Alteration of anterior cruciate ligament orientation in knees with trochlear dysplasia: description of a novel angle on MRI.

AIM: To assess changes in anterior cruciate ligament (ACL) geometry and inclination in trochlear dysplasia (TD) and analyse their significance. MATERIALS AND METHODS: Ninety-nine consecutive knees with TD and 23 normal knee magnetic resonance imaging (MRI) examinations were included as controls (n=122). Varying degrees of TD were classified into four distinct groups (A-D) according to the Dejour classification. MRI images were reviewed independently to measure four ACL angles. Interobserver and intra-observer agreements with statistical significance were determined for TD and various angles. RESULTS: A significant association was found between TD and two measured angles compared with the control group (sagittal ACL and anteromedial ACL angles, p<0.001 for each). The results indicate that TD can predispose to more vertical ACL inclination as measured in the coronal plane on MRI. No association was found with the Blumenstat angle. CONCLUSION: The present study found significant associations with TD and steeper sagittal ACL, which have been implicated in ACL failure. A novel angle (anteromedial ACL angle) is described which has significant association with TD and is specific for the anteromedial bundle as measured in the coronal plane. Careful consideration of ACL fibre orientation in the coronal plane on MRI is suggested in knees with TD and the use of this newly described angle in assessing ACL reconstruction (ACLR) grafts.

In vitro simulation and quantification of wear within the patellofemoral joint replacement.

Quantification of the wear rate in vitro is now considered an essential step in the development of a new joint replacement prior to clinical trials. However, little research exists around in vitro simulation of wear in the patellofemoral joint (PFJ) despite over 200,000 being implanted annually within the European Union. A method to simulate wear in the laboratory using four input degrees of freedom within the PFJ of total knee replacement (TKR) has been developed. Wear simulation was validated through comparison of functional kinematics and patellar surface damage modes produced in vitro to clinical outcomes. The technique has been shown to replicate the prescribed in vivo kinematics in a reproducible and repeatable manner. The wear scar areas were similar to those found in vivo. However, geometrical measurements of wear were not reliable due to creep and geometry changes. As has been found previously with tibial inserts, geometrical determination of wear volume was not found to be an effective method of comparing wear from simulators and retrievals. Change in volume calculated gravimetrically was seen to be the most repeatable measure of patellar wear in vitro.

Axillary artery injury secondary to displaced proximal humeral fractures: a report of two cases.

We report 2 cases of axillary artery injury secondary to low-energy proximal humeral fractures. In case 1, early diagnosis based on signs of acute ischaemia of the arm enabled early treatment and a favourable outcome. In case 2, there were no signs of ischaemia or neurological deficit, resulting in delayed diagnosis and increased severity of the injury. The patient developed a false aneurysm and sepsis and eventually died. A high index of suspicion is necessary for diagnosing an axillary artery injury. We recommend that all patients with proximal humeral fractures with severe medial displacement of the shaft and a bone spike should routinely undergo Doppler ultrasound scanning to rule out vascular injuries and the presence of a false aneurysm.

Continuous Hyperfractionated Accelerated Radiotherapy (CHART) for Non-small Cell Lung Cancer (NSCLC): 7 Years' Experience From Nine UK Centres.

AIM: Continuous hyperfractionated accelerated radiotherapy (CHART) remains an option to treat non-small cell lung cancer (NSCLC; NICE, 2011). We have previously published treatment outcomes from 1998-2003 across five UK centres. Here we update the UK CHART experience, reporting outcomes and toxicities for patients treated between 2003 and 2009. MATERIALS AND METHODS: UK CHART centres were invited to participate in a retrospective data analysis of NSCLC patients treated with CHART from 2003 to 2009. Nine (of 14) centres were able to submit their data into a standard database. The Kaplan-Meier method estimated survival and the Log-rank test analysed the significance. RESULTS: In total, 849 patients had CHART treatment, with a median age of 71 years (range 31-91), 534 (63%) were men, 55% had undergone positron emission tomography-computed tomography (PET-CT) and 26% had prior chemotherapy; 839 (99%) patients received all the prescribed treatment. The median overall survival was 22 months with 2 and 3 year survival of 47% and 32%, respectively. Statistically significant differences in survival were noted for stage IA versus IB (33.2 months versus 25 months; P = 0.032) and IIIA versus IIIB (20 months versus 16 months; P = 0.018). Response at 3 months and outcomes were significantly linked; complete response showing survival of 34 months against 19 months, 15 months and 8 months for partial response, stable and progressive disease, respectively (P < 0.001). Age, gender, performance status, prior chemotherapy and PET-CT did not affect the survival outcomes. Treatment was well tolerated with <5% reporting ≥grade 3 toxicity. CONCLUSION: In routine practice, CHART results for NSCLC remain encouraging and we have been able to show an improvement in survival compared with the original trial cohort. We have confirmed that CHART remains deliverable with low toxicity rates and we are taking a dose-escalated CHART regimen forward in a randomised phase II study of sequential chemoradiotherapy against other accelerated dose-escalated schedules.

What impact have NICE guidelines had on the trends of hip arthroplasty since their publication? The results from the Trent Regional Arthroplasty Study between 1990 and 2005.

The National Institute for Clinical Excellence (NICE) published the guidelines on the selection of prostheses for primary hip replacement in 2000. They supported the use of cemented hip prostheses to the exclusion of uncemented and hybrid implants. The information from the Trent (and Wales) Regional Arthroplasty Study has been examined to identify retrospectively the types of hip prostheses used between 1990 and 2005, and to assess the impact that the guidelines have had on orthopaedic practice. The results show that the publication of the NICE guidelines has had little impact on clinical practice, with the use of uncemented prostheses increasing from 6.7% (137) in 2001 to 19.2% (632) in 2005. The use of hybrid prostheses has more than doubled from 8.8% (181) to 22% (722) of all hips implanted in the same period. The recommendations made by NICE are not being followed, which calls into question their value.

A 15-year follow-up study of 4606 primary total knee replacements.

This is a 15-year follow-up observational study of 4390 patients with 4606 primary total knee replacements (TKRs) implanted in the Trent health region between 1990 and 1992. The operations were performed in 21 hospitals, including both district general and teaching hospitals, with 77 different surgeons as named consultant. The main objective was to analyse the survival of the patients and of the prostheses, and to evaluate what impact different variables have on survival. In addition, the 1480 patients (33.7%) (1556 TKRs) alive at 15 years following operation were sent a self-administered questionnaire which examined their level of satisfaction, of pain, and their quality of life at 15 years. Completed responses were received from 912 TKRs (58.6%). Three survival curves were constructed: a best-case scenario based on the patients entered into the life tables, another included failures not reported in the revision database, and a third worst-case scenario based on all patients lost to follow-up presumed to have had a failed primary TKR. In the best-case scenario survival at 15 years was 92.2%, and in the worst-case scenario was 81.1%. Survival was significantly increased in women and older patients (Mantel-Cox log-rank test, p < 0.005 and p < 0.001, respectively). Revision as a result of infection was required in 40 TKRs (18.8%) representing 0.87% of the original cohort. The limited information available from the questionnaire indicated that satisfaction was less frequent among men, patients with osteoarthritis and those who required revision (chi-squared test, p < 0.05, p < 0.05 and p < 0.0001, respectively). With regard to pain, older patients, females and patients who still had their primary replacement in place at 15 years, reported the least pain (chi-squared test for trends, p < 0.0005, p < 0.005 and p < 0.0001, respectively). The reported quality of life was not affected by any variable.

A randomised controlled trial of cemented versus cementless press-fit condylar total knee replacement: 15-year survival analysis.

We report the long-term survival of a prospective randomised consecutive series of 501 primary knee replacements using the press-fit condylar posterior cruciate ligament-retaining prosthesis. Patients received either cemented (219 patients, 277 implants) or cementless (177 patients, 224 implants) fixation. Altogether, 44 of 501 knees (8.8%) underwent revision surgery (24 cemented vs 20 cementless). For cemented knees the 15-year survival rate was 80.7% (95% confidence interval (CI) 71.5 to 87.4) and for cementless knees it was 75.3% (95% CI 63.5 to 84.3). There was no significant difference between the two groups (cemented vs cementless; hazard ratio (HR) 0.83, 95% CI 0.45 to 1.52, p = 0.55). When comparing the covariates there was no significant difference in the rates of survival between the side of operation (HR 0.58, p = 0.07), age (HR 0.97, p = 0.10) and diagnosis (HR 1.25 p = 0.72). However, there was a significant gender difference, with males having a higher failure rate with cemented fixation (HR 2.48, p = 0.004). Females had a similar failure rate in both groups. This single-surgeon series, with no loss to follow-up, provides reliable data of the revision rates of one of the most commonly-used total knee replacements. The survival of the press-fit condylar total knee replacement remained good at 15 years, irrespective of the method of fixation.

Outcome of Charnley total hip replacement across a single health region in England. The results at ten years from a regional arthroplasty register.

Using the Trent regional arthroplasty register, we analysed the survival at ten years of 1198 consecutive Charnley total hip replacements carried out across a single health region of the United Kingdom in 1990. At ten years, information regarding outcome was available for 1001 hips (83.6%). The crude revision rate was 6.2% (62 of 1001) and the cumulative survival rate with revision of the components as an end-point was 93.1%. At five years, a review of this series of patients identified gross radiological failure in 25 total hip replacements which had previously been unrecognised. At ten years the outcome was known for 18 of these 25 patients (72%), of whom 13 had not undergone revision. This is the first study to assess the survival at ten years for the primary Charnley total hip replacement performed in a broad cross-section of hospitals in the United Kingdom, as opposed to specialist centres. Our results highlight the importance of the arthroplasty register in identifying the long-term outcome of hip prostheses.

Extra-abdominal desmoid fibromatosis: A review of management, current guidance and unanswered questions.

Extra abdominal desmoid fibromatosis is a complex condition with many recognised treatments including active observation, hormonal therapy, chemotherapy, radiotherapy and surgical resection. There is large variation in the natural history of individual desmoid tumours, with some cases progressing aggressively and others regressing spontaneously when observed alone. This combined with an absence of accurate clinical predictors of a desmoid tumour's behaviour has led to difficulties in identifying which patients would benefit most from aggressive treatment, and which could be adequately managed with a policy of active observation alone. This review explores the aetiology and common presentation of extra-abdominal desmoid fibromatosis including the condition's histopathological, clinical and radiological characteristics. The current evidence for potential predictors of desmoid tumour behaviour is also reviewed, along with the indications and evidence for the multitude of treatments available. We also summarise the published guidelines that are currently available for oncologists and surgeons managing extra-abdominal desmoid fibromatosis, and highlight some of the unanswered questions that need to be addressed to optimise the management of this condition.

Nationwide trends in the current management of desmoid (aggressive) fibromatosis.

AIMS: The optimal management of desmoid fibromatosis remains unclear, leading to significant variability in patient management. To assess this problem, the current approach of clinicians managing this complex condition in the UK was investigated. MATERIALS AND METHODS: A hypothetical case of intramuscular limb girdle desmoid fibromatosis in a fit 65-year-old patient was devised. Surgical and non-surgical oncology members of the British Sarcoma Group were questioned on how they would manage this case in three scenarios: primary disease with function-sparing surgery possible, primary disease with neurovascular involvement and disease recurrence after a previous R0 resection. Initial management, management of symptomatic disease progression, follow-up preferences and any differences in respondents' management choices in a younger case were investigated. RESULTS: The responses from 14 sarcoma surgeons and 23 oncologists (14 clinical, nine medical) were analysed. Desmoid fibromatosis management is generally shared by surgeons and oncologists within sarcoma multidisciplinary teams in the UK. Variation exists in the chosen initial management of primary desmoid fibromatosis in the UK, with function-sparing surgery possible (observation 51%, resection 51%), primary desmoid fibromatosis with neurovascular involvement (hormone therapy with non-steroidal anti-inflammatory drugs 51%, radiotherapy 27%, observation 22%) and for cases of desmoid fibromatosis recurrence (radiotherapy 41%, hormone therapy and non-steroidal anti-inflammatory drugs 27%, observation 24%). There was a clear preference of surgical resection of symptomatic disease progression in cases of primary desmoid fibromatosis without neurovascular involvement (60%). By contrast, radiotherapy was the preferred treatment for progression in cases with neurovascular involvement (47%) or cases of recurrence after a previous R0 resection (34%). Clinical follow-up was selected 3 months after intervention in 68% of scenarios. Follow-up imaging was selected 3 or 6 months after intervention in 57% and 21% of cases, respectively. Most respondents would not change their chosen management in younger patients. DISCUSSION: Several groups have issued formal guidelines for clinicians managing desmoid fibromatosis, including the British Sarcoma Group, the National Comprehensive Cancer Network and the European Society for Medical Oncology. However, these are in some ways contradictory and may not reflect recent publications, potentially explaining the significant variation in the management of desmoid fibromatosis in the UK shown by this survey. We propose a review of current evidence; a national consensus or a desmoid fibromatosis registry may help to standardise desmoid fibromatosis care.

Synthesis and cytotoxicity of 4-amino-5-oxopyrido[2,3-d]pyrimidine nucleosides.

A number of nucleoside analogues have been either used clinically as anticancer drugs or evaluated in clinical studies, while new nucleoside analogues continue to show promise. In this article, we report synthesis and cytotoxicity of a series of new pyrido[2, 3-d]pyrimidine nucleosides. 2-Amino-3-cyano-4-methoxypyridine was converted, in two steps, to 4-amino-5-oxopyrido[2,3-d]pyrimidine. A variety of 1-O-acetylated pentose sugar derivatives were condensed with silylated 4-amino-5-oxopyrido[2,3-d]pyrimidine, followed by protection, to afford a series of 4-amino-5-oxopyrido[2, 3-d]pyrimidine nucleosides. Further derivatizations provided an additional group of pyrido[2,3-d]pyrimidine nucleosides. These nucleosides were evaluated for in vitro cytotoxicity to human prostate cancer (HTB-81) and mouse melanoma (B16) cells as well as normal human fibroblasts (NHF). A number of compounds (1a,b, 2a-c,f, 3f+4d) showed significant cytotoxicity to cancer cells, with 4-amino-5-oxo-8-(beta-D-ribofuranosyl)pyrido[2,3-d]pyrimidine (1b) being the most potent proliferation inhibitor (EC(50): 0.06-0.08 microM) to all types of cells tested. However, a selective inhibition to the cancer cells was observed for 4-amino-5-oxo-8-(beta-D-xylofuranosyl)pyrido[2,3-d]pyrimidine (2b), which is a potent inhibitor of HTB-81 (EC(50): 0.73 microM) and has a favorable in vitro selectivity index (28).

Reversible inhibition of IL-8 receptor B mRNA expression and proliferation in non-small cell lung cancer by antisense oligonucleotides.

We examined the importance of IL-8 receptor B mRNA expression in the growth of non-small cell lung cancer (NSCLC). Using antisense oligonucleotide ICN 197, we were able to inhibit IL-8 R B mRNA expression in vitro. The sequence specific effect of antisense oligonucleotide and down-regulation of IL-8 R B mRNA was shown by Reverse Transcription Polymerase Chain Reaction (RT-PCR) and Southern blot analysis. The proliferation of treated cells was measured by 3H thymidine incorporation. We found that treatment of NSCLC cells caused reversible growth inhibition and reversible down regulation of IL-8 R B mRNA. Furthermore, we observed that the treatment of nude mice with oligonucleotide ICN 197 inhibited the growth of tumors developed from NSCLC cells injected subcutaneously. Our data in vitro suggest that IL-8 receptor B mRNA expression is required to maintain the proliferative rate of NSCLC. Based on the data in vivo. oligonucleotide ICN 197 may be considered for the development of novel therapeutic treatment for lung cancer.

Frozen shoulder and lipids.

We prospectively studied 50 patients with the diagnosis of primary frozen shoulder. The serum lipid levels were measured in 43 of these patients and compared with those in 43 age-matched and sex-matched control subjects. The fasting serum triglyceride and cholesterol levels were significantly elevated in the frozen-shoulder group (cholesterol p < 0.01; triglyceride p < 0.02).

Microbiological culture results for the femoral head. Are they important to the donor?

We determined the rate of contamination of donated femoral heads at primary hip arthroplasty within a single region between July 1992 and July 2001. We established the null hypothesis that culture results played no role in predicting early failure of the joint because of infection. The rate of contamination was 9%. A positive culture, at the time of retrieval, was found in 367 of 4045 femoral heads. Coagulase-negative staphylococcus was isolated in 77% of the positive cases. At a minimum follow-up of one year, there was no statistically significant difference in the rate of complications or of revision of age-matched patients whose femoral heads had a positive culture compared with those whose femoral heads were sterile. Our findings confirm that culture of the femoral head plays no part in determining future failure of joint replacement in the donor.

The use of a closed-suction drain in total knee arthroplasty. A prospective, randomised study.

We prospectively randomised 100 patients undergoing cemented total knee replacement to receive either a single deep closed-suction drain or no drain. The total blood loss was significantly greater in those with a drain (568 ml versus 119 ml, p < 0.01; 95% CI 360 to 520) although those without lost more blood into the dressings (55 ml versus 119 ml, p < 0.01; 95% CI -70 to 10). There was no statistical difference in the postoperative swelling or pain score, or in the incidence of pyrexia, ecchymosis, time at which flexion was regained or the need for manipulation, or in the incidence of infection at a minimum of five years after surgery in the two groups. We have been unable to provide evidence to support the use of a closed-suction drain in cemented knee arthroplasty. It merely interferes with mobilisation and complicates nursing. Reinfusion drains may, however, prove to be beneficial.

Manipulation of total knee replacements. Is the flexion gained retained?

As part of a prospective study of 476 total knee replacements (TKR), we evaluated the use of manipulation under anaesthesia in 47 knees. Manipulation was considered when intensive physiotherapy failed to increase flexion to more than 80 degrees. The mean time from arthroplasty to manipulation was 11.3 weeks (median 9, range 2 to 41). The mean active flexion before manipulation was 62 degrees (35 to 80). One year later the mean gain was 33 degrees (Wilcoxon signed-rank test, range -5 to 70, 95% CI 28.5 to 38.5). Definite sustained gains in flexion were achieved even when manipulation was performed four or more months after arthroplasty (paired t-test, p < 0.01, CI 8.4 to 31.4). A further 21 patients who met our criteria for manipulation declined the procedure. Despite continued physiotherapy, there was no significant increase in flexion in their knees. Six weeks to one year after TKR, the mean change was 3.1 degrees (paired t-test, p = 0.23, CI -8.1 to +2).

Rotator-cuff tear of the hip.

We describe an apparently unreported finding during hip operations: a tear at the insertion of gluteus medius and gluteus minimus. This defect may well be known to many surgeons with experience of hip replacement and hemiarthroplasty for fractures of the neck of the femur, but a Medline search has failed to find a previous description. We made a prospective study of 50 consecutive patients with fractures of the neck of the femur to quantify the incidence of this condition: 11 (22%) had such a tear.

Synthesis and anticancer activity of 4-amino-5-oxo-8-(beta-D-xylofuranosyl)pyrido[2,3-d]pyrimidine.

4-Amino-5-oxo-8-(beta-D-xylofuranosyl)pyrido[2,3-d]pyrimidine (4) was recently synthesized and evaluated in our laboratories for anticancer activities. This compound showed potent in vitro inhibitory effects on the growth of HTB-81 prostate cancer cells and Daudi-lymphoma. In vivo studies showed that the compound could inhibit HTB-81 tumor growth in syngeneic mice by 93% at a daily dose of 8.5 mg/kg for 10 days.

Inhibition of cell growth and proliferation in human glioma cells and normal human astrocytes induced by 8-Cl-cAMP and tiazofurin.

8-Cl-cAMP and tiazofurin (TR) are anti-tumor agents that besides their antiproliferative effect, also induce differentiation of tumor cells. Although, these agents exert a profound effect on the same events of tumor cell life, it is thought that 8-Cl-cAMP and TR act by modulating the signal transduction pathway through distinct mechanisms. We have compared their effect on two human glioma cell lines (U87 MG and U251 MG) and examined if there is selectivity in their action toward normal human astrocytes.