Associations of Patients with Pericardial Effusion Secondary to Light-Chain or Transthyretin Amyloidosis- A Systematic Review.

BACKGROUND: Pericardial effusion is associated with amyloidosis, specifically amyloid light chain (AL) and transthyretin (ATTR) subtypes. However, the patients might present with different clinical symptoms. OBJECTIVE: To determine the characteristics and associations of patients with pericardial effusion owing to either AL or ATTR amyloidosis. METHODS: This study reviewed 26 studies from databases such as PubMed, MEDLINE, Web of Science, Google Scholar and CINAHL databases after protocol registration. The data were analyzed in IBM SPSS 21. Many statistical tests, such as Student t- and the Mann-Whitney U tests, were used. Multivariate logistic regression analysis was also performed. A p-value< 0.05 was considered significant. RESULTS: A total of 531 patients with pericardial effusion secondary to amyloidosis were included. The mean age was 58.4±24.5 years. Most of the patients were male (72.9%). Common co-morbid conditions included hypertension (16.8%) and active smoking (12.9%). The most common time from symptom onset to the clinical presentation was less than 1 week (45%). ATTR amyloidosis was more common in older patients (p<0.05). Abdominal and chest discomfort were commonly associated with AL and ATTR amyloidosis, respectively (p<0.05). Patients with AL amyloidosis had a higher association with interventricular septal thickening and increased posterior wall thickness (p<0.05). First-degree atrioventricular block, left bundle branch block (LBBB), and atrial fibrillation (AF) were more associated with ATTR amyloidosis (p<0.05). CONCLUSION: Pericardial effusion in patients with AL amyloidosis was associated with hypertrophic remodeling, while conduction abnormalities were associated with ATTR amyloidosis.

Novel Immunotherapeutic Approaches for the Treatment of Glioblastoma.

Glioblastoma is highly aggressive and remains difficult to treat despite being the most common malignant primary brain tumor in adults. Current standard-of-care treatment calls for maximum resection of the tumor mass followed by concurrent chemotherapy and radiotherapy and further adjuvant chemotherapy if necessary. Despite this regimen, prognosis remains grim. Immunotherapy has shown promising success in a variety of solid tumor types, but efficacy in glioblastoma is yet to be demonstrated. Barriers to the success of immunotherapy in glioblastoma include: a heterogeneous tumor cell population, a highly immunosuppressive microenvironment, and the blood-brain barrier, to name a few. Several immunotherapeutic approaches are actively being investigated and developed to overcome these limitations. In this review, we present different classes of immunotherapy targeting glioblastoma, their most recent results, and potential future directions.

An unusual case of a grade I meningioma with perineural spread.

A 39-year-old lady with worsening intermittent diplopia and headaches was diagnosed with a WHO Grade I Meningothelial Meningioma with highly unusual perineural spread on imaging, making this the first reported case of this behaviour. Complete surgical resection was deemed too great a risk and the patient remains under observation. The process of perineural spread is not restricted to more aggressive brain tumours.

Endovascular and surgical obliteration rates of spinal dural arteriovenous fistulae: a single UK Centre experience.

OBJECTIVE: Endovascular treatment (EVT) of spinal dural arteriovenous fistulae (SDAVF) has become increasingly popular given its less invasive nature. This study aims to assess radiological obliteration rates after surgery and EVT for SDAVF in a major tertiary referral centre serving a population of 2.2 million. METHOD: A retrospective review of all patients diagnosed with SDAVF between February 2010 and February 2018 was undertaken, identifying baseline demographics, treatment modality and the final radiological outcome (i.e., persistence of the SDAVF). Patients were identified from the departmental neurovascular database, clinical notes and imaging reports. RESULTS: Twenty patients were identified with an angiographically confirmed SDAVF. Two (10%) were managed conservatively. Nine patients (45%) underwent EVT. Obliteration was achieved in one patient (11%) after a single procedure, while one patient required two sessions. Further surgery was required in five patients (56%) to achieve complete obliteration. Nine patients (45%) underwent surgical disconnection as first treatment. Obliteration was radiologically confirmed in eight patients (89%). No radiological (MRI or angiographic) follow-up data was available for two patients (one from each group) and these were excluded from analysis. In this study, the obliteration rate of SDAVF after surgery was superior compared to EVT (p <0.01). CONCLUSION: Complete obliteration and recurrence rates after single treatment with EVT were inferior compared to surgical intervention. EVT may be better suited for specific presentations of SDAVF either in isolation or as an adjunct in multi-modality treatment. A national registry of outcomes may aid ongoing refinement of patient selection for EVT.

Xanthomatous hypophysitis causing hypogonadotropic hypogonadism resulting in delayed presentation of slipped capital femoral epiphysis.

An 18-year-old man who underwent bilateral pinning of his hip joints after a left unstable Slipped Capital Femoral Epiphysis (right pinned prophylactically) was noted to have delayed secondary sexual characteristics and post-operative diabetes insipidus. The patient also described a history of fatigue, headache and polydipsia for the past 4 years. Endocrine investigations revealed reduced androgen levels, hypocortisolism, a borderline normal Serum ACE and secondary hypothyroidism. Magnetic Resonance Imaging of the pituitary gland identified an enhancing mass and a thickened stalk which trans-nasal endoscopic biopsy found to be necrotic with pus. Histology confirmed a diagnosis of Xanthomatous Hypophysitis, an inflammatory condition likely related to a partial rupture of a Rathke cleft cyst. The patient was subsequently commenced on Androgen, Thyroxine, Desmopressin and Hydrocortisone therapy with on-going endocrine follow-up. Although endocrine dysfunction & hypogonadism has been recognised to be a risk factor for SCFE at an atypically older age, due to reduced androgen levels leading to a weakened physeal plate, this is the first known case of a Xanthomatous Hypophysitis resulting in pituitary dysfunction and eventual SCFE. This case highlights that an increased range of pituitary disorders should be considered in late presentations of SCFE; and vice versa the risk of SCFE should be considered in patients with prolonged hypogonadotropic hypogonadism.

Designing Clinical Trials for Combination Immunotherapy: A Framework for Glioblastoma.

Immunotherapy has revolutionized treatment for many hard-to-treat cancers but has yet to produce significant improvement in outcomes for patients with glioblastoma. This reflects the multiple and unique mechanisms of immune evasion and escape in this highly heterogeneous tumor. Glioblastoma engenders profound local and systemic immunosuppression and is remarkably effective at inducing T-cell dysfunction, posing a challenge to any immunotherapy-based approach. To overcome these mechanisms, multiple disparate modes of immune-oriented therapy will be required. However, designing trials that can evaluate these combinatorial approaches requires careful consideration. In this review, we explore the immunotherapy resistance mechanisms that have been encountered to date and how combinatorial approaches may address these. We also describe the unique aspects of trial design in both preclinical and clinical settings and consider endpoints and markers of response best suited for an intervention involving multiple agents.

For whom the T cells troll? Bispecific T-cell engagers in glioblastoma.

Glioblastoma is the the most common primary brain tumor in adults. Onset of disease is followed by a uniformly lethal prognosis and dismal overall survival. While immunotherapies have revolutionized treatment in other difficult-to-treat cancers, these have failed to demonstrate significant clinical benefit in patients with glioblastoma. Obstacles to success include the heterogeneous tumor microenvironment (TME), the immune-privileged intracranial space, the blood-brain barrier (BBB) and local and systemic immunosuppressions. Monoclonal antibody-based therapies have failed at least in part due to their inability to access the intracranial compartment. Bispecific T-cell engagers are promising antibody fragment-based therapies which can bring T cells close to their target and capture them with a high binding affinity. They can redirect the entire repertoire of T cells against tumor, independent of T-cell receptor specificity. However, the multiple challenges posed by the TME, immune privilege and the BBB suggest that a single agent approach may be insufficient to yield durable, long-lasting antitumor efficacy. In this review, we discuss the mechanism of action of T-cell engagers, their preclinical and clinical developments to date. We also draw comparisons with other classes of multispecific antibodies and potential combinations using these antibody fragment therapies.

Enhancing T Cell Chemotaxis and Infiltration in Glioblastoma.

Glioblastoma is an immunologically 'cold' tumor, which are characterized by absent or minimal numbers of tumor-infiltrating lymphocytes (TILs). For those tumors that have been invaded by lymphocytes, they are profoundly exhausted and ineffective. While many immunotherapy approaches seek to reinvigorate immune cells at the tumor, this requires TILs to be present. Therefore, to unleash the full potential of immunotherapy in glioblastoma, the trafficking of lymphocytes to the tumor is highly desirable. However, the process of T cell recruitment into the central nervous system (CNS) is tightly regulated. Naïve T cells may undergo an initial licensing process to enter the migratory phenotype necessary to enter the CNS. T cells then must express appropriate integrins and selectin ligands to interact with transmembrane proteins at the blood-brain barrier (BBB). Finally, they must interact with antigen-presenting cells and undergo further licensing to enter the parenchyma. These T cells must then navigate the tumor microenvironment, which is rich in immunosuppressive factors. Altered tumoral metabolism also interferes with T cell motility. In this review, we will describe these processes and their mediators, along with potential therapeutic approaches to enhance trafficking. We also discuss safety considerations for such approaches as well as potential counteragents.

Targeting Immunometabolism in Glioblastoma.

We have only recently begun to understand how cancer metabolism affects antitumor responses and immunotherapy outcomes. Certain immunometabolic targets have been actively pursued in other tumor types, however, glioblastoma research has been slow to exploit the therapeutic vulnerabilities of immunometabolism. In this review, we highlight the pathways that are most relevant to glioblastoma and focus on how these immunometabolic pathways influence tumor growth and immune suppression. We discuss hypoxia, glycolysis, tryptophan metabolism, arginine metabolism, 2-Hydroxyglutarate (2HG) metabolism, adenosine metabolism, and altered phospholipid metabolism, in order to provide an analysis and overview of the field of glioblastoma immunometabolism.

Improving the surgical consenting process for patients with acute hip fractures: a pilot quality improvement project.

BACKGROUND: Consenting patients for trauma procedures following hip fracture is a key stage in the treatment pathway from admission to the operating theatre. Errors in this process can result in delayed procedures which may negatively impact patient recovery. The aim of this project was to identify and reduce errors in our consenting process for patients with capacity. METHODS: Consent forms for all adult patients with capacity admitted for surgical repair of traumatic hip fracture were reviewed over a 4-week period. The baseline measurement (n = 24), identified errors in three key process measures: clarity of documentation, failure to record procedure-specific risks and not offering a copy of the consent form to the patient. Pre-printed stickers and targeted teaching were then introduced as quality improvement measures. Their impact was evaluated over subsequent 4-week review of the same patient demographic, with further refinement of these interventions being carried out and re-evaluated for a final cycle. RESULTS: Cycle 1 (n = 26) following targeted teaching demonstrated a reduction in abbreviations from 38 to 20%, while doubling the documentation of discussion of procedure-specific risks from 31 to 72%. More patients were offered a copy of their consent form, rising from 12 to 48%. Cycle 2 (n = 24) saw the introduction of pre-printed "risk of procedure" stickers. Although clarity measures continued to improve, quality of pre-procedure risk documentation remained static while the number of forms being offered to patients fell to 8%. CONCLUSIONS: Our project would suggest that while pre-printed stickers can be useful memory aids, specific teaching on consenting produces the greatest benefit. The usage of such tools should therefore be limited, as adjuncts only to specific training.

Does time of surgery influence the rate of false-negative appendectomies? A retrospective observational study of 274 patients.

BACKGROUND: Multiple disciplines have described an "after-hours effect" relating to worsened mortality and morbidity outside regular working hours. This retrospective observational study aimed to evaluate whether diagnostic accuracy of a common surgical condition worsened after regular hours. METHODS: Electronic operative records for all non-infant patients (age > 4 years) operated on at a single centre for presumed acute appendicitis were retrospectively reviewed over a 56-month period (06/17/2012-02/01/2017). The primary outcome measure of unknown diagnosis was compared between those performed in regular hours (08:00-17:00) or off hours (17:01-07:59). Pre-clinical biochemistry and pre-morbid status were recorded to determine case heterogeneity between the two groups, along with secondary outcomes of length of stay and complication rate. RESULTS: Out of 289 procedures, 274 cases were deemed eligible for inclusion. Of the 133 performed in regular hours, 79% were appendicitis, compared to 74% of the 141 procedures performed off hours. The percentage of patients with an unknown diagnosis was 6% in regular hours compared to 15% off hours (RR 2.48; 95% CI 1.14-5.39). This was accompanied by increased numbers of registrars (residents in training) leading procedures off hours (37% compared to 24% in regular hours). Pre-morbid status, biochemistry, length of stay and post-operative complication rate showed no significant difference. CONCLUSIONS: This retrospective study suggests that the rate of unknown diagnoses for acute appendicitis increases overnight, potentially reflecting increased numbers of unnecessary procedures being performed off hours due to poorer diagnostic accuracy. Reduced levels of staffing, availability of diagnostic modalities and changes to workforce training may explain this, but further prospective work is required. Potential solutions may include protocolizing the management of common acute surgical conditions and making more use of non-resident on call senior colleagues.

Improving access to Early Intervention in Psychosis (EIP): the 2-week wait for cancer comes to psychosis.

Early Intervention in Psychosis (EIP) services aim to rapidly initiate specialist packages of care for those people newly experiencing symptoms. The intention of such rapid engagement is to mitigate the negative effects of a prolonged duration of untreated psychosis. Aiming to achieve a 'parity of esteem' between mental and physical health, a new target was introduced by the National Health Service (NHS) England, where 50% of new referrals were expected to receive a concordant package of care within 2 weeks from the National Institute for Health and Care Excellence. A baseline assessment in late 2014 found that just 21% of all referrals received and accepted met this target within the EIP Team for the North-East London NHS Foundation Trust. This project sought to improve the team's performance, seeking input from all team members and using an iterative process with the primary aim of meeting the target ahead of its roll-out. It was determined that the relatively high number of inappropriate referrals (34% at baseline) is a key causative agent in delaying staff from processing eligible cases in a timely fashion. These are defined as referrals which do not meet basic eligibility criteria such as no previous treatment for psychosis. Interventions were therefore designed targeting three domains of improving staff awareness of the new target, improving efficiency by changing the case allocation process and improving the referral pathway for external sources. The impact of these changes was re-evaluated over two cycles beyond baseline. By the final cycle, 62% of new referrals were seen within 2 weeks, while inappropriate referrals declined to just 3%. The multi-interventional nature of this project limits its generalisability and further work should be carried out to identify those changes that were most impactful. Nevertheless, focused targeting of the referral pathway may prove to be of benefit to other EIP services struggling with lengthy wait times.