Avascular necrosis of humeral head after proximal humerus fracture: comparison between classification systems in predicting necrosis risk.

BACKGROUND AND AIM: Avascular necrosis (AVN) of the humeral head is a relatively frequent complication after proximal humerus fractures (PHF). There are many factors related to the risk of developing AVN, with fracture complexity being one of the most relevant. Aim of the present study is to evaluate the correlation between different classification systems and the risk of post-operative AVN in patients treated with locking plate fixation for Neer 3 and 4-part PHFs. METHODS: The study population included 44 patients (F:M 2:1, mean age 62) treated between December 2014 and April 2019. Fractures were classified according to Neer, Russo and Lego classifications and Hertel's criteria. AVN was established on postoperative radiographs after a minimum follow-up of 6 months. The odds ratio (OR) for AVN for each classification subtype was calculated. RESULTS: The incidence of necrosis was 11%. Significant association with AVN was found for Neer 4 part (OR=8), Russo IVB (OR=4), Lego pattern 12 (OR=8) and in presence of 3 mayor Hertel's criteria (OR=15,5). CONCLUSIONS: There is a significant association between AVN and Neer 4 part, Russo type IVB and Lego pattern 12 fractures. AVN risk is also significantly higher in presence of 3 major Hertel's criteria.

Combined Targeting of the Glutathione and Thioredoxin Antioxidant Systems in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma is characterized by increased generation of reactive oxygen species that can cause lethal oxidative stress. Here, we evaluated the combined inhibition of the glutathione and thioredoxin antioxidant systems in preclinical models of pancreatic ductal adenocarcinoma, using buthionine sulfoximine (BSO) that targets glutathione synthesis, and auranofin that targets thioredoxin recycling. BSO potentiated the cytotoxicity of auranofin and induced lethal oxidative stress in primary pancreatic cancer cells. As assessed by the cellular thermal shift assay, auranofin engaged with thioredoxin reductase 1 in primary cells at concentrations known to induce cell death. Moreover, we used imaging mass cytometry to map the biodistribution of atomic gold in patient-derived xenografts treated with auranofin, and the drug was readily detectable throughout the epithelial and stromal compartments after treatment with a clinically relevant dose. In conclusion, combinatorial treatment with BSO and auranofin could serve as a potential therapeutic strategy in pancreatic ductal adenocarcinoma.

The current landscape of systemic therapy for recurrent glioblastoma: A systematic review of randomized-controlled trials.

AIM: Conduct a systematic review of the effectiveness of systemic therapies for adult recurrent glioblastoma (rGBM). METHODS: We electronically searched for randomized controlled trials from three major databases and four conferences from 2009-Dec 2020. Two independent reviewers conducted screening, data extraction, and quality assessment. RESULTS: 48 randomized trials were identified. Outcome reporting was inconsistent: overall survival (OS) in 46 studies, progression free survival in 37 studies, 6-month PFS in 30 studies, objective response rate in 28 studies, and 6-month OS in 7 studies. Network meta-analysis was not feasible due to heterogeneity in outcome reporting and single-study linkages. Most studies compared lomustine (8 studies), bevacizumab (18), or temozolomide (8) with other treatments. The median OS across all studies ranged from 3 to 17.6 months. CONCLUSIONS: Based on level one evidence, there is no superior systemic regimen for rGBM. rGBM is a heterogeneous population with no single regimen demonstrating OS benefit. Registration number: CRD42020148512.

Topical cannabis-based medicines - A novel adjuvant treatment for venous leg ulcers: An open-label trial.

Venous leg ulcers are highly prevalent lower limb integumentary wounds that remain challenging to heal despite the use of evidence-based compression therapies. A multitude of adjuvant treatments has been studied but none have demonstrated enough efficacy to gain adoption into treatment guidelines. Global attention on Cannabis-Based Therapies is increasing and has been driven by quantum scientific advancements in the understanding of the endocannabinoid signalling system. Topical Cannabis-Based Medicines represent a novel treatment paradigm for venous leg ulcers in terms of promoting wound closure. Fourteen complex patients with sixteen recalcitrant leg ulcers were treated with Topical Cannabis-Based Medicines in conjunction with compression bandaging, every second day, to both wound bed and peri-wound tissues. The cohort had a mean age of 75.8 years and was medically complex as reflected by a mean M3 multimorbidity index score of 2.94 and a mean Palliative Performance Scale score of 67.1%. Complete wound closure, defined as being fully epithelialized, was achieved among 11 patients (79%) and 13 wounds (81%) within a median of 34 days. All three remaining patients demonstrated progressive healing trends but were lost to follow-up. The treatments were well tolerated, and no significant adverse reactions were experienced. The rapid wound closure of previously non-healing venous leg ulcers among elderly and highly complex patients suggests that Topical Cannabis-Based Medicines may become effective adjuvants in conjunction with compression therapy. This may also indicate that they may have an even broader role within integumentary and wound management. Therefore, this treatment paradigm warrants being subjected to controlled trials.

Topical cannabis-based medicines - A novel paradigm and treatment for non-uremic calciphylaxis leg ulcers: An open label trial.

Non-Uremic Calciphylaxis (NUC) is a rare condition that often manifests as intractable and painful integumentary wounds, afflicting patients with a high burden of co-morbidity. The Endocannabinoid System (ECS) is a ubiquitous signalling system that is theorised to be dysregulated within wound beds and associated peri-wound tissues. Preclinical research has shown that the dominant chemical classes derived from the cannabis plant, cannabinoids, terpenes, and flavonoids, interact with the integumentary ECS to promote wound closure and analgesia. This is a prospective open label cohort study involving two elderly Caucasian females with recalcitrant NUC leg ulcers of greater than 6 months duration. Topical Cannabis-Based Medicines (TCBM) composed of cannabinoids, terpenes, and flavonoids were applied daily to both the wound bed and peri-wound tissues until complete wound closure was achieved. Wounds were photographed regularly, and the digital images were subjected to planimetric analysis to objectively quantify the degree of granulation and epithelization. Analgesic utilisation, as a surrogate/proxy for pain scores, was also tracked. The cohort had a mean M3 multimorbidity index score of 3.31. Complete wound closure was achieved in a mean of 76.3 days. Additionally, no analgesics were required after a mean of 63 days. The treatments were well tolerated with no adverse reactions. The positive results demonstrated in very challenging wounds such as NUC, among highly complex patients, suggest that TCBM may have an even broader role within integumentary and wound management. This treatment paradigm warrants being trialled in other wound types and classes, and ultimately should be subjected to randomised controlled trials.

Post-operative periprosthetic humeral fractures after reverse shoulder arthroplasty: a review of the literature.

BACKGROUND AND AIM OF THE WORK: Post-operative periprosthetic shoulder fractures incidence is gradually raising due to aging of population and increasing of reverse total shoulder arthroplasty (RTSA). Management of this complication represents a challenge for the orthopedic surgeon. Aim of the present study is to critically review the recent literature about epidemiology, risk factors, diagnosis, management and outcome of post-operative periprosthetic humeral  fractures occurring on RTSA. METHODS: A systematic search of Embase, Medline and Pubmed was performed by two reviewers who selected the eligible papers favoring studies published in the last ten years. Epidemiology, risk factors, diagnostic features, clinical management and outcome of different techniques were all reviewed. RESULTS: 31 studies including reviews, meta-analysis, case reports, clinical and biomechanical studies were selected. CONCLUSIONS: Correct clinical management requires adequate diagnosis and evaluation of risk factors. Conservative treatment is rarely indicated. Locking plate fixation and revision arthroplasty are both valuable treatment methods. Surgical technique should be chosen considering age and functional demand, comorbidities, fracture morphology and location, bone quality and stability of the implant. Given the correct indication all surgical treatment can lead to satisfactory clinical and radiographic results despite a relevant complication rate.

Molecular Biomarkers of Response to PD-1/ PD-L1 Immune Checkpoint Blockade in Advanced Bladder Cancer.

BACKGROUND: The activity of PD-1/PD-L1 inhibitors in the treatment of advanced bladder cancer (BC) is promising for many patients. However, a subset of patients do not benefit from treatment, thus leading to an effort to better identify predictive molecular biomarkers of response. OBJECTIVE: To conduct a systematic review of the literature on predictive molecular biomarkers associated with response to PD-1 and PD-L1 inhibitors in advanced bladder cancer, defined as locally-advanced, unresectable, or metastatic (mBC) disease. METHODS: A search of the literature was performed using Embase (1947 - January 2019), Medline (1946 - January 2019), and EBM Reviews for Cochrane Central Register of Controlled Trials (as of December 2018). Studies examining the association of molecular biomarkers with clinical outcome in BC treated with PD-1 or PD-L1 monotherapy were included. Outcomes of interest were overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), duration of response, and objective response rate (ORR). RESULTS: Using the study search criteria, 899 unique abstract citations were found, of which 834 did not meet the eligibility criteria. Full text of the remaining 65 citations were screened, and 50 studies excluded, including 18 review articles. Eight additional studies from the bibliography of the review papers were included, making a total of 23 studies. Five PD-1 / PD-L1 antibodies have been tested in BC immunohistochemistry (IHC). These studies used different expression scoring criteria and generally had poor ability to discriminate likelihood for response. Overall, the data suggests CD8+ T cell infiltration is necessary to mediate an antitumor immune response, but other immune cell populations, such as neutrophils may suppress T cell-mediated immunity and efficacy of PD-1/PD-L1 blockade. An IFNγ signature is a promising predictor, but there needs to be consensus on the optimal gene panel composition, and prospective validation. Tumor mutation burden (TMB) is a promising predictor in six studies reporting on 1200 patients, but there is not a consensus on the optimal definition of "high TMB". Detection of T cell receptor (TCR) clonal expansion has only been conducted in small studies and so its predictive value remains inconclusive. Epithelial-mesenchymal transformation (EMT) and transforming growth factor ß (TGFß) are associated with poor prognosis and possibly intrinsic resistance to PD-1/PD-L1 checkpoint blockade, but more work needs to be done to build upon and confirm the initial findings. CONCLUSIONS: Currently no molecular biomarker is sufficiently mature for routine clinical use, while some candidates, or a combination show great promise and need further study.

Modulation of Mrp1 (ABCc1) and Pgp (ABCb1) by bilirubin at the blood-CSF and blood-brain barriers in the Gunn rat.

Accumulation of unconjugated bilirubin (UCB) in the brain causes bilirubin encephalopathy. Pgp (ABCb1) and Mrp1 (ABCc1), highly expressed in the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) respectively, may modulate the accumulation of UCB in brain. We examined the effect of prolonged exposure to elevated concentrations of UCB on expression of the two transporters in homozygous, jaundiced (jj) Gunn rats compared to heterozygous, not jaundiced (Jj) littermates at different developmental stages (2, 9, 17 and 60 days after birth). BBB Pgp protein expression was low in both jj and Jj pups at 9 days (about 16-27% of adult values), despite the up-regulation in jj animals (2 and 1.3 fold higher than age matched Jj animals at P9 and P17-P60, respectively); Mrp1 protein expression was barely detectable. Conversely, at the BCSFB Mrp1 protein expression was rather high (60-70% of the adult values) in both jj and Jj at P2, but was markedly (50%) down-regulated in jj pups starting at P9, particularly in the 4(th) ventricle choroid plexuses: Pgp was almost undetectable. The Mrp1 protein down regulation was accompanied by a modest up-regulation of mRNA, suggesting a translational rather than a transcriptional inhibition. In vitro exposure of choroid plexus epithelial cells obtained from normal rats to UCB, also resulted in a down-regulation of Mrp1 protein. These data suggest that down-regulation of Mrp1 protein at the BSCFB, resulting from a direct effect of UCB on epithelial cells, may impact the Mrp1-mediated neuroprotective functions of the blood-cerebrospinal fluid barrier and actually potentiate UCB neurotoxicity.