Long-term safety of selpercatinib for Rearrenged during transfection (RET)-activated advanced solid tumors in LIBRETTO-001: differing patterns of adverse events over time.

BACKGROUND: Selpercatinib is a selective RET inhibitor approved for treatment of RET-activated cancers. Adverse events (AEs) are manageable with dose modifications. This post hoc analysis characterized selpercatinib's clinical safety profile after long-term follow-up in the safety population of LIBRETTO-001. PATIENTS AND METHODS: LIBRETTO-001 is an ongoing phase I/II, single-arm, open-label trial (NCT03157128). Eligible patients were ≥18 years old with diagnosis of advanced/metastatic RET fusion-positive solid tumor, RET-mutant medullary thyroid cancer, or other RET-activated tumors. In phase I, patients received selpercatinib 20 mg QD or 20-240 mg BID; patients in phase II received 160 mg BID. The analyzed population comprised all patients who received ≥1 selpercatinib dose and were followed up until data cutoff (January 13, 2023). RESULTS: For the 837 patients, median follow-up was 45.4 months (95% CI, 44.5-46.6); median time on treatment was 30.1 months (range 0.1-66.8). Grade ≥3 treatment-emergent AEs (TEAEs) were reported in 76.2% of patients; most common events were hypertension (19.7%), ALT increased (11.8%), and hyponatremia (9.2%). Serious TEAEs were reported in 51.4% of patients. Most frequently reported any-grade AEs at <6 months of treatment were fatigue (36.6%), dry mouth (32.8%), and ALT increased (30.5%); at ≥24 months of treatment, these were edema (63.2%), diarrhea (60.7%), and fatigue (53.0%). Selpercatinib-related TEAEs leading to reduced dosage were reported in 39.3%, those leading to treatment interruption were reported in 47.1%, and those leading to discontinuation were reported in 4.3% of patients. CONCLUSION: Long-term treatment with selpercatinib is feasible. AEs are manageable with dose modifications, allowing most patients to continue safely on therapy.

Midterm clinical and radiologic survivorship of a stemless total shoulder arthroplasty.

AIM: The aim of this study was to evaluate the clinical and radiologic outcomes of stemless total shoulder arthroplasty (TSA) in patients with glenohumeral arthritis. PATIENTS AND METHODS: This is a retrospective case series of all patients who underwent a TSA with Affinis Short prosthesis during the period 2010-2017. Seventy-two TSAs were performed within our unit, in 62 patients (45 females and 17 males), with 10 patients having bilateral TSAs with this prosthesis. The mean follow-up was 3.9 years (2-8.7 years). Patients were evaluated clinically with the Oxford Shoulder Score, range of movement assessment, and a numerical patient satisfaction score. Follow-up radiographs were evaluated by 2 reviewers assessing for lucency and assigned a Lazarus grade. RESULTS: Six patients were lost to follow-up prior to their 2-year review. At last follow-up, the mean forward elevation was 157° (80°-180°), abduction was 150° (60°-180°), and external rotation was 39° (20°-60°). The mode internal rotation was to the lumbar spine, with 95% of patients achieving internal rotation to L5 or higher. The mean Oxford Shoulder Score was 45 (18-48). The mean patient satisfaction score was 4.93/5. No humeral lucencies were observed. Sixty-four percent (n=47) of the glenoids were Lazarus grade 0, showing no evidence of radiolucency. The remaining patients were Lazarus grade 1-3, although none were progressive and all patients were asymptomatic. No patients were revised for aseptic loosening. Four patients underwent revision: 1 for infection, 1 for heterotrophic ossification and stiffness, and 2 for rotator cuff failure. CONCLUSION: Midterm follow-up results indicate good clinical and radiologic survivorship for this stemless TSA. Our findings suggest good patient function and satisfaction, and no patients have required revision for aseptic loosening. Further follow-up is required to determine long-term survivorship.

Emu Oil Improves Clinical Indicators of Disease in a Mouse Model of Colitis-Associated Colorectal Cancer.

BACKGROUND/AIMS: Ulcerative colitis is a remitting and relapsing inflammatory bowel disorder. Current treatments are limited, and if poorly controlled, colitis may progress to colorectal cancer. Previously, Emu Oil protected the intestine in experimental models of gut damage. We aimed to determine whether Emu Oil could reduce the severity of chronic colitis and prevent the onset of neoplasia in a mouse model of colitis-associated colorectal cancer. METHODS: Female C57BL/6 mice were injected (day 0) with azoxymethane, followed by ad libitum access to three dextran sulfate sodium/water cycles (7 days of dextran sulfate sodium and 14 days of water). Mice (n = 9/group) were orally administered either water or Emu Oil (low dose 80 µL or high dose 160 µL), thrice weekly for 9 weeks. Bodyweight and disease activity index were measured daily. Colitis progression was monitored by colonoscopy on days 20, 41 and 62. At killing, tumor number and size were recorded. RESULTS: Azoxymethane/dextran sulfate sodium induced significant bodyweight loss (maximum 24%) which was attenuated by Emu Oil treatment (low dose days 9, 10, 14: maximum 7%; high dose days 7-15, 30-36: maximum 11%; p < 0.05). Emu Oil reduced disease activity index of azoxymethane/dextran sulfate sodium mice at most time points (maximum 20%; p < 0.05). Additionally, Emu Oil reduced colonoscopically assessed colitis severity (days 20 and 62) compared to disease controls (p < 0.05). Finally, in azoxymethane/dextran sulfate sodium mice, low-dose Emu Oil resulted in fewer small colonic tumors (p < 0.05) compared to controls. CONCLUSIONS: Emu Oil improved clinical indicators and reduced severity of colitis-associated colorectal cancer, suggesting therapeutic potential in colitis management.

Assessment Following Distal Radius Fractures: A Comparison of 4 Scoring Systems, Visual Numerical Scales, and Objective Measurements.

PURPOSE: To compare 4 recognized upper-limb scoring systems that are regularly used to assess wrist function after injury. METHODS: We reviewed 116 patients 6 months after volar locking plate fixation for distal radius fractures. Two purely subjective and 2 composite scoring systems composed of both subjective and objective components were compared along with visual numerical scores for pain and function and objective measures of function. Each score was standardized into a scale from 0 to 100. RESULTS: The distribution of the standardized total scores was statistically significantly different and indicated marked variability between scoring systems and therefore the information provided. Overall, the subjective scoring systems correlated well with each other and with both visual numerical scores for pain and function. However, the composite scores and objective measures of function correlated poorly with the subjective scores including the visual numerical scores. CONCLUSIONS: Results from wrist scoring systems should be interpreted with caution. It is important to ensure that the component parts of each score are taken into consideration separately because total scores may be misleading. CLINICAL RELEVANCE: Composite scores may be outdated and should be avoided.

Trial Design and Optimal Determination of CNS Activity of Small Molecule Targeted Therapy in NSCLC.

Central nervous system (CNS) metastases are frequently diagnosed in patients with non-small cell lung cancer (NSCLC). Only recently, clinical trials are broadening eligibility to include patients with brain metastases, offering the potential for some assessment of CNS efficacy to be made. In this work we aim to review the available information on the activity of small molecule targeted drugs for advanced NSCLC with respect to CNS metastases. We analyze a framework for evaluation assessment regarding trials of systemic agents being conducted in patients with, or at risk from, CNS metastases, and provide examples of NSCLC targeted therapies evaluated in the CNS.

Stress shielding of the proximal humerus in stemless anatomic total shoulder arthroplasty.

Background: This study aimed to assess the radiographic proximal humerus bony adaptations to stress shielding and associated clinical outcomes following stemless total shoulder arthroplasty. Methods: A retrospective review of all patients who underwent stemless total shoulder arthroplasty surgery at our centre from 2010 to 2020 was performed. Results: In total, 115 stemless total shoulder arthroplasty utilising a single implant design with a minimum one-year follow-up were identified over a 10-year period. The median follow-up was 3.5 years (range: 1-8.9 years). Evidence of stress shielding was observed in 20 cases (17%), (9 mild (8%), 0 moderate (0%), 11 severe (9%). No significant differences were seen between stress shielding and gender, body mass index, post-operative range-of-motion, patient satisfaction, or Oxford shoulder score. No significant differences were seen between the operative technique and stress shielding. No cases had evidence of humeral lucency. In total, 24 cases (21%) had evidence of glenoid lucency of Lazarus grade 0-3. No cases had Lazarus grades 4 or 5. There was no association between stress shielding and humeral lucency, glenoid lucency, or revision procedure. Discussion: Stress shielding in this study occurred at lower rates than anticipated following stemless total shoulder arthroplasty and was not associated with radiographic evidence of lucency, revision procedures, or adverse effect on clinical outcome measures.

Restoration of the joint geometry after stemless shoulder arthroplasty.

Aim: This study aims to evaluate restoration of anatomy following Total Shoulder Arthroplasty (TSA) with the Mathys Affinis Short prosthesis. Background: Over the last decade stemless shoulder arthroplasty has increased in popularity. One of the reported advantages of the stemless designs is the ability to restore anatomy following surgery. However, very few studies have evaluated restoration of anatomy following stemless shoulder arthroplasty. Methods: The study included all patients who had undergone TSA using the Affinis Short (Mathys Ltd, Bettlach, Switzerland) prosthesis for primary osteoarthritis between 2010 and 2016. The mean follow up was 42.8 months (range 9.4 to 83.4 months). Pre and post-operative radiographs were assessed for Centre of Rotation (COR), Humeral Head Height (HHH), Humeral Head Diameter (HHD), Humeral Height (HH) and, Neck Shaft Angle (NSA) using the best fit circle method on PACS software. Measurements were scored and compared to assess the accuracy of the implant in restoring the native geometry, including the intraobserver variability. The same data was collected by another experienced observer to measure the interobserver variability. Results: The deviation of COR of the prosthesis from the anatomical centre was less than 3 mm in 58 cases (85%). Humeral head height and humeral head diameter showed a variation of less than 3 mm in 66 cases (97%) and 43 cases (63%) respectively. Humeral height followed a similar trend, with 62 cases (91.2%) showing a difference of less than 5 mm. The neck shaft angle showed a variation of more than 8 degrees in 38 cases (55%), and 29 cases (42.6%) had a postoperative angle of less than 130 degrees. Conclusion: Overall, stemless total shoulder arthroplasty with the Affinis Short prosthesis allows excellent restoration of anatomy confirmed by most of the measured radiographic parameters. The variability in neck shaft angle might be due to differing surgical techniques, with some surgeons preferring a slightly vertical neck cut to protect the rotator cuff insertion.

Comparative Effectiveness of First-Line Selpercatinib versus Standard Therapies in Patients with RET-Activated Cancers: An Exploratory Interpatient Analysis of LIBRETTO-001.

Selpercatinib is indicated for locally advanced/metastatic RET-activated solid tumors after progression or following prior systemic therapies. Until the recently published data from LIBRETTO-431 and LIBRETTO-531, there were limited effectiveness data comparing selpercatinib with other first-line treatments in RET-activated non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and thyroid cancer (TC). This study analyzed patient data from LIBRETTO-001 and compared the outcomes (time to treatment discontinuation {TTD}, time to next treatment or death {TTNT-D}, time to progression {TTP}, and the objective response rate {ORR}) of first-line selpercatinib (selpercatinib arm) use with the outcomes of first-line standard therapies in patients who then received selpercatinib in later lines of treatment (comparator arm). Overall, the first-line selpercatinib arm had a longer TTD, TTNT-D, and TTP versus the first-line comparator arm. The hazard ratios (HRs) for TTD were 0.29 (NSCLC), 0.15 (MTC), 0.08 (TC); for TTNT-D, the HRs were 0.48 (NSCLC), 0.11 (MTC), 0.09 (TC); and for TTP, the HRs were 0.54 (NSCLC), 0.15 (MTC), and 0.12 (TC). The ORR was higher for first-line selpercatinib versus the first-line comparator (NSCLC: 85.3% vs. 39.7%; MTC: 82.6% vs. 15.2%; and TC: 81.8% vs. 31.8%). First-line selpercatinib use is associated with improved outcomes compared to first-line comparator therapies for patients with advanced/metastatic RET-activated cancers.

Selpercatinib in Patients With RET Fusion-Positive Non-Small-Cell Lung Cancer: Updated Safety and Efficacy From the Registrational LIBRETTO-001 Phase I/II Trial.

PURPOSE: Selpercatinib, a first-in-class, highly selective, and potent CNS-active RET kinase inhibitor, is currently approved for the treatment of patients with RET fusion-positive non-small-cell lung cancer (NSCLC). We provide a registrational data set update in more than double (n = 316) of the original reported population (n = 144) and better characterization of long-term efficacy and safety. METHODS: Patients were enrolled to LIBRETTO-001, a phase I/II, single-arm, open-label study of selpercatinib in patients with RET-altered cancers. An analysis of patients with RET fusion-positive NSCLC, including 69 treatment-naive and 247 with prior platinum-based chemotherapy, was performed. The primary end point was objective response rate (ORR; RECIST v1.1, independent review committee). Secondary end points included duration of response (DoR), progression-free survival (PFS), overall survival, and safety. RESULTS: In treatment-naive patients, the ORR was 84% (95% CI, 73 to 92); 6% achieved complete responses (CRs). The median DoR was 20.2 months (95% CI, 13.0 to could not be evaluated); 40% of responses were ongoing at the data cutoff (median follow-up of 20.3 months). The median PFS was 22.0 months; 35% of patients were alive and progression-free at the data cutoff (median follow-up of 21.9 months). In platinum-based chemotherapy pretreated patients, the ORR was 61% (95% CI, 55 to 67); 7% achieved CRs. The median DoR was 28.6 months (95% CI, 20.4 to could not be evaluated); 49% of responses were ongoing (median follow-up of 21.2 months). The median PFS was 24.9 months; 38% of patients were alive and progression-free (median follow-up of 24.7 months). Of 26 patients with measurable baseline CNS metastasis by the independent review committee, the intracranial ORR was 85% (95% CI, 65 to 96); 27% were CRs. In the full safety population (n = 796), the median treatment duration was 36.1 months. The safety profile of selpercatinib was consistent with previous reports. CONCLUSION: In a large cohort with extended follow-up, selpercatinib continued to demonstrate durable and robust responses, including intracranial activity, in previously treated and treatment-naive patients with RET fusion-positive NSCLC.

In vivo temperature measurement in the subacromial bursa during arthroscopic subacromial decompression.

BACKGROUND: The purpose of the study was to evaluate whether use of a bi-polar radiofrequency (RF) ablation wand would cause excess heating, which may lead to collateral damage to the surrounding tissues during arthroscopic subacromial decompression. Cadaveric studies have shown that high temperatures can potentially be reached when using RF ablation wands in arthroscopic shoulder surgery. Only 1 other published study assesses these temperature rises in the clinical setting. METHODS: Fifteen patients were recruited to participate in the study. A standard arthroscopic subacromial decompression was performed using continuous flow irrigation, with intermittent use of the RF ablation wand for soft tissue debridement. The temperature of the irrigation fluid within the subacromial bursa and the outflow fluid from the suction port of the wand were measured during the procedure using fiber-optic thermometers. RESULTS: The mean peak temperature recorded in the subacromial bursa was 32.0°C (29.3-43.1°C), with a mean rise from baseline of 9.8°C. The mean peak temperature recorded from the outflow fluid from the wand was 71.6°C (65.6-77.6°C), with a mean rise from baseline of 49.4°C. CONCLUSION: High temperatures were noted in the outflow fluid from the wand; however, this was not evident in the subacromial bursa itself. Use of room temperature inflow fluid, maintenance of flow through the bursa, and avoidance of prolonged uninterrupted use of the wand all appear to ensure that safe temperatures are maintained in the subacromial bursa not only in the laboratory but also in a clinical setting.

Operative versus non-operative treatment of humeral shaft fractures: A systematic review.

BACKGROUND: Humeral shaft fractures are common but debate still occurs as to whether these are best managed operatively or non-operatively. We sought to undertake a systematic review and meta-analysis of randomised and non-randomised studies to clarify the optimal treatment. METHODS: We performed a search for all randomised and non-randomised comparative studies on humeral shaft fracture. We included only those with an operative and non-operative cohort in adult patients. We undertook a meta-analysis of the following outcome measures: nonunion, malunion, delayed union, iatrogenic nerve injury and infection. Non-operative management was with a functional brace. RESULTS: Non-operative management resulted in a significantly higher nonunion rate of 17.6% compared to 6.3% with fixation. Operative management had a significantly higher iatrogenic nerve injury rate of 3.4% and infection rate of 3.7%. All nonunions within the included studies went on to union after plate fixation. There was no significant difference in delayed union or patient reported outcome measures. There was a significantly increased risk of malunion with non-operative treatment however this did not correlate with the outcome. DISCUSSION: Our findings suggest that in the majority of cases, humeral shaft fractures can be managed with non-operative treatment, and any subsequent nonunion should be treated with plate fixation.

Treatment Patterns and Healthcare Resource Utilization among Patients with Advanced or Metastatic Soft Tissue Sarcoma in US Community Practices.

INTRODUCTION: This study was designed to describe demographic and clinical characteristics of patients diagnosed with advanced or metastatic soft tissue sarcoma (STS) and to examine treatment and healthcare resource utilization patterns of this patient population in a United States (US) community-based oncology practice setting over time. METHODS AND MATERIALS: A retrospective observational study was conducted within the US Oncology Network (USON). Patients were eligible if they were diagnosed with advanced or metastatic STS and were treated at a USON site between 01 July 2015 and 31 August 2018. Demographic, clinical, and treatment characteristics were described for the overall study population. Comparisons between patients by time period (prior to and after October 2016) were evaluated using the T test for continuous variables and chi-squared test for categorical variables. Data were available for analysis through 31 August 2018. RESULTS: Demographic and clinical characteristics of the eligible study cohort (N = 376) were similar between patients who initiated treatment before and after October 2016 (all p > 0.05). Forty-three unique regimens were observed in the first-line setting, with the predominant regimen (gemcitabine + docetaxel) received by 33.2% (n = 125) patients. Prior to October 2016, 45.4% of patients received first-line gemcitabine + docetaxel, while 29.0% received this regimen after October 2016. CONCLUSIONS: While demographic and clinical characteristics were similar, treatment patterns changed in 2016. Future research should evaluate the impact of changing drug approvals and clinical trial results on future treatment patterns.

Relationship between Progression-free Survival and Overall Survival in Randomized Clinical Trials of Targeted and Biologic Agents in Oncology.

Introduction: With a gap in a full understanding of the mechanisms by which survival is extended for patients with cancer who are treated with novel biologic and targeted agents, there is the risk that discordant progression-free and overall survival outcomes are observed due to poor clinical trial design or biases in the interpretation of data. This study was designed to examine the role of study quality and design on the outcomes observed with biologic and targeted agents. Methods: A review of studies in clinicaltrials.gov supplemented with a literature review in OVID Medline was conducted to identify all randomized trials of a biologic/targeted agent versus a non-biologic/targeted comparator in oncology that report both median overall and progression-free survival outcomes. Details of the study, design, population, drugs, and outcomes were extracted. Study quality was evaluated using the PEDro scale. Data were summarized using SPSS 22.0.0.0. Results: A total of 192 unique studies of 206 pairwise comparisons between a biologic/targeted and comparator were identified. The average absolute magnitude of post-progression survival (difference between OS and PFS) was 9.7 months for biologic/targeted therapy and 9.8 for the comparator. A total of 64 comparisons (31.1%) showed an increase in OS and decrease in PFS, or vice versa, and 25 (12.1%) showed a magnitude of more than 4 months difference between the delta of OS and delta of PFS between the biologic/targeted and comparator arms. Average study quality was high overall (7.7/10), and was comparable for studies with directional differences (7.2/10) as well as for those with the greatest magnitude in post-progression survival (7.4/10). Conclusion: This review and analysis specifically examined small PFS benefit with large OS benefit as well as small OS benefit with large PFS benefit, including differences in direction of PFS and OS outcomes. No evidence was identified that these are the result of poor study design, but may rather be due to the mechanism of action, specific disease, and population under study. Further work is needed to understand the mechanism of action of novel biologic/targeted agents to better understand their interaction with the tumor microenvironment.

Simultaneous bilateral hip fractures following a simple fall in an elderly patient: A case report.

Bilateral fractured necks of femur are rare, particularly in the absence of high energy trauma or metabolic bone disease. We describe a case of an 89 year old man with no history of metabolic bone disease who presented with bilateral neck of femur fractures following a simple fall. Clinicians must be vigilant to ensure that bilateral neck of femur fractures are identified and treated appropriately.

Incidence and Management of Olaratumab Infusion-Related Reactions.

PURPOSE: Olaratumab is a human monoclonal immunoglobulin G1 antibody against platelet-derived growth factor receptor-α. We report the nature and frequency of infusion-related reactions (IRRs) with olaratumab in clinical trials and postmarketing reports. METHODS: Data from patients exposed to olaratumab across nine clinical trials were reviewed for IRRs. Blood samples were also analyzed for pre-existing immunoglobulin E anti-galactose-α-1,3-galactose (anti-α-Gal) antibodies. RESULTS: In the clinical trials, IRRs were identified in 70 of 485 patients (14.4%). The most frequent symptoms included flushing, fever or chills, and dyspnea. For 68 of 70 patients (97.1%), the first IRR occurred during the first two cycles of treatment. Grade 3 or worse IRRs were reported in 11 patients (2.3%), all during the first infusion and usually within 15 minutes of the start of the infusion. One IRR-related fatality (0.2%) occurred in a nonpremedicated patient with grade 3 or worse cardiac comorbidities. There was an association between grade 3 or worse IRRs and pre-existing anti-α-Gal antibodies, with a trend toward higher IRR rates in US geographies known to have a higher prevalence of anti-α-Gal antibodies. IRRs in postmarketing reports were consistent in nature and severity with those in the clinical trials. CONCLUSION: Premedication with corticosteroids and antihistamines should occur in all patients before olaratumab infusion, as indicated in labels in the United States and the European Union. Patients receiving olaratumab should be monitored for IRRs in a setting where resuscitation equipment is available for the treatment of IRRs.

Characterization of pancreatic ductal cells in human islet preparations.

Substantial amounts of nonendocrine cells are implanted as part of human islet grafts, and a possible influence of nonendocrine cells on clinical islet transplantation outcome has been postulated. There are currently no product release criteria specific for nonendocrine cells due to lack of available methods. The aims of this study were to develop a method for the evaluation of pancreatic ductal cells (PDCs) for clinical islet transplantation and to characterize them regarding phenotype, viability, and function. We assessed 161 human islet preparations using laser scanning cytometry (LSC/iCys) for phenotypic analysis of nonendocrine cells and flow cytometry (FACS) for PDC viability. PDC and beta-cells obtained from different density fractions during the islet cell purification were compared in terms of viability. Furthermore, we examined PDC ability to produce proinflammatory cytokines/chemokines, vascular endothelial growth factor (VEGF) and tissue factor (TF) relevant to islet graft outcome. Phenotypic analysis by LSC/iCys indicated that single staining for CK19 or CA19-9 was not enough for identifying PDCs, and that double staining for amylase and CK19 or CA19-9 allowed for quantitative evaluation of acinar cells and PDC content in human islet preparation. PDC showed a significantly higher viability than beta-cells (PDC vs beta-cell: 75.5+/-13.9 and 62.7+/-18.7%; P<0.0001). Although beta-cell viability was independent of its density, that of PDCs was higher as the density from which they were recovered increased. There was no correlation between PDCs and beta-cell viability (R(2)=0.0078). PDCs sorted from high-density fractions produced significantly higher amounts of proinflammatory mediators and VEGF, but not TF. We conclude that PDCs isolated from different fractions had different viability and functions. The precise characterization and assessment of these cells in addition to beta-cells in human islet cell products may be of assistance in understanding their contribution to islet engraftment and in developing strategies to enhance islet graft function.

Anti-proinflammatory effects of sirolimus on human islet preparations.

BACKGROUND: Sirolimus plays a critical role in facilitating steroid-free immunosuppression, in conjunction with low dose tacrolimus, in current islet transplantation. Although several studies have investigated the effects of sirolimus on islet cells, conflicting results have been reported. In this study, we assessed the effects of sirolimus supplementation in culture media on human islet preparations, focusing on the anti-proinflammatory aspects. METHODS: Human islet preparations were divided into four groups: pure (purity >90%) sirolimus (30 ng/mL); pure control (0 ng/mL); impure (purity 40%-60%) sirolimus; and impure control. All groups were cultured for 3 days and assessed regarding glucose stimulated insulin release, fractional beta-cell viability, beta-cell, and macrophage content. Cytokine and chemokine production from islet preparations and sorted pancreatic ductal cells were also examined. RESULTS: Stimulated insulin release in the impure sirolimus group was significantly increased (P=0.024), as previously reported. Although fractional beta-cell viability showed no significant differences, beta-cell survival during culture significantly increased in impure sirolimus group when compared with the impure control group (P=0.015). Tumor necrosis factor-alpha, interleukin-1beta, monocyte chemotactic protein-1, and macrophage inflammatory protein-1beta production from the impure sirolimus group significantly decreased (P<0.05). Furthermore, tumor necrosis factor-alpha and macrophage inflammatory protein-1beta production from sorted ductal cells significantly decreased in the sirolimus group (P<0.05). The number of macrophages contained in islet preparations significantly decreased in the impure sirolimus group when compared with the impure control group (P<0.05). CONCLUSIONS: Sirolimus improved not only stimulated insulin release, but also beta-cell survival during culture. The antiinflammatory effects of sirolimus also appear beneficial to islet cells in culture and may be a useful strategy in improving islet transplantation outcomes.

Open release versus radiofrequency microtenotomy in the treatment of lateral epicondylitis: a prospective randomized controlled trial.

BACKGROUND: Optimal surgical treatment of lateral epicondylitis remains uncertain. Recently, radiofrequency microtenotomy (RFMT) has been proposed as a suitable treatment. We compared RFMT with standard open release (OR) in this prospective randomized controlled trial. METHODS: In total, 41 patients with symptoms for at least 6 months were randomized into two groups: 23 patients had RFMT and 18 had OR. Two patients from RFMT withdrew. Each patient underwent Numerical Rating Scale (NRS) pain score, grip strength and Disabilities of the Arm, Shoulder and Hand (DASH) scores pre-operatively and at 6 weeks. Pain and DASH scores were repeated at 6 months and 12 months. RESULTS: NRS pain scores improved by 4.8 points for RFMT and by 3.9 points for OR. There was a significant improvement in both groups from pre-operative scores, although there was no statistically significant difference between the groups at 1 year. Grip strength improved by 31% in the RFMT group compared to 38% in OR. There was no significant difference between the initial and 6 weeks scores or between treatments. At 1 year, DASH was 39.8 points for RFMT and 24.4 points for OR. There was a significant improvement in both groups from pre-operative scores, although there was no statistically significant difference between the groups at 1 year. CONCLUSIONS: Both groups showed significant improvements and similar benefit to the patient. The results of the present study do not show any benefit of RFMT over the standard OR. As a result of the extra expense of RFMT, we therefore recommend that OR is offered as the standard surgical management.

Pemetrexed With Platinum Combination as a Backbone for Targeted Therapy in Non-Small-Cell Lung Cancer.

Standard platinum-based chemotherapy combinations for advanced non-small-cell lung cancer (NSCLC) have reached a plateau in terms of the survival benefit they offer for patients. In addition, the emerging clinical trend of tailored treatment based on patient characteristics has led to the development of therapeutic strategies that target specific cancer-related molecular pathways, including epidermal growth factor receptor (EGFR), angiogenesis, and anaplastic lymphoma kinase inhibitors. Current research is focused on combining targeted therapy with platinum-based chemotherapy in an endeavor to achieve an additional benefit in specific patient populations. Currently, pemetrexed is indicated for use in the first-line, maintenance, and second-line settings for the treatment of nonsquamous NSCLC. The combination of pemetrexed and cisplatin is well tolerated and is the approved standard first-line therapy. Thus, the pemetrexed-platinum backbone provides an attractive option for combination with targeted therapies. This review aims to summarize the current knowledge and future prospects of the use of pemetrexed-platinum as a backbone for combination with targeted therapies for NSCLC.

Ultrasound-guided platelet-rich plasma injection for distal biceps tendinopathy.

BACKGROUND: Distal biceps tendinopathy is an uncommon cause of elbow pain. The optimum treatment for cases refractory to conservative treatment is unclear. Platelet-rich plasma has been used successfully for other tendinopathies around the elbow. METHODS: Six patients with clinical and radiological evidence of distal biceps tendinopathy underwent ultrasound-guided platelet-rich plasma (PRP) injection. Clinical examination findings, visual analogue score (VAS) for pain and Mayo Elbow Performance scores were recorded. RESULTS: The Mayo Elbow Performance Score improved from 68.3 (range 65 to 85) (fair function) to 95 (range 85 to 100) (excellent function). The VAS at rest improved from a mean of 2.25 (range 2 to 5) pre-injection to 0. The VAS with movement improved from a mean of 7.25 (range 5 to 8) pre-injection to 1.3 (range 0 to 2). No complications were noted. DISCUSSION: Ultrasound-guided PRP injection appears to be a safe and effective treatment for recalcitrant cases of distal biceps tendinopathy. Further investigation with a randomized controlled trial is needed to fully assess its efficacy.