Implementing the "Getting It Right First Time" (GIRFT) Report Recommendations: The Results of Introducing a Shoulder and Elbow Multidisciplinary Team.

Objective In this study, we aimed to analyse the impact of implementing the "Getting It Right First Time" (GIRFT) recommendations in our shoulder and elbow unit, which included the introduction of a shoulder and elbow multidisciplinary team (MDT) meeting for all patients being considered for surgery. Methods A retrospective patient case-note review was undertaken to assess the impact of replacing the pre-admission clinic with an MDT meeting. We analysed how many of the proposed management plans were changed as a result of this new MDT, as well as the associated cost savings. Results Of note, 118/148 patients who attended the MDT had a provisional operative plan; 24/118 (20%) had their plan changed to non-operative management, 13/118 (11%) had a change of operation, and 6/118 (5%) were recommended further investigations or tertiary referral. This reduced theatre time required by 47 hours, an estimated saving of over £51,000. Significantly, 20/24 patients who had their plan changed from operative to non-operative still had not had an operation after a median follow-up of 39 months. Conclusion The introduction of a shoulder and elbow MDT for all patients being considered for an operation has improved decision-making, allowed optimisation of non-operative management, and helped prevent patients from having unnecessary operations. This has led to a better patient experience and a more efficient service delivery, which is associated with cost savings.

Dual Surgeon Operating in Reverse Geometry Total Shoulder Replacement: The Learning Curve and Its Effects on Complication Rates.

Aims We analyse the impact of implementing dual surgeon operating for reverse geometry total shoulder replacement (RGTSR) as part of the "Getting It Right First Time" (GIRFT) recommendations in our shoulder and elbow unit, and the learning curve associated with it. Methods We performed a retrospective cohort study comparing operative time and complication rates in patients who underwent RGTSR performed by a single consultant surgeon versus two consultant surgeons over a six-year period in a single centre, in addition to an analysing the learning curve over the same period. Results A total of 74 RGTSRs were performed over a six-year period: 35 patients had a single surgeon perform their procedure and 39 had dual surgeon operating. Observed complication rates for RGTSR nearly halved following the introduction of dual surgeon operating (22.9% vs 12.8%, p=0.36). The complication rate for the first 37 cases was 9/37 (24.4%) versus 4/37 (10.8%, p=0.22) for the next 37 cases. Conclusion The implementation of dual surgeon operating may lead to reduced operative complications, provide cost savings to the hospital and produced several other non-tangible benefits to the surgeons and the department. An observed reduction in complication rates demonstrates the learning curve associated with this procedure.

Discovery of ( R)-8-(6-Methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4- b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-2-((1-methylcyclopropyl)amino)quinazolin-4(3 H)-one, a Potent and Selective Pim-1/2 Kinase Inhibitor for Hematological Malignancies.

Pim kinases are a family of constitutively active serine/threonine kinases that are partially redundant and regulate multiple pathways important for cell growth and survival. In human disease, high expression of the three Pim isoforms has been implicated in the progression of hematopoietic and solid tumor cancers, which suggests that Pim kinase inhibitors could provide patients with therapeutic benefit. Herein, we describe the structure-guided optimization of a series of quinazolinone-pyrrolodihydropyrrolone analogs leading to the identification of potent pan-Pim inhibitor 28 with improved potency, solubility, and drug-like properties. Compound 28 demonstrated on-target Pim activity in an in vivo pharmacodynamic assay with significant inhibition of BAD phosphorylation in KMS-12-BM multiple myeloma tumors for 16 h postdose. In a 2-week mouse xenograft model, daily dosing of compound 28 resulted in 33% tumor regression at 100 mg/kg.

Improving analgesia prescription for trauma inpatients.

Patients value effective pain relief. Complications of inadequate pain control include increased risk of infection, decreased patient comfort and progression to chronic pain, all of which have significant socioeconomic consequence. Accessibility to analgesia is vital to effective administration. This improvement project aimed to improve the consistency and adequacy of analgesia prescribing for trauma inpatients over a 12-month period. Four PDSA ('plan, do, study, act') cycles resulted in sustained and significant improvements in analgesia prescription. The interventions included senior encouragement, teaching sessions, targeted inductions and implementation of a novel e-prescribing protocol. Prospective data and real-time discussion from stakeholder medical and management teams enabled iterative change to practice. Drug charts were reviewed for all trauma inpatients (n=276) over a 10-month period, recording all analgesia prescribed within 24 hours of admission. Each prescription was scored (maximum of 10 points) according to parameters agreed by the acute pain specialty leaders. An improving trend was observed in the analgesia score over the study period. Each intervention was associated with improved practice. Based on observed improvements, a novel electronic prescribing protocol was developed in conjunction with the information technology department, resulting in maximum scores for prescribing which were sustained over the final 3 months of the study. This was subsequently adopted as standard practice within the department. One year following completion of the project, a further 3 weeks of data were collected to assess long-term sustainability-scores remained 10 out of 10. Addressing the prescribing habits of junior doctors improved accessibility to analgesia for trauma patients. The electronic prescribing tool made prescribing straightforward and faster, and was the most successful intervention. Doctor satisfaction using this time-saving tool was high. Identifying a stakeholder within the information technology department proved pivotal to transferring the project aims into clinical practice.

Discovery of imidazopyridazines as potent Pim-1/2 kinase inhibitors.

High levels of Pim expression have been implicated in several hematopoietic and solid tumor cancers, suggesting that inhibition of Pim signaling could provide patients with therapeutic benefit. Herein, we describe our progress towards this goal using a screening hit (rac-1) as a starting point. Modification of the indazole ring resulted in the discovery of a series of imidazopyridazine-based Pim inhibitors exemplified by compound 22m, which was found to be a subnanomolar inhibitor of the Pim-1 and Pim-2 isoforms (IC50 values of 0.024nM and 0.095nM, respectively) and to potently inhibit the phosphorylation of BAD in a cell line that expresses high levels of all Pim isoforms, KMS-12-BM (IC50=28nM). Profiling of Pim-1 and Pim-2 expression levels in a panel of multiple myeloma cell lines and correlation of these data with the potency of compound 22m in a proliferation assay suggests that Pim-2 inhibition would be advantageous for this indication.

The Panitumumab EGFR Complex Reveals a Binding Mechanism That Overcomes Cetuximab Induced Resistance.

Panitumumab and cetuximab target the epidermal growth factor receptor for the treatment of metastatic colorectal cancer. These therapies provide a significant survival benefit to patients with metastatic colorectal cancer with wild-type RAS. A single point mutation in the ectodomain of EGFR (S468R) confers acquired or secondary resistance in cetuximab treated patients, which is not observed in panitumumab-treated patients. Structural and biophysical studies presented here show this mutation directly blocks cetuximab binding to EGFR domain III and describes a unique mechanism by which panitumumab uses a central cavity to accommodate this mutation.

Discovery and Optimization of Quinazolinone-pyrrolopyrrolones as Potent and Orally Bioavailable Pan-Pim Kinase Inhibitors.

The high expression of proviral insertion site of Moloney murine leukemia virus kinases (Pim-1, -2, and -3) in cancers, particularly the hematopoietic malignancies, is believed to play a role in promoting cell survival and proliferation while suppressing apoptosis. The three isoforms of Pim protein appear largely redundant in their oncogenic functions. Thus, a pan-Pim kinase inhibitor is highly desirable. However, cell active pan-Pim inhibitors have proven difficult to develop because Pim-2 has a low Km for ATP and therefore requires a very potent inhibitor to effectively block the kinase activity at cellular ATP concentrations. Herein, we report a series of quinazolinone-pyrrolopyrrolones as potent and selective pan-Pim inhibitors. In particular, compound 17 is orally efficacious in a mouse xenograft model (KMS-12 BM) of multiple myeloma, with 93% tumor growth inhibition at 50 mg/kg QD upon oral dosing.

Discovery and Optimization of Macrocyclic Quinoxaline-pyrrolo-dihydropiperidinones as Potent Pim-1/2 Kinase Inhibitors.

The identification of Pim-1/2 kinase overexpression in B-cell malignancies suggests that Pim kinase inhibitors will have utility in the treatment of lymphoma, leukemia, and multiple myeloma. Starting from a moderately potent quinoxaline-dihydropyrrolopiperidinone lead, we recognized the potential for macrocyclization and developed a series of 13-membered macrocycles. The structure-activity relationships of the macrocyclic linker were systematically explored, leading to the identification of 9c as a potent, subnanomolar inhibitor of Pim-1 and -2. This molecule also potently inhibited Pim kinase activity in KMS-12-BM, a multiple myeloma cell line with relatively high endogenous levels of Pim-1/2, both in vitro (pBAD IC50 = 25 nM) and in vivo (pBAD EC50 = 30 nM, unbound), and a 100 mg/kg daily dose was found to completely arrest the growth of KMS-12-BM xenografts in mice.

Systematic Study of the Glutathione (GSH) Reactivity of N-Arylacrylamides: 1. Effects of Aryl Substitution.

Success in the design of targeted covalent inhibitors depends in part on a knowledge of the factors influencing electrophile reactivity. In an effort to further develop an understanding of structure-reactivity relationships among N-arylacrylamides, we determined glutathione (GSH) reaction rates for a family of N-arylacrylamides independently substituted at ortho-, meta-, and para-positions with 11 different groups common to inhibitor design. We find that substituent effects on reaction rates show a linear Hammett correlation for ortho-, meta-, and para-substitution. In addition, we note a correlation between (1)H and (13)C NMR chemical shifts of the acrylamide with GSH reaction rates, suggesting that NMR chemical shifts may be a convenient surrogate measure of relative acrylamide reactivity. Density functional theory calculations reveal a correlation between computed activation parameters and experimentally determined reaction rates, validating the use of such methodology for the screening of synthetic candidates in a prospective fashion.

Oxopyrido[2,3-d]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors.

In nonsmall cell lung cancer (NSCLC), the threonine(790)-methionine(790) (T790M) point mutation of EGFR kinase is one of the leading causes of acquired resistance to the first generation tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. Herein, we describe the optimization of a series of 7-oxopyrido[2,3-d]pyrimidinyl-derived irreversible inhibitors of EGFR kinase. This led to the discovery of compound 24 which potently inhibits gefitinib-resistant EGFR(L858R,T790M) with 100-fold selectivity over wild-type EGFR. Compound 24 displays strong antiproliferative activity against the H1975 nonsmall cell lung cancer cell line, the first line mutant HCC827 cell line, and promising antitumor activity in an EGFR(L858R,T790M) driven H1975 xenograft model sparing the side effects associated with the inhibition of wild-type EGFR.

Discovery of 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2-amines as potent PIM inhibitors.

PIM kinases are a family of Ser/Thr kinases that are implicated in tumorigenesis. The discovery of a new class of PIM inhibitors, 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2-amines, is discussed with optimized compounds showing excellent potency against all three PIM isoforms.

Unfolded Protein Response in Cancer: IRE1α Inhibition by Selective Kinase Ligands Does Not Impair Tumor Cell Viability.

The kinase/endonuclease inositol requiring enzyme 1 (IRE1α), one of the sensors of unfolded protein accumulation in the endoplasmic reticulum that triggers the unfolded protein response (UPR), has been investigated as an anticancer target. We identified potent allosteric inhibitors of IRE1α endonuclease activity that bound to the kinase site on the enzyme. Structure-activity relationship (SAR) studies led to 16 and 18, which were selective in kinase screens and were potent against recombinant IRE1α endonuclease as well as cellular IRE1α. The first X-ray crystal structure of a kinase inhibitor (16) bound to hIRE1α was obtained. Screening of native tumor cell lines (>300) against selective IRE1α inhibitors failed to demonstrate any effect on cellular viability. These results suggest that IRE1α activity is not essential for viability in most tumor cell lines, in vitro, and that interfering with the survival functions of the UPR may not be an effective strategy to block tumorigenesis.

The discovery and optimization of aminooxadiazoles as potent Pim kinase inhibitors.

High levels of Pim expression have been implicated in several hematopoietic and solid tumor cancers. These findings suggest that inhibition of Pim signaling by a small molecule Pim-1,2 inhibitor could provide patients with therapeutic benefit. Herein, we describe our progress towards this goal starting from the highly Pim-selective indole-thiadiazole compound (1), which was derived from a nonselective hit identified in a high throughput screening campaign. Optimization of this compound's potency and its pharmacokinetic properties resulted in the discovery of compound 29. Cyclopropane 29 was found to exhibit excellent enzymatic potency on the Pim-1 and Pim-2 isoforms (Ki values of 0.55nM and 0.28nM, respectively), and found to inhibit the phosphorylation of BAD in the Pim-overexpressing KMS-12 cell line (IC50=150nM). This compound had moderate clearance and bioavailability in rat (CL=2.42L/kg/h; %F=24) and exhibited a dose-dependent inhibition of p-BAD in KMS-12 tumor pharmacodynamic (PD) model with an EC50 value of 6.74µM (18µg/mL) when dosed at 10, 30, 100 and 200mg/kg po in mice.

The discovery of novel 3-(pyrazin-2-yl)-1H-indazoles as potent pan-Pim kinase inhibitors.

The three Pim kinases are a small family of serine/threonine kinases regulating several signaling pathways that are fundamental to tumorigenesis. As such, the Pim kinases are a very attractive target for pharmacological inhibition in cancer therapy. Herein, we describe our efforts toward the development of a potent, pan-Pim inhibitor. The synthesis and hit-to-lead SAR development from a 3-(pyrazin-2-yl)-1H-indazole derived hit 2 to the identification of a series of potent, pan-Pim inhibitors such as 13o are described.

Discovery and in vivo evaluation of (S)-N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and related PI3Kδ inhibitors for inflammation and autoimmune disease.

The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation.

Phosphoinositide-3-kinase inhibitors: evaluation of substituted alcohols as replacements for the piperazine sulfonamide portion of AMG 511.

Replacement of the piperazine sulfonamide portion of the PI3Kα inhibitor AMG 511 (1) with a range of aliphatic alcohols led to the identification of a truncated gem-dimethylbenzylic alcohol analog, 2-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-((5-fluoro-6-methoxypyridin-3-yl)amino)pyridin-3-yl)propan-2-ol (7). This compound possessed good in vitro efficacy and pharmacokinetic parameters and demonstrated an EC50 of 239 ng/mL in a mouse liver pharmacodynamic model measuring the inhibition of hepatocyte growth factor (HGF)-induced Akt Ser473 phosphorylation in CD1 nude mice 6 h post-oral dosing.

Minimally invasive total knee arthroplasty; a pragmatic randomised controlled trial reporting outcomes up to 2 year follow up.

BACKGROUND: We present a prospective, randomised, multi-surgeon, controlled trial comparing minimally invasive (MIS) and standard approach total knee arthroplasty (TKA). METHODS: Participants underwent unilateral TKA. Patients were randomised to Bristol, quadriceps sparing MIS or standard medial parapatellar approaches. Length of stay with secondary outcome measures including knee range of movement, Oxford Knee Score (OKS), Western Ontario and McMaster Universities Arthritis Index (WOMAC) and American Knee Society Score (KSS) up to 2 years. Radiographic and post operative assessment was blinded. RESULTS: 86 patients (92 knees) participated in the study. Mean operative time between MIS and control groups was 95.5 (95% CI 90.0-101.0) and 94.8 (95% CI 88.2-101.4) minutes respectively. Mean readiness for discharge was shorter in the MIS group 4.5±1.5 (95% CI, 4.1-4.9) days versus 5.9±2.7 (95% CI, 5.1-6.7) days amongst controls (p=0.004). Patients in the MIS group had fewer complications (p=0.003). One patient developed a deep vein thrombosis (DVT) and one required revision surgery, both in the control group. 83 patients completed follow up to 2 years (40 MIS, 43 controls). Range of movement and other outcome measures improved up to 1 year post-operatively with no statistically significant differences between MIS and controls. We found no evidence of radiographic loosening in either group at the 2 year follow up. CONCLUSIONS: MIS offers reduced length of stay and fewer complications for patients following TKR without evidence of component mal-alignment. Our findings of fewer systemic complications in MIS TKR patients warrant further future study. LEVEL OF EVIDENCE: Level 1.

The influence of rotator cuff pathology on functional outcome in total shoulder replacement.

INTRODUCTION: Total shoulder replacement (TSR) is a reliable treatment for glenohumeral osteoarthritis. In addition to proper component orientation, successful arthroplasty requires accurate restoration of soft tissues forces around the joint to maximize function. We hypothesized that pathological changes within the rotator cuff on preoperative magnetic resonance imaging (MRI) adversely affect the functional outcome following TSR. MATERIALS AND METHODS: A retrospective analysis of case notes and MRI of patients undergoing TSR for primary glenohumeral osteoarthritis over a 4-year period was performed. Patients were divided into three groups based upon their preoperative MRI findings: (1) normal rotator cuff, (2) the presence of tendonopathy within the rotator cuff, or (3) the presence of a partial thickness rotator cuff tear. Intra-operatively tendonopathy was addressed with debridement and partial thickness tears with repair. Functional outcome was assessed with the Oxford Shoulder Score (OSS), and quick disabilities of the arm, shoulder and hand score (quick-DASH). RESULTS: We had a full dataset of complete case-notes, PACS images, and patient reported outcome measures available for 43 patients, 15 in group 1, 14 in group 2, and 14 in group 3. Quick-DASH and OSS were calculated at a minimum of 24 months following surgery. There was no statistically significant difference between the results obtained between the three groups of either the OSS (P = 0.45), or quick-DASH (P = 0.46). CONCLUSIONS: TSR is an efficacious treatment option for patients with primary glenohumeral osteoarthritis in the medium term, even in the presence of rotator cuff tendonopathy or partial tearing. Minor changes within the cuff do not significantly affect functional outcome following TSR.

Selective class I phosphoinositide 3-kinase inhibitors: optimization of a series of pyridyltriazines leading to the identification of a clinical candidate, AMG 511.

The phosphoinositide 3-kinase family catalyzes the phosphorylation of phosphatidylinositol-4,5-diphosphate to phosphatidylinositol-3,4,5-triphosphate, a secondary messenger which plays a critical role in important cellular functions such as metabolism, cell growth, and cell survival. Our efforts to identify potent, efficacious, and orally available phosphatidylinositol 3-kinase (PI3K) inhibitors as potential cancer therapeutics have resulted in the discovery of 4-(2-((6-methoxypyridin-3-yl)amino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (1). In this paper, we describe the optimization of compound 1, which led to the design and synthesis of pyridyltriazine 31, a potent pan inhibitor of class I PI3Ks with a superior pharmacokinetic profile. Compound 31 was shown to potently block the targeted PI3K pathway in a mouse liver pharmacodynamic model and inhibit tumor growth in a U87 malignant glioma glioblastoma xenograft model. On the basis of its excellent in vivo efficacy and pharmacokinetic profile, compound 31 was selected for further evaluation as a clinical candidate and was designated AMG 511.