Systematic review of management of chronic pain after surgery.

BACKGROUND: Pain present for at least 3 months after a surgical procedure is considered chronic postsurgical pain (CPSP) and affects 10-50 per cent of patients. Interventions for CPSP may focus on the underlying condition that indicated surgery, the aetiology of new-onset pain or be multifactorial in recognition of the diverse causes of this pain. The aim of this systematic review was to identify RCTs of interventions for the management of CPSP, and synthesize data across treatment type to estimate their effectiveness and safety. METHODS: MEDLINE, Embase, PsycINFO, CINAHL and the Cochrane Library were searched from inception to March 2016. Trials of pain interventions received by patients at 3 months or more after surgery were included. Risk of bias was assessed using the Cochrane risk-of-bias tool. RESULTS: Some 66 trials with data from 3149 participants were included. Most trials included patients with chronic pain after spinal surgery (25 trials) or phantom limb pain (21 trials). Interventions were predominantly pharmacological, including antiepileptics, capsaicin, epidural steroid injections, local anaesthetic, neurotoxins, N-methyl-d-aspartate receptor antagonists and opioids. Other interventions included acupuncture, exercise, postamputation limb liner, spinal cord stimulation, further surgery, laser therapy, magnetic stimulation, mindfulness-based stress reduction, mirror therapy and sensory discrimination training. Opportunities for meta-analysis were limited by heterogeneity. For all interventions, there was insufficient evidence to draw conclusions on effectiveness. CONCLUSION: There is a need for more evidence about interventions for CPSP. High-quality trials of multimodal interventions matched to pain characteristics are needed to provide robust evidence to guide management of CPSP.

Persistent pain after knee replacement: do factors associated with pain vary with degree of patient dissatisfaction?

OBJECTIVE: Up to 20% of patients experience long-term pain and dissatisfaction following knee replacement. The aim of this study was to investigate factors associated with persistent pain following knee replacement and their implications for patient satisfaction. DESIGN: A case-controlled analysis compared patients with established persistent pain with patients who were pain-free. 2:1 frequency matching for age, gender, time from surgery and prosthesis was performed. 1310 patients were approached and 100 patients with persistent pain and 200 matched pain-free controls were included. Variables assessed included mechanical, biological, psychosocial and generalised factors. RESULTS: The study found that the degree of dissatisfaction experienced by the patient with persistent pain following knee replacement affected the factors associated with pain. In the most dissatisfied patients, pain was associated with instability in the coronal plane (OR 19.8, 95% CI 3.8-104.0), stiffness (OR 6.4, 95% CI 2.3-18.4) and negative social support (OR 3.3, 95% CI 1.1-10.0). In patients who were less dissatisfied, pain was associated with patellofemoral problems (OR 10.3, 95% CI 3.6-29.6), elevated BMI (OR 2.8, 95% CI 1.4-5.7) and reduced local pain thresholds (OR 4.4, 95% CI 2.0-9.6). Depression (OR 13.6, 95% CI 1.9-96.6) and presence of proximal tibial tenderness (OR 23.5 95% CI 7.8-70.7) were strongly associated with pain regardless of level of satisfaction. CONCLUSIONS: Patients with persistent pain after knee replacement are dissatisfied. This study identifies factors associated with the worst pain outcomes, which lead to the greatest levels of dissatisfaction. Particular efforts with a holistic multidisciplinary approach should be focused towards these "red flag" factors in order to minimise persistent pain after knee replacement.

The outcome at ten years of lateral closing-wedge high tibial osteotomy: determinants of survival and functional outcome.

The aim of this study was to examine the functional outcome at ten years following lateral closing wedge high tibial osteotomy for medial compartment osteoarthritis of the knee and to define pre-operative predictors of survival and determinants of functional outcome. 164 consecutive patients underwent high tibial osteotomy between 2000 and 2002. A total of 100 patients (100 knees) met the inclusion criteria and 95 were available for review at ten years. Data were collected prospectively and included patient demographics, surgical details, long leg alignment radiographs, Western Ontario and McMaster Universities osteoarthritis index (WOMAC) and Knee Society scores (KSS) pre-operatively and at five and ten years follow-up. At ten years, 21 patients had been revised at a mean of five years. Overall Kaplan-Meier survival was 87% (95% confidence interval (CI) 81 to 94) and 79% (95% CI 71 to 87) at five and ten years, respectively. When compared with unrevised patients, those who had been revised had significantly lower mean pre-operative WOMAC Scores (47 (21 to 85) vs 65 (32 to 99), p < 0.001), higher mean age (54 yrs (42 to 61) vs 49 yrs (26 to 66), p = 0.006) and a higher mean BMI (30.2; 25 to 39 vs 27.9; 21 to 36, p = 0.005). Each were found to be risk factors for revision, with hazard ratios of 10.7 (95% CI 4 to 28.6; pre-operative WOMAC < 45), 6.5 (95% CI 2.4 to 17.7; age > 55) and 3.0 (95%CI 1.2 to 7.6; BMI > 30). Survival of patients with pre-operative WOMAC > 45, age < 55 and BMI < 30 was 97% at five and ten years. WOMAC and KSS in surviving patients improved significantly between pre-operative (mean 61; 32 to 99) and five (mean 88; 35 to 100, p = 0.001) and ten years (mean 84; 38 to 100, p = 0.001). Older patients had better functional outcomes overall, despite their higher revision rate. This study has shown that improved survival is associated with age < 55 years, pre-operative WOMAC scores > 45 and, a BMI < 30. In patients over 55 years of age with adequate pre-operative functional scores, survival can be good and functional outcomes can be significantly better than their younger counterparts. We recommend the routine use of pre-operative functional outcome scores to guide decision-making when considering suitability for high tibial osteotomy.

Medial patellofemoral ligament reconstruction for patellar instability in patients with hypermobility: a case control study.

Hypermobility is an acknowledged risk factor for patellar instability. In this case control study the influence of hypermobility on clinical outcome following medial patellofemoral ligament (MPFL) reconstruction for patellar instability was studied. A total of 25 patients with hypermobility as determined by the Beighton criteria were assessed and compared with a control group of 50 patients who were matched for age, gender, indication for surgery and degree of trochlear dysplasia. The patients with hypermobility had a Beighton Score of ≥ 6; the control patients had a score of < 4. All patients underwent MPFL reconstruction performed using semitendinosus autograft and a standardised arthroscopically controlled technique. The mean age of the patients was 25 years (17 to 49) and the mean follow-up was 15 months (6 to 30). Patients with hypermobility had a significant improvement in function following surgery, with reasonable rates of satisfaction, perceived improvement, willingness to repeat and likelihood of recommendation. Functional improvements were significantly less than in control patients (p < 0.01). Joint hypermobility is not a contraindication to MPFL reconstruction although caution is recommended in managing the expectations of patients with hypermobility before consideration of surgery.

Medial patellofemoral ligament reconstruction: a prospective outcome assessment of a large single centre series.

We report a prospective analysis of clinical outcome in patients treated with medial patellofemoral ligament (MPFL) reconstruction using an autologous semitendinosus graft. The technique includes superolateral portal arthroscopic assessment before and after graft placement to ensure correct graft tension and patellar tracking before fixation. Between October 2005 and October 2010, a total of 201 consecutive patients underwent 219 procedures. Follow-up is presented for 211 procedures in 193 patients with a mean age of 26 years (16 to 49), and mean follow-up of 16 months (6 to 42). Indications were atraumatic recurrent patellar dislocation in 141 patients, traumatic recurrent dislocation in 50, pain with subluxation in 14 and a single dislocation with persistent instability in six. There have been no recurrent dislocations/subluxations. There was a statistically significant improvement between available pre- and post-operative outcome scores for 193 patients (all p < 0.001). Female patients with a history of atraumatic recurrent dislocation and all patients with history of previous surgery had a significantly worse outcome (all p < 0.05). The indication for surgery, degree of dysplasia, associated patella alta, time from primary dislocation to surgery and evidence of associated cartilage damage at operation did not result in any significant difference in outcome. This series adds considerably to existing evidence that MPFL reconstruction is an effective surgical procedure for selected patients with patellofemoral instability.

High-energy open tibial fractures in children: treatment with a programmable circular external fixator.

Between 2005 and 2010 ten consecutive children with high-energy open diaphyseal tibial fractures were treated by early reduction and application of a programmable circular external fixator. They were all male with a mean age of 11.5 years (5.2 to 15.4), and they were followed for a mean of 34.5 months (6 to 77). Full weight-bearing was allowed immediately post-operatively. The mean time from application to removal of the frame was 16 weeks (12 to 21). The mean deformity following removal of the frame was 0.15° (0° to 1.5°) of coronal angulation, 0.2° (0° to 2°) sagittal angulation, 1.1 mm (0 to 10) coronal translation, and 0.5 mm (0 to 2) sagittal translation. All patients achieved consolidated bony union and satisfactory wound healing. There were no cases of delayed or nonunion, compartment syndrome or neurovascular injury. Four patients had a mild superficial pin site infection; all settled with a single course of oral antibiotics. No patient had a deep infection or re-fracture following removal of the frame. The time to union was comparable with, or better than, other published methods of stabilisation for these injuries. The stable fixator configuration not only facilitates management of the accompanying soft-tissue injury but enables anatomical post-injury alignment, which is important in view of the limited remodelling potential of the tibia in children aged > ten years. Where appropriate expertise exists, we recommend this technique for the management of high-energy open tibial fractures in children.

Radiographic landmarks for tunnel placement in reconstruction of the medial patellofemoral ligament.

PURPOSE: To verify the findings of previous studies in confirming radiographic landmarks for the femoral attachment of the medial patellofemoral ligament (MPFL), but also to define radiographic landmarks for the patellar attachment. Assess the effect of limb rotation upon these radiographic landmarks. METHODS: The medial patellofemoral ligament was identified in ten fresh-frozen human cadaveric knees. A headed pin was used to mark the centre of the femoral and patellar attachments. True lateral radiographs were performed followed by lateral radiographs in 10° and 20° of internal and external rotation. Posterior-anterior and proximal-distal position of the headed pin was evaluated. RESULTS: The femoral attachment averaged 3.8 ± 5.0 mm anterior to the posterior femoral cortical line and 0.9 ± 2.4 mm distal to the perpendicular line intersecting the posterior aspect of Blumensaat's line. The patellar attachment averaged 7.4 ± 3.5 mm anterior to the posterior patellar cortical line, 5.4 ± 2.6 mm distal to the perpendicular line intersecting the proximal margin of the patellar articular surface. There was a significant relationship between limb rotation and distance of femoral and patellar attachment from the posterior cortical line (P < 0.0001 and P < 0.0002 respectively). CONCLUSION: Radiographic landmarks for the femoral attachment of the MPFL identified in this study are comparable with other recent work. This study describes new radiographic landmarks for the patellar attachment of the MPFL and highlights that it is essential to acquire true lateral radiographs if these radiographic landmarks are to be interpreted accurately.

Retention of arthroscopic shoulder skills learned with use of a simulator. Demonstration of a learning curve and loss of performance level after a time delay.

BACKGROUND: In orthopaedic surgery, arthroscopy is an irreplaceable diagnostic and interventional tool, and its breadth of use is increasing. The aim of this study was to investigate the surgeon's capacity for retention of an unfamiliar arthroscopic skill. METHODS: Six fellowship-trained lower-limb surgeons were given standardized instruction regarding the performance of an arthroscopic Bankart suture on a laboratory-based simulator. They performed three single Bankart sutures on each of four occasions, one to two weeks apart. Six months later, the same surgeons repeated the study. They received no further instruction or guidance. Their performance was objectively assessed with use of validated motion-analysis equipment to record the total path length of the surgeon's hands, number of hand movements, and time taken to perform the sutures. RESULTS: A learning curve showing significant and objective improvement in performance was demonstrated for all outcome parameters in both experiments (p < 0.005). The learning curve at six months was a repeated learning curve showing no significant difference from the initial learning curve. CONCLUSIONS: This study objectively demonstrated a loss of all of the initial improvement in the performance of an arthroscopic Bankart suture following a six-month interval in which the surgeons did not do the procedure.

Transferring simulated arthroscopic skills to the operating theatre: a randomised blinded study.

The aim of this study was to investigate the effect of laboratory-based simulator training on the ability of surgical trainees to perform diagnostic arthroscopy of the knee. A total of 20 junior orthopaedic trainees were randomised to receive either a fixed protocol of arthroscopic simulator training on a bench-top knee simulator or no additional training. Motion analysis was used to assess performance objectively. Each trainee then received traditional instruction and demonstrations of diagnostic arthroscopy of the knee in theatre before performing the procedure under the supervision of a blinded consultant trainer. Their performance was assessed using a procedure-based assessment from the Orthopaedic Competence Assessment Project and a five-point global rating assessment scale. In theatre the simulator-trained group performed significantly better than the untrained group using the Orthopaedic Competence Assessment Project score (p = 0.0007) and assessment by the global rating scale (p = 0.0011), demonstrating the transfer of psychomotor skills from simulator training to arthroscopy in the operating theatre. This has implications for the planning of future training curricula.

The casualty profile from the Reading train crash, November 2004: proposals for improved major incident reporting and the application of trauma scoring systems.

OBJECTIVE: To report the casualty profile of the major incident at the Royal Berkshire Hospital, Reading, following the Ufton Nervet Train crash, November 2004. To make further proposals regarding major incident reporting and implementation of trauma-scoring systems. METHOD: Retrospective analysis of emergency department and hospital notes. Calculation of index Injury Severity Score (ISS) and Trauma and Injury Severity Score (TRISS) in all patients. RESULTS: Of 61 casualties, the majority (74%) were seen in the minors area of our emergency department with a mixture of blunt impact and penetrating glass injuries. One died and 16 were admitted. 10% had an ISS >16. All surviving patients had a TRISS predicted probability of survival >90%. CONCLUSION: We propose mandatory major incident reporting within 6 months of a major incident to aid development of a national database. As previously proposed, this will aid education and facilitate future major incident planning. We further propose the widespread use of trauma scoring systems to facilitate comparative analysis between major incidents, perhaps extrapolating this to develop a major incident score.

Soluble CD44 inhibits melanoma tumor growth by blocking cell surface CD44 binding to hyaluronic acid.

Proteolytic cleavage of the extracellular domain of CD44 from the surface of cells has been observed recently in different cell types. In cell culture supernatants of human melanoma cell lines a 70 kDa soluble CD44 protein (solCD44) was detected at concentrations of 250-300 ng/ml. Protease inhibitor studies revealed that serine proteases and metalloproteases are involved in the cleavage of CD44 from the surface of melanoma cells. To analyse a possible function of soluble CD44 a human malignant melanoma cell line was stably transfected with cDNAs encoding either wild type soluble CD44s or mutated forms with defective HA binding properties (CD44sR41A and CD44sR150A/R154A). Soluble CD44s almost completely inhibited hyaluronic acid binding by melanoma cells, whereas soluble CD44 mutated in the HA binding domain had no effect. When cultivated on hyaluronic acid, melanoma cell proliferation was induced by 30% for both the parental and the control transfected cells. This increase in proliferation was blocked completely in solCD44s-secreting transfectants, whereas solCD44sR41A and solCD44sR150A/R154A-secreting cells again showed hyaluronic acid-induced cell proliferation. These cell lines were subcutaneously injected into MF1 nu/nu mice to compare their growth as tumors in vivo. Compared to tumors derived from parental and control transfected cells, we observed a dramatic reduction of primary tumor growth with solCD44s expressing MM cells. Transfectants expressing solCD44s mutated in the HA binding domain in contrast developed fast-growing primary tumors. These results provide strong evidence that direct solCD44 interactions with hyaluronic acid interfere competitively with processes induced by hyaluronic acid binding to surface CD44. Autocrine, or drug-induced secretion of solCD44 by human melanoma cells may thus exert potent antitumoral effects in vivo.

CD44 expression and regulation during mammary gland development and function.

The CD44v6 epitope has been widely reported to be expressed in human mammary carcinomas, yet its prognostic significance is controversial and its function in mammary tumors and mammary glands is unknown. To begin to resolve these issues, we analysed in detail the normal postnatal expression patterns and regulation of the CD44v6 epitope in murine mammary glands. We demonstrate that significant CD44v6 epitope expression is first seen during puberty, and that after puberty CD44v6 epitope expression follows the estrous cycle. CD44v6 epitope expression is observed in the myoepithelium and also less widely in luminal epithelial cells. During lactation, CD44v6 epitope expression is turned off and reappears during involution. The CD44 variant isoform bearing the v6 epitope is CD44v1-v10. Using HC11, a mammary epithelial cell line with stem cell characteristics, and facilitated by the cloning of the murine CD44 promoter, we show that growth factors and hormones which regulate ductal growth and differentiation modulate CD44 transcription. Together our data suggest that the CD44v6 epitope is expressed in mammary epithelial stems cells and in lineages derived from these cells, and that CD44v6 expression is regulated in part by hormones and growth factors such as IGF-1 and EGF which regulate the growth and differentiation of the mammary epithelium. The function of these same growth factors and hormones is often perturbed in mammary carcinomas, and we suggest that CD44v6 expression in tumors reflects this perturbation. We conclude that the expression of the CD44v6 epitope observed in some mammary tumors reflects the stem cell origin of breast tumors, and that whether or not the CD44v6 epitope is expressed in a mammary tumor is determined by the differentiation status of the tumor cells.

The Wilms tumor suppressor gene wt1 is required for development of the spleen.

The Wilms tumor suppressor gene WT1 (wt1 in mouse) is unique among tumor suppressors because, in addition to its involvement in cancer [1] [2] and various other diseases [3] [4] [5] [6], it has an essential role in the development of certain organs. This is revealed by the phenotype of mice with inactivated wt1 alleles [7]. These animals exhibit a complete failure of kidney and gonad development as well as abnormalities of the heart and mesothelial structures. On a C57BL/6 genetic background, wt1(-/-) animals die between day 13.5 (E13.5) and 15.5 (E15.5) of embryonic development [7]. We report here that crossing of the wt1 mutation onto different mouse backgrounds delayed embryonic lethality until birth. In wt1(-/-) mice on these different genetic backgrounds, we observed a dramatic failure of spleen development, in addition to the well characterized phenotypic abnormalities. The spleen anlage formed at around E12 to E13 and involuted by the E15 stage, before the invasion of hematopoietic cells. The absence of proper spleen development in these wt1(-/-) embryos correlated with enhanced apoptosis in the primordial spleen cells. The expression of hox11, a gene that also controls development of the spleen [8] [9], was not altered by the inactivation of wt1. In situ hybridization revealed that the two genes are regulated independently. These findings demonstrate that the penetrance of the wt1(-/-) phenotype depends on the existence of one or more modifier gene(s) and that wt1 plays a pivotal role in the development of the spleen, thereby extending its role in organogenesis.

Inhibition of MT-450 rat mammary tumour growth by antibodies recognising subtypes of blood group antigen B.

Using subtractive immunization to identify cell surface epitopes expressed in a metastasis-specific fashion on cells of the rat MT-W9 mammary carcinoma model, we generated a monoclonal antibody called M-N#1. This antibody binds specifically to metastasizing cells of the MT-W9 series and also to certain other metastasizing rat mammary carcinoma cell lines. We demonstrate that the M-N#1 antibody recognizes a fucosylated N-glycosyl sugar modification, and furthermore show that the epitope specificity of the M-N#1 antibody is for blood group antigen B subtypes 2, 3 and 4 with slight cross-reactivity with blood group antigen A subtype 2. The expression of these carbohydrate epitopes on MT-450 cells is functionally important, because the M-N#1 antibody efficiently inhibits MT-450 tumour growth in spontaneous metastasis assays. These results suggest that expression of the subtypes of blood group antigen B recognized by the M-N#1 antibody does not directly participate in the metastatic cascade but rather confers a growth or survival advantage on the tumour cells.

CD44 variant isoforms are essential for the function of epidermal Langerhans cells and dendritic cells.

Upon antigen encounter epidermal Langerhans cells (LC) and dendritic cells (DC) emigrate from peripheral organs and invade lymph nodes through the afferent lymphatic vessels and then assemble in the paracortical T cell zone and present antigen to T lymphocytes. Part of this process is mimicked by metastasizing tumor cells. Since splice variants of CD44 promote metastasis to lymph nodes we explored the expression of CD44 proteins on migrating LC and DC. We show that following antigen contact, LC and DC upregulate pan CD44 epitopes and epitopes encoded by variant exons v4, v5, v6 and v9. Antibodies against CD44 epitopes arrest LC in the epidermis, prevent the binding of activated LC and DC to the T cell zones of lymph nodes, and severely inhibit their capacity to induce a delayed type hypersensitivity reaction to a skin hapten in vivo. Our results demonstrate that CD44 splice variant expression is obligatory for the migration and function of LC and DC.

Development of an aromatherapy service at a Cancer Centre.

The aromatherapy service at the Cancer Support and Information Centre (CSIC) of this regional Cancer Centre has been continually assessed since its inception in 1993. New methods of assessing complementary therapies, based on the 'therapy-as-practised', have been explored. The present study evaluates the service following changes made after an initial pilot. The professional aromatherapist developed an evaluation tool, and formal questionnaires were limited to the Hospital Anxiety and Depression Scale (HADS). HADS was completed before and after a course of six aromatherapy sessions. Of 89 patients referred, 58 patients completed the six sessions. Referrals were made by health professionals working in the Cancer Centre and in the CSIC. The majority of patients were female with breast cancer and were receiving radical oncological treatment. Tension, stress and anxiety/fear were the most common reasons for referral, and this was reflected in high initial HADS scores. There were significant improvements in HADS scores in the 58 patients completing the course (mean anxiety, depression, and combined scores dropped from 8.9 to 6.2 6.1 to 4.0 and 15.0 to 10.2, respectively, P < 0.001). Fifty per cent or more of the sample reported a significant improvement in the eight most commonly assessed symptoms. The therapist was initially cautious about using questionnaires, but she gained confidence in using HADS as an assessment tool. The areas covered by her own evaluation tools were broadly comparable to established instruments such as the EORTC QLQ-C30. We conclude that aromatherapy massage has a role in reducing psychological distress, and improving symptom control in cancer patients. Further service evaluation is needed to promote appropriate referral and effective planning of treatment, and to justify cost. Given the multifaceted nature of complementary therapies, the need to develop new research methodologies is acknowledged.

Complementary therapists and cancer patient care: developing a regional network to promote co-operation, collaboration, education and patient choice.

Complementary therapies, particularly aromatherapy, reflexology and relaxation techniques are increasingly valued by cancer patients. However, many health professionals doubt their value, and often question whether therapists claim inappropriate benefits, lack understanding of cancer-related issues and pose a potential danger to patients. The Lynda Jackson Macmillan Centre for Cancer Support and Information, which has provided therapies since 1993, explored some of these issues and attempted to identify common areas of interest, possible collaboration, and an additional source of meeting patient needs. Two hundred and fifty questionnaires were sent to aromatherapists and reflexologists within the region served by the hospital to: (1) identify and profile interested therapists; (2) assess the need for cancer-related educational programmes; and (3) address some of the professionals' concerns. One hundred and four responses described work patterns, qualifications, cancer-related experience, the contribution of therapies to cancer care and interest in cancer-related training. A lack of information on cancer was identified. Therapists appeared to be working sensitively, even over-cautiously, and misgivings concerning this group appeared to be unfounded. Subsequent workshops resulted in a therapists' network, whose members collaborate with the centre in various ways. Patients and carers appreciate access to therapists informed about cancer, treatments and related issues.

Identification of IHABP, a 95 kDa intracellular hyaluronate binding protein.

The extracellular matrix component hyaluronan is believed to play important roles in various processes of organogenesis, cell migration and cancer. Recognition of and binding to hyaluronan is mediated by cell surface receptors. Three of them, CD44, ICAM-1 and RHAMM (receptor for hyaluronic acid mediated motility), have been identified. A cDNA clone designated RHAMM turned out to possess transforming capacity. Based on this published sequence, we isolated the complete cDNA of the murine gene. The cDNA comprises an open reading frame of 2.3 kb and encodes a 95 kDa protein. The protein carries a hyaluronan binding motif which binds to hyaluronan in vitro but not to heparin or chondroitin sulphate. It is ubiquitously expressed in normal cells and in all tumour cell lines irrespective of their metastatic properties. One tumour cell line, the metastatic Lewis lung carcinoma, expresses a larger 105 kDa variant form of the protein due to a genomic rearrangement. Antibodies raised against the 95 kDa protein were used for subcellular localization studies. The hyaluronan binding protein is not detectable at the cell surface but is rather localized exclusively intracellularly. Clearly, the sequence we have identified encodes a protein with properties substantially different to the RHAMM protein. We tentatively name the protein intracellular hyaluronic acid binding protein, IHABP.