A Randomized Trial of Autologous Chondrocyte Implantation Versus Alternative Forms of Surgical Cartilage Management in Patients With a Failed Primary Treatment for Chondral or Osteochondral Defects in the Knee.

BACKGROUND: There are limited randomized controlled trials with long-term outcomes comparing autologous chondrocyte implantation (ACI) versus alternative forms of surgical cartilage management within the knee. PURPOSE: To determine at 5 years after surgery whether ACI was superior to alternative forms of cartilage management in patients after a failed previous treatment for chondral or osteochondral defects in the knee. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: In total, 390 participants were randomly assigned to receive either ACI or alternative management. Patients aged 18 to 55 years with one or two symptomatic cartilage defects who had failed 1 previous therapeutic surgical procedure in excess of 6 months prior were included. Dual primary outcome measures were used: (1) patient-completed Lysholm knee score and (2) time from surgery to cessation of treatment benefit. Secondary outcome measures included International Knee Documentation Committee and Cincinnati Knee Rating System scores, as well as number of serious adverse events. Analysis was performed on an intention-to-treat basis. RESULTS: Lysholm scores were improved by 1 year in both groups (15.4 points [95% CI, 11.9 to 18.8] and 15.2 points [95% CI, 11.6 to 18.9]) for ACI and alternative, with this improvement sustained over the duration of the trial. However, no evidence of a difference was found between the groups at 5 years (2.9 points; 95% CI, -1.8 to 7.5; P = .46). Approximately half of the participants (55%; 95% CI, 47% to 64% with ACI) were still experiencing benefit at 5 years, with time to cessation of treatment benefit similar in both groups (hazard ratio, 0.97; 95% CI, 0.72 to 1.32; P > .99). There was a differential effect on Lysholm scores in patients without previous marrow stimulation compared with those with marrow stimulation (P = .03; 6.4 points in favor of ACI; 95% CI, -0.4 to 13.1). More participants experienced a serious adverse event with ACI (P = .02). CONCLUSION: Over 5 years, there was no evidence of a difference in Lysholm scores between ACI and alternative management in patients who had previously failed treatment. Previous marrow stimulation had a detrimental effect on the outcome of ACI. REGISTRATION: International Standard Randomised Controlled Trial Number: 48911177.

Unique features of vaccine-induced immune thrombotic thrombocytopenia; a new anti-platelet factor 4 antibody-mediated disorder.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a highly prothrombotic disorder caused by anti-PF4 antibodies that activate platelets and neutrophils, leading to thrombosis. Heparin-induced thrombocytopenia (HIT) is a related anti-PF4 mediated disorder, with similar pathophysiology and clinical manifestations but different triggers (i.e., heparin vs adenoviral vector vaccine). Clinically, both HIT and VITT typically present with thrombocytopenia and thrombosis, although the risk of thrombosis is significantly higher in VITT, and the thromboses occur in unusual anatomical sites (e.g., cerebral venous sinus thrombosis and hepatic vein thrombosis). The diagnostic accuracy of available laboratory testing differs between HIT and VITT; for VITT, ELISAs have better specificity compared to HIT and platelet activation assays require the addition of PF4. Treatment of VITT and HIT is anticoagulation non-heparin anticoagulants; however, heparin may be considered for VITT if no other option is available.

Anemia-Induced Bleeding in Patients with Platelet Disorders.

Anemia is not only a consequence of bleeding, but also a modifiable risk factor for bleeding in patients with thrombocytopenia or platelet function defects. In this review we outline the mechanism of anemia-induced bleeding in patients with platelet disorders, which involves a disturbance in normal red blood cell (RBC) rheology and reduced platelet margination to the endothelial surface due to a decrease in RBC mass, leading to impaired primary hemostasis and bleeding. Biologically, anemia reduces the mass of RBCs in the central column of flowing blood through a vessel resulting in fewer platelets coming into contact with the endothelial surface at the periphery of the flowing blood column. Thus, anemia results in impaired primary hemostasis. Von Willebrand factor (vWF) is another component of primary hemostasis and vWF deficiency, especially a deficiency of the highest vWF multimers, can also manifest with bleeding when concomitant anemia occurs. Clinically, patients at greatest risk for anemia-induced bleeding include patients with hematological malignancies in whom anemia and thrombocytopenia occur as a result of the underlying disease or the myelotoxic effects of treatment; patients with renal insufficiency with uremic thrombocytopathy and hypoproliferative anemia; and patients with inherited or acquired bleeding disorders affecting primary hemostasis (eg, Bernard-Soulier syndrome, von Willebrand disease) with chronic blood loss and iron deficiency anemia. Underlying abnormalities of any components of primary hemostasis plus concomitant anemia may result in major bleeding disorders; therefore, correction of remediable abnormalities-most notably, correction of the anemia- would be expected to have important clinical benefit. In this review we discuss how the correction of the anemia may lead to improvement of bleeding outcomes in patients with a primary hemostatic defect, supported by evidence from animal models, clinical trials and clinical experience.

Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: The interim analysis of the multicentre New EPOC trial in patients with resectable colorectal liver metastasis showed a significant reduction in progression-free survival in patients allocated to cetuximab plus chemotherapy compared with those given chemotherapy alone. The focus of the present analysis was to assess the effect on overall survival. METHODS: New EPOC was a multicentre, open-label, randomised, controlled, phase 3 trial. Adult patients (aged ≥18 years) with KRAS wild-type (codons 12, 13, and 61) resectable or suboptimally resectable colorectal liver metastases and a WHO performance status of 0-2 were randomly assigned (1:1) to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done centrally with minimisation factors of surgical centre, poor prognosis cancer, and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m2 administered intravenously over 2 h, l-folinic acid (175 mg flat dose administered intravenously over 2 h) or d,l-folinic acid (350 mg flat dose administered intravenously over 2 h), and fluorouracil bolus 400 mg/m2 administered intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m2 repeated every 2 weeks (regimen one), or oxaliplatin 130 mg/m2 administered intravenously over 2 h and oral capecitabine 1000 mg/m2 twice daily on days 1-14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m2 intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given intravenously, 500 mg/m2 every 2 weeks with regimen one and three or a loading dose of 400 mg/m2 followed by a weekly infusion of 250 mg/m2 with regimen two. The primary endpoint of progression-free survival was published previously. Secondary endpoints were overall survival, preoperative response, pathological resection status, and safety. Trial recruitment was halted prematurely on the advice of the Trial Steering Committee on Nov 1, 2012. All analyses (except safety) were done on the intention-to-treat population. Safety analyses included all randomly assigned patients. This trial is registered with ISRCTN, number 22944367. FINDINGS: Between Feb 26, 2007, and Oct 12, 2012, 257 eligible patients were randomly assigned to chemotherapy with cetuximab (n=129) or without cetuximab (n=128). This analysis was carried out 5 years after the last patient was recruited, as defined in the protocol, at a median follow-up of 66·7 months (IQR 58·0-77·5). Median progression-free survival was 22·2 months (95% CI 18·3-26·8) in the chemotherapy alone group and 15·5 months (13·8-19·0) in the chemotherapy plus cetuximab group (hazard ratio [HR] 1·17, 95% CI 0·87-1·56; p=0·304). Median overall survival was 81·0 months (59·6 to not reached) in the chemotherapy alone group and 55·4 months (43·5-71·5) in the chemotherapy plus cetuximab group (HR 1·45, 1·02-2·05; p=0·036). There was no significant difference in the secondary outcomes of preoperative response or pathological resection status between groups. Five deaths might have been treatment-related (one in the chemotherapy alone group and four in the chemotherapy plus cetuximab group). The most common grade 3-4 adverse events reported were: neutrophil count decreased (26 [19%] of 134 in the chemotherapy alone group vs 21 [15%] of 137 in the chemotherapy plus cetuximab group), diarrhoea (13 [10%] vs 14 [10%]), skin rash (one [1%] vs 22 [16%]), thromboembolic events (ten [7%] vs 11 [8%]), lethargy (ten [7%] vs nine [7%]), oral mucositis (three [2%] vs 14 [10%]), vomiting (seven [5%] vs seven [5%]), peripheral neuropathy (eight [6%] vs five [4%]), and pain (six [4%] vs six [4%]). INTERPRETATION: Although the addition of cetuximab to chemotherapy improves the overall survival in some studies in patients with advanced, inoperable metastatic disease, its use in the perioperative setting in patients with operable disease confers a significant disadvantage in terms of overall survival. Cetuximab should not be used in this setting. FUNDING: Cancer Research UK.

Protocol for the melatools skin self-monitoring trial: a phase II randomised controlled trial of an intervention for primary care patients at higher risk of melanoma.

INTRODUCTION: Melanoma is the fifth most common cancer in the UK. Incidence rates have quadrupled over the last 30 years and continue to rise, especially among younger people. As routine screening of the general population is not currently recommended in the UK, a focus on secondary prevention through early detection and prompt treatment in individuals at increased risk of melanoma could make an important contribution to improve melanoma outcomes. This paper describes the protocol for a phase II, multisite, randomised controlled trial, in the primary care setting, for patients at increased risk of melanoma. A skin self-monitoring (SSM) smartphone 'App' was used to improve symptom appraisal and encourage help seeking in primary care, thereby promoting early presentation with skin changes suspicious of melanoma. METHODS AND ANALYSIS: We aim to recruit 200 participants from general practice waiting rooms in the East of England. Eligible patients are those identified at higher melanoma risk (using a real-time risk assessment tool), without a personal history of melanoma, aged 18 to 75 years. Participants will be invited to a primary care nurse consultation, and randomised to the intervention group (standard written advice on skin cancer detection and sun protection, loading of an SSM 'App' onto the participant's smartphone and instructions on use including self-monitoring reminders) or control group (standard written advice alone). The primary outcomes are consultation rates for changes to a pigmented skin lesion, and the patient interval (time from first noticing a skin change to consultation). Secondary outcomes include patient sun protection behaviours, psychosocial outcomes, and measures of trial feasibility and acceptability. ETHICS AND DISSEMINATION: NHS ethical approval has been obtained from Cambridgeshire and Hertfordshire research ethics committee (REC reference 16/EE/0248). The findings from the MelaTools SSM Trial will be disseminated widely through peer-reviewed publications and scientific conferences. TRIAL REGISTRATION NUMBER: ISCTRN16061621.

A prospective determination of the incidence of perceived inappropriate care in critically ill patients.

BACKGROUND: Health care providers' perceptions regarding appropriateness in end-of-life treatments have been widely studied. While nurses and physicians believe that rationing and other cost-related practices sometimes occur in the intensive care unit (ICU), they allege that treatment is often excessive. OBJECTIVE: To prospectively determine the incidence and causes of health care providers' perceptions regarding appropriateness of end-of-life treatments. METHODS: The present prospective study collected data from patients admitted to the medical-surgical trauma ICU of a 30-bed, Canadian teaching hospital over a three-month period. Daily surveys were completed independently by bedside nurses, charge nurses and attending physician. RESULTS: In total, 5224 of 6558 expected surveys (representing 294 patients) were analyzed, yielding a response rate of 79.7%. The incidence of perceived inappropriate care in the present study was 6.5% (19 of 294 patients), with ongoing treatment for >2 days after this determination occurring in 1% (three of 294 patients). However, at least one caregiver perceived inappropriate care at some point in 110 of 294 (37.5%) patients. In these cases, in which processes to address care were not already underway, respondents believed that important issues resulting in provision of inappropriate treatments included patient-family issues and communication before or in the ICU. Caregivers did not know their patients' wishes 22% (1129 of 5224) of the time. CONCLUSIONS: Although ongoing inappropriate care appeared to be a rare occurrence, the issue was a concern to at least one caregiver in one-third of cases. Public awareness for end-of-life issues, adequate communication, and up-to-date knowledge and practice in determining the wishes of critically ill patients are potential target areas to improve end-of-life care and reduce inappropriate care in the ICU. A daily, prospective survey of multidisciplinary caregivers, such as the survey used in the present study, is a viable and valuable means of determining the scope and causes of inappropriate care in the ICU.

The natural history of a bioabsorbable interference screw used for anterior cruciate ligament reconstruction with a 4-strand hamstring technique.

PURPOSE: The purpose of this study was to assess radiologically the rate of absorption of the Arthrex poly L-lactide bioabsorbable interference screw (Arthrex, Naples, FL) used in anterior cruciate ligament reconstruction with a 4-strand hamstring technique. TYPE OF STUDY: Case series. METHODS: Eight sequential patients undergoing anterior cruciate ligament reconstruction with a 4-strand hamstring technique were assessed with magnetic resonance imaging (MRI) scans at 1, 2, and 4 years postoperatively. RESULTS: There was no radiologic evidence of absorption of the screw on any of the scans. The MRI appearance remained essentially unchanged from 1 to 4 years with the exception of the presence of a small cyst in the tibial tunnel of one of the patients. No edema was seen associated with the tibial tunnel in any of our patients. CONCLUSIONS: There are several quoted theoretical advantages to using bioabsorbable screws. The rate of absorption is dependent on material, weight, and degree of crystallization. In our series using an amorphous low crystallization poly L-lactide screw, there was no evidence of any progression to absorption 4 years after implantation. This may be because all series quoted to date look at absorption using a bone-patellar tendon-bone graft. LEVEL OF EVIDENCE: Level IV.

Alternative routes to healing in Bangladesh.

The mission to find 'the secret of the village' is one attraction of engaging in mental health services in Bangladesh. Over the last 15 years much attention in world psychiatry has been given to the fairly robust finding that the prognosis of people with established and severe mental illness is better in 'developing countries' than in 'developed' ones (e.g. World Health Organization, 1979; Leff et al, 1990; Jablensky et al, 1992). Earlier assumptions that 'developing' is a simple variable were almost certainly a result of racist ignorance (Kulhara, 1994). Developing countries are not homogeneous. The variation in mental health outcomes seems to be clearer in more remote villages and tribal areas (Chatterjee et al, 2003), especially those that have less contact with Western (colonial) models of psychiatry and ways of life. More studies on this topic across a wider range of rural and urban settings would have much to offer. Is there something poisonous that comes with lots of expensive services? Or is there something missing?