PJI in clinics, further preclinical testing is still required to study optimal delivery methods as well as the interaction between phage and the immune system in vivo. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1051-1060, 2018.

The pathway to RCTs: how many roads are there? Examining the homogeneity of RCT justification.

BACKGROUND: Randomized controlled trials (RCTs) form the foundational background of modern medical practice. They are considered the highest quality of evidence, and their results help inform decisions concerning drug development and use, preventive therapies, and screening programs. However, the inputs that justify an RCT to be conducted have not been studied. METHODS: We reviewed the MEDLINE and EMBASE databases across six specialties (Ophthalmology, Otorhinolaryngology (ENT), General Surgery, Psychiatry, Obstetrics-Gynecology (OB-GYN), and Internal Medicine) and randomly chose 25 RCTs from each specialty except for Otorhinolaryngology (20 studies) and Internal Medicine (28 studies). For each RCT, we recorded information relating to the justification for conducting RCTs such as average study size cited, number of studies cited, and types of studies cited. The justification varied widely both within and between specialties. RESULTS: For Ophthalmology and OB-GYN, the average study sizes cited were around 1100 patients, whereas they were around 500 patients for Psychiatry and General Surgery. Between specialties, the average number of studies cited ranged from around 4.5 for ENT to around 10 for Ophthalmology, but the standard deviations were large, indicating that there was even more discrepancy within each specialty. When standardizing by the sample size of the RCT, some of the discrepancies between and within specialties can be explained, but not all. On average, Ophthalmology papers cited review articles the most (2.96 studies per RCT) compared to less than 1.5 studies per RCT for all other specialties. CONCLUSIONS: The justifications for RCTs vary widely both within and between specialties, and the justification for conducting RCTs is not standardized.

Graft rejection rate and graft failure rate of penetrating keratoplasty (PKP) vs lamellar procedures: a systematic review.

PURPOSE: The aim of our investigation was to conduct a quantitative meta-analysis of the present world literature comparing the major surgical outcomes of penetrating keratoplasty (PKP) to lamellar procedures. Our goal is that clinicians, eye bank administrators, and health policy makers will be able to utilize this study in implementing decisions in regards to corneal transplantation. METHODS: Pooled measures of association were with odds ratios and because of study heterogeneity, the pooled effects were assumed to follow a random effects model (DerSimonian-Laird). The comparisons were between 1) PKP's and all lamellar procedures (anterior AND posterior) and then 2) between PKP's and all anterior lamellar procedures and 3) PKP and all posterior lamellar procedures. RESULTS: For PKP vs anterior lamellar procedures, the pooled odds ratio for rejection of PKP over lamellar keratoplasty (LK) was 3.56 (95% CI: 1.76-7.20) and for outright failure, the pooled odds ratio of PKP failure vs LK was 2.85 (95% CI: 0.84-9.66). For posterior lamellar procedures, the pooled odds ratio for rejection of PKP over LK was 1.52 (95% CI: 1.00-2.32). The pooled odds ratio for outright failure of PKP over posterior lamellar procedures was 2.09 (95% CI: 0.57-7.59). The follow up time was significantly longer for full transplants than for lamellar procedures. CONCLUSIONS: For both anterior and posterior lamellar procedures, the odds ratios comparing rejection of full transplants to lamellar procedures (both anterior and posterior individually) were significantly higher in the PKP group. For outright failure, the PKP group also had a higher risk of failure than the lamellar groups but this was not statistically significant in either instance (anterior or posterior). Some of the clinical differences benefitting lamellar procedures may at least be partly explained by follow up time differences between groups and this needs to be accounted for more rigorously in future studies.