Roles of PI3Kγ and PI3Kδ in mantle cell lymphoma proliferation and migration contributing to efficacy of the PI3Kγ/δ inhibitor duvelisib.

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma that is incurable with existing therapies, and therefore presents a significant unmet clinical need. The ability of this disease to overcome therapy, including those that target the B cell receptor pathway which has a pathogenic role in MCL, highlights the need to develop new treatment strategies. Herein, we demonstrate that a distinguishing feature of lymph node resident MCL cells is the expression of phosphatidylinositol 3-kinase γ (PI3Kγ), a PI3K isoform that is not highly expressed in other B cells or B-cell malignancies. By exploring the role of PI3K in MCL using different PI3K isoform inhibitors, we provide evidence that duvelisib, a dual PI3Kδ/γ inhibitor, has a greater effect than PI3Kδ- and PI3Kγ-selective inhibitors in blocking the proliferation of primary MCL cells and MCL cell lines, and in inhibiting tumour growth in a mouse xenograft model. In addition, we demonstrated that PI3Kδ/γ signalling is critical for migration of primary MCL cells and cell lines. Our data indicates that aberrant expression of PI3Kγ is a critical feature of MCL pathogenesis. Thus, we suggest that the dual PI3Kδ/γ duvelisib would be effective for the treatment of mantle cell lymphoma.

What is the patient experience following revision knee replacement: A systematic review and meta-analysis of the medium term patient reported outcomes.

AIMS: Revision knee replacement is an increasingly common procedure, however, information on patient-focused outcomes is limited. This systematic review and meta-analysis aimed to investigate the medium-term patient reported outcomes following a revision knee replacement. METHODS: We performed a systematic review of MEDLINE and EMBASE (from inception to 1st March 2021) for articles reporting five year or greater patient reported outcome measures (PROMs) following revision knee replacement. A meta-analysis of PROMs data was undertaken using the Standardised Mean Difference (SMD). Quality of methodology was assessed using Wylde's non-summative four-point system. The study was registered with PROPSERO (CRD42021199289). RESULTS: A total of 23 studies met the inclusion criteria containing 2414 patients at a mean minimum follow-up of 74 months (60-122). The reporting of PROMs were poorly standardised with several PROMs being used. The most commonly reported patient reported outcome was the Knee Society Score reported in 65% of studies (15/23). A meta-analysis of 629 eligible patients undergoing revision knee replacement revealed a significant improvement in pre-operative state with a SMD 2·05 95% CI 0.87, 3.23. CONCLUSION: This systematic review has found a significant and sustained improvement in patient-reported outcomes following a revision knee arthroplasty beyond five years. We found a variation in the usage and administration of PROMs which hinders a clear synthesis of results. Furthermore, the PROMs have not been robustly tested for validity in the context of a revision knee replacement.

Bilateral luxatio erecta: recognition and reduction.

Luxatio erecta is the rarest form of shoulder dislocation, accounting for 0.5% of all glenohumeral dislocations. Bilateral cases are rarer still with only 12 accounts described in medical literature. We describe an unusual case and its management.

Morbidity and medication preferences of individuals with headache presenting to a community pharmacy.

OBJECTIVE: To assess the degree of debilitation and the treatment views of individuals with headache presenting to a community pharmacy. BACKGROUND: Migraine and chronic daily headache are common poorly managed illnesses. Pharmacists recommend an over-the-counter "headache product" to customers more than 53 000 times daily, thus they are well positioned to help those with headache. DESIGN: Pilot project of 22 self-administered surveys of individuals presenting to a community pharmacy with a complaint of headache. RESULTS: Thirteen persons had Migraine Disability Assessment scores of grade III or grade IV. Of the sample population, a substantial minority (41%) did not believe their headaches could be effectively managed with over-the-counter medications, 72% did not feel over-the-counter agents were safer than prescription products, 96% did not indicate that over-the-counter drugs were more effective than prescription drugs, and 50% disagreed that a physician's evaluation was not necessary. Only half of the population was satisfied with their current therapy, and individuals overwhelmingly (91%) wished they could prevent their headaches. CONCLUSIONS: The majority of individuals with headache presenting to a community pharmacy had high levels of morbidity and were in need of education regarding the proper role of over-the-counter medications, the advantages of prescription agents, and the benefits of a physician's referral. These preliminary results indicate that community pharmacies are potentially important locations for identification, education, and referral of individuals with headache.