Aims: PMMA is currently used as grouting agent of arthroprostheses and for filling of bone cavities after bone curettage. It is moreover used as a carrier of antibiotics in the local treatment of bone infections and it has been proposed as a carrier of antiblastic drugs in the local treatment of bone metastases. The aim of this study is to analyse the biological properties and compressive strenght of PMMA-Methotrexate mixture to be used for the local treatment of bone metastases. Methods: Cylinders of PMMA containing Methotrexate in different concentrations were manufactured according to ASTM F-451. Cylinders of PMMA were used as control. The porosity of the cylinders was characterised by SEM. Drug elution rate in saline solution was measured by HPLC. The biological activity of Methotrexate was analysed on human breast cancer cells using MTT test at different time (from 5 minutes to 30 days). Compressive tests was performed in conformity to ASTM F-451 on PMMA- Methotrexate samples and control as-made and after 30 days of aging in saline. Results: SEM analysis showed the presence of granules of Methotrexate on the surface of as-made cylinders that can be readily released from PMMA cylinders. The release occurred in large amount within 24 hours after immersion. We observed a relative release rate is more sustained in samples containing the drug in lower concentration. Also the biological activity was time dependent: cell death decreased progressively from 60% at 24 hours to 10% at 30 days. Compressive tests showed no statistical differences between PMMA cylinders containing Methotrexate and controls before and after aging in saline. Conclusions: The results show that PMMA-Metho-trexate may be considered an interesting option in the treatment of bone metastases because cement allows mechanical resistance after bone curettage or resection and Methotrexate improves locally anticancer activity

The aim of our study was to increase of survival of children with osteosarcoma by intensification of chemotherapy by inclusion of high dose methotrexate. 53 patients were treated in our centre between 2003 and 2007. Age are ranged from 5 to 16 years. 23 (43,4%) patients had metastetic disease. Polychemotherapy consist of alternating courses of CDDP, adriamicin, ifosfamide and etoposide and high-dose methotrexate (8–12 g/m. 2. ). In 25 (51%) cases have been received objective response (CR+PR). 38 (71,7%) patients alive at present time. 2 patients died from complications of treatment. 7 patients had PD, 1 — local relapse, 4 — metastatic relapse, 1 — combined relapse. 2-year OAS was 75,2±6,8%, 2-year RFS was 65±7,8%

Summary. Methotrexate chemotherapy (commonly used in treating cancers and rheumatoid arthritis) creates an inflammatory condition in bone, decreasing osteogenesis, enhancing adipogenesis, increasing osteoclastogenesis, leading to bone loss and marrow adiposity; treatment with fish oil or folinic acid counteracts these negative effects and prevents bone loss. Introduction. Chemotherapy with anti-metabolite methotrexate (MTX) is commonly used in treating cancers and rheumatoid arthritis; however it is known to cause bone loss for which currently there are no adjunct preventative treatments. Methods and Materials. Using a rat model, this study investigated the damaging effects in bones caused by daily MTX injections (0.75mg/kg) for 5 consecutive days (mimicking induction phase treatment for childhood leukaemia) and also the potential protective benefits of omega-3 fatty acid-rich fish oil at different doses (0.25, 0.5 or 0.75 mL/100g BW) in comparison to antidote folinic acid (given i.p at 0.75mg/kg 6 hours post MTX, which is clinically used to reduce MTX toxicities in soft tissues). Results. Histological analysis showed that MTX significantly reduced primary spongiosa bone height and metaphyseal trabecular bone volume. MTX also significantly reduced density of osteoblasts at the secondary spongiosa. Ex vivo differentiation assays with bone marrow stromal cell populations of treated rats revealed a significant reduction in osteogenic differentiation but an increase in adipogenesis. Consistently, RT-PCR gene expression study within the stromal cell population revealed a lower expression of osteogenic transcription factors Runx2 and Osx and bone matrix protein osteocalcin but a significantly upregulated adipogenesis-related genes FABP4 and PPARγ, indicating that MTX chemotherapy induces a switch in the differentiation potential towards adipogenesis at the expense of osteogenesis. MTX increased the density of osteoclasts within the metaphyseal bone as revealed by histological analysis and osteoclast precursor cell pool as shown by ex vivo osteoclastogenesis assay with bone marrow samples. Consistently, mRNA expression of proinflammatory and osteoclastogenic cytokines IL-1, IL-6, TNF-α, and the RANKL/OPG ratio were significantly upregulated by MTX. Supplementary treatment with fish oil (0.5mL/100g BW) or folinic acid significantly preserved metaphyseal trabecular bone volume, osteoblast density, and bone marrow stromal cell osteogenic differentiation and suppressed MTX-induced adipogenesis. These supplements also prevented MTX-induced increased osteoclast density, osteoclastogenesis, and expression of proinflammatory and osteoclastogenic cytokines. Conclusion. These results suggest that MTX chemotherapy creates an inflammatory condition in bone resulting in increased osteoclast formation and decreased osteoblast formation thus leading to bone loss, and that supplementary treatment with fish oil at 0.5mL/100g BW or folinic acid counteract these negative effects, helping to conserve bone formation, suppress bone resorption and bone marrow adiposity, and thus prevent bone loss during MTX chemotherapy

Introduction. In rheumatoid (RA) patients undergoing total joint arthroplasty, evidence suggests methotrexate should be continued without increase in post-operative infection. Prednisolone increases post-operative infection risk, but cannot be stopped without risk of Addisonian events. Insufficient evidence exists to clarify perioperative biologic agent management. We currently stop biologics 2 weeks prior to operation and reintroduced following wound healing. Patients/Materials & Methods. This service evaluation reviewed infection rates and length of stay in RA patients following lower-limb arthroplasty, on various anti-rheumatoid therapies across a 28-month period. Results. Forty cases were identified: 15% on no anti-rheumatoid treatment, 45% on mono-therapy (8 on methotrexate, 8 on prednisolone, 2 on biologics)) and 40% on combination-therapy. The total population post-operative infection rate was 18% (all superficial wound). Mean length of stay was 8.0 days (SD=6.8). Methotrexate takers had an infection rate of 5% versus 33% in non-methotrexate takers (p=0.017), and a length of stay of 6.5 days versus 9.9 days in non-MTX takers (p=0.005). Prednisolone takers had an infection rate of 37% versus 0% in non-prednisolone takers (p=0.002) and length of stay was 12.0 days versus 4.7 days in non-prednisolone takers days (p=0.006). Biologics takers had similar infection rates of 9% versus 21% in non-biologic takers (p>0.05), and a similar length of stay of 6.6 days versus 8.6 days in non-biologic takers (p>0.05). Discussion. This data supports current evidence that methotrexate should be continued without detriment to infection risk and length of stay. Biologic agents stopped 2 weeks prior to operation appear to have no effect on infection rate and length of stay. Patients on prednisolone should be identified as at a higher risk of infection and should plan for a longer length of stay. Conclusion. Larger scale cohort studies are required to determine whether biologic agents should be continued per-operatively

Introduction. Chronic recurrent multifocal osteomyelitis (CRMO) is a rare condition characterised by bony pain and swelling which may be initially mistaken for bacterial osteomyelitis. The episodic course of the disease may confound the diagnosis and potentially be mistaken for a partial response to antimicrobial therapy. It is an orphan disease and consequently results in many unclear aspects of diagnosis, treatment and follow up for patients. The aim of this study is to evaluate a national tertiary centre's experience with the clinical condition and present one of the largest cohorts to date, emphasizing the vast array of clinical spectrum, course and response to treatment. Methods. We retrospectively evaluated all children identified with CRMO from the period 2000–2022 within Wales. Demographic data and clinical parameters were selectively identified through the utilisation of a national clinical platform (Welsh Clinical Portal). The diagnosis was based on clinical findings, radiological images, histopathological and microbiological studies. Results. A total of 21 patients were identified as suitable for inclusion. The mean age of diagnosis was 9.4 ±2 years. The age range of children being diagnosed was 6–14 years. Of the 21 patients, only 2 reported feeling unwell prior to their first presentation with generalized coryzal illness reported. The most common presenting site for CRMO was knee (33%) followed by back pain (28%). 19% of the included cases at initial presentation had localised warmth and had nocturnal pain. 4 of the patients went on to have dermatological conditions of which psoriasis was the most common (14%). Bilateral symptoms developed in 38% of the included patients. Biochemical investigations revealed only 19% of patients had a raised C-reactive protein level and erythrocyte sedimentation rate whilst 9/21 patients went on to have a bone biopsy to aid diagnosis. 100% of patients had MRI whilst whole body MRI was utilised in 8/21 patients. NSAID's were utilised for 81%, Pamidronate for 33% and methotrexate for 14%. Biologics were utilised for a further 24% of the total population in failed medical therapy. Surgical intervention was utilised for a single individual in this cohort of patients in the form of posterior spinal stabilisation. The most common referring speciality for these patients was Rheumatology (71%) followed by Orthopaedics (33%). Discussion. CRMO represents a challenging diagnosis to make with such varied clinical and biochemical presentations for this condition. The absence of diagnostic Radiological features on X-ray could argue over early MRI imaging. The utilisation of whole body-MRI can now identify multifocal disease burden which may facilitate a timely diagnosis and ensure that effective medical treatment is started promptly without delay. This study is the largest cohort of CRMO patients conducted in this country. Future work will serve to build upon a framework and national referral pathway so that these patients can be seen by the appropriate specialist in a timely manner

Methotrexate and Cox-2 inhibitors are thought to interfere with bone healing. There have been controversial results published in the literature. The effect of newer antirheumatoids (Leflunomide, Etanercept, Infliximab) has not been studied. The aim of this study was to find the in-vitro effect of methotrexate, newer anti-rheumatoids, steroids and cox-2 inhibitors on Osteoblasts. Osteoblasts were cultured from femoral heads obtained from young otherwise healthy patients undergoing total hip replacement. The cells were cultured using techniques that have been previously described. A computer aided design of experiment was used as a model for setting up the experiment on samples obtained from five patients. Normal therapeutic concentration of the various antirheumatoids was added alone and in combination to the media. The cell growth was estimated after two weeks using spectrophotometric technique using Roche Cell proliferation Kit. Multiple regression analysis was done to estimate the best predictor of the final result. Patient was found to be the most significant factor (p< 0.001) in predicting the ultimate response. Cox-2 inhibitor (Etoricoxib) was found to be the next best predictor (p=0.043). Etoricoxib in fact had a stimulatory effect (R=0.219) on the osteoblast growth, which was accentuated in the presence of other agents that varied amongst different patients. Different patients respond differently to the drugs. None of the antirheumatoids inhibit osteoblast proliferation and differentiation in-vitro. If osteoblastic activity is considered to be the primary factor responsible for bone healing, then an inhibition should not result in patients who are on these drugs

Osteosarcoma rarely affects young children. To determine the clinical characteristics and the prognosis of this cancer in children of less than 5 years at diagnosis, we retrospectively analysed medical records of these patients treated in French centers between 1980 and 2007. A centralised histological review was carried out. Fifteen patients were studied. Long bones were involved in 14 cases. Metastases at diagnosis were observed in 40% of patients. Histologic type was 74% osteoblastic. In 3 cases (20%) tumours occurred on a particular background (tall constitutional size, treatment with growth hormone and pregnancy induced by clomiphene). One child had a second cancer 13 years after the first diagnosis. Twelve children received pre-operative chemotherapy including high dose methotrexate: 5 of them had progressive disease; only 36% had good histological response (less than 10% viable cells). Limb salvage surgery was performed in six cases (40%). Chemotherapy was well tolerated in most patients. A one-year-old child developed a severe late convulsant encephalopathy with lesions of the white substance that could be due to methotrexate despite adjustment of doses to his weight. The functional recovery of the three analysable children who underwent limb salvage surgery is uneven and shows frequent mechanical or infectious complications (2 to 5 reinterventions per patients). First complete remission (CR) was obtained in 12 children, six of them relapsed. With a median follow-up of 15 years, six are alive in CR, six died of disease (40%), two were lost to follow-up and one has stable disease with metastasis. This study shows that osteosarcoma seems to be more aggressive in children under five years of age. Surgical management remains difficult in this population. Prospective studies are still needed to confirm these observations

Osteosarcoma is the most common malignant bone tumour in children and young people. Approximately 40% patients respond poorly to highly toxic preoperative MAP (methotrexate adriamycin, cisplatin) chemotherapy with consequent inferior survival. The role of genetic polymorphisms in drug response and toxicity is reported in acute leukaemia and some solid tumours. Recent evidence in osteosarcoma suggests increased chemotherapy toxicity is associated with improved survival. The aim of this pilot study is to investigate the influence of drug target and metabolising gene polymorphisms on tumour response and chemotherapy toxicity in osteosarcoma. Patients who have completed MAP chemotherapy are eligible. Chemotherapy toxicity (CTCAE grade) is collected from patient records. Tumour response is graded as good (> 90% necrosis) or poor (< 90% necrosis) in resection specimen. Peripheral blood DNA is typed for genome-wide single nucleotide polymorphisms (SNP) using the Illumina 610 Quad array and analysed using Bead Studio software. Standard PCR techniques are used to genotype the Thymidylate synthase (TS) gene (folate pathway) for the presence of 2 or 3 copies of a 28 base pair repeat (2R/3R) and a G/C SNP in the 3R allele. 52 patients have entered to date: 33 good responders, 12 poor and 7 unevaluable for response. Median age 18 years (range 10–51), males:females 1.3:1. Median follow up is 39 months (range 2–76) with 11 patients relapsing. 23 patients have TS genotype 2R/2R, nineteen 2R/3R, six 3R/3R, three 2R/4R and one 2R/7R. Neither TS repeat or G/C SNP genotype correlated with histological response or degree of methotrexate stomatitis. Interestingly, presence of the 2R allele was significantly related to relapse (p=0.01) but may reflect small patient numbers. Recurrent methotrexate stomatitis (> 2 episodes of CTCAE grade 2) was weakly correlated with no relapse (p=0.07). Analysis of SNP array data with emphasis on MAP pathway polymorphisms will be presented when complete

Aims

Osteosarcoma is the most common primary bone malignancy among children and adolescents. We investigated whether benzamil, an amiloride analogue and sodium-calcium exchange blocker, may exhibit therapeutic potential for osteosarcoma in vitro.

Introduction: Osteomyelitis often causes functional impairment due to tissue destruction and the incidence of this condition appears to be increasing. Antimicrobial peptides (AP) are effectors of the innate defence system and play a key role in host protection at cellular surfaces. Human beta-defensins (HBD) represent a major subclass of antimicrobial peptides and act as a first line defence through their broad spectrum of potent antimicrobial activity (1). The aim of the present in vitro and in vivo investigations was to study the expression and regulation of HBD-2 and -3 in the case of bacterial bone infection and to analyze the effects of immunosuppressive drugs on bone-derived AP-expression. Methods: Samples of healthy human bone, osteomyelitic bone and cultured osteoblasts (primary-, hFOB- and SAOS-2 cells) were assessed for the expression of HBD-2/-3 by RT-PCR, immunohistochemistry or ELISA. Regulation of HBD-2/-3 was studied after exposure to Staphylococcus aureus (SAS) or Pseudomonas aeruginosa (PAS), proinflammatory cytokines (IL-1, 10ng/ml) and immunosuppressive drugs (glucocorticoids, methotrexate) and was assayed by ELISA. An osteomyelitis mouse model was performed to demonstrate the regulation of the murine homologues of HBD-2/-3 by real time RT-PCR and immunohistochemistry. Results: ELISA experiments demonstrated, that samples of infected bone produce higher levels of endogenous antibiotics such as HBD-2 when compared with samples of healthy bone. After exposure of osteoblasts to bacteria or proinflammatory cytokines a clear HBD-2/-3 induction was observed. Additional treatment with glucocorticoids or methotrexate prevented bacteria mediated HBD-2 induction in cultured osteoblasts. The osteomyelitis mouse model demonstrated transcriptional up-regulation of the murine HBD-homologues in bone after intra-osseous contamination of the tibia. Discussion: Our study firstly demonstrate that osteoblasts are able to produce anti-inflammatory peptides such as HBD-2 in vitro and in an animal model of staphylococcal osteomyelitis. We provide evidence for a new role of osteoblasts during infection of bone tissues, namely, the ability to produce antimicrobial peptides and modulating immune responses in inflammatory bone diseases. Immunosuppressive drugs such as glucocorticoids or methotrexate may increase the susceptibility to bone infection by decreasing AP-expression levels in case of microbial challenge. Novel approaches to management are required particularly in the era of multi-resistant bacterial strains. Current investigation will focus on the regulation of human β-Defensins in bone and may allow artificial amplification for prevention of bacterial bone infection in the future

Desmoid tumours are a rare fibroblastic proliferation of monoclonal origin, arising in deep soft-tissues. Histologically, they are characterized by locally aggressive behaviour and an inability to metastasize, and clinically by a heterogeneous and unpredictable course. Desmoid tumours can occur in any anatomical site, but commonly arise in the limbs. Despite their benign nature, they can be extremely disabling and sometimes life-threatening, causing severe pain and functional limitations. Their surgical management is complex and challenging, due to uncertainties surrounding the biological and clinical behaviour, rarity, and limited available literature. Resection has been the first-line approach for patients with a desmoid tumour but, during the last few decades, a shift towards a more conservative approach has occurred, with an initial ‘wait and see’ policy. Many medical and regional forms of treatment are also available for the management of this condition, and others have recently emerged with promising results. However, many areas of controversy remain, and further studies and global collaboration are needed to obtain prospective and randomized data, in order to develop an appropriate shared stepwise approach.

Cite this article: Bone Joint J 2023;105-B(7):729–734.

Listeria monocytogenes is usually thought of as a bacterial pathogen that causes invasive disease including meningitis and bacteraemia in susceptible hosts. It remains a rare cause of bone and joint infection; there is therefore potential for clinical and laboratory delay in diagnosis and for uncertainty over optimal management. We describe our experience of two such cases of L. monocytogenes prosthetic joint infection to highlight key features in clinical presentation and management. Two case reports of L. monocytogenes prosthetic joint infection are described with reference to previous published cases. A 57 year old woman presented with a 10 day history of severe pain and swelling around a left knee prosthesis which had been implanted as bilateral total knee replacements three years previously. She had a background of rheumatoid arthritis, controlled with prednisolone, methotrexate and ritixumab. Cultures from the left knee isolated L. monocytogenes. The patient was commenced on IV amoxicillin and after 4 weeks underwent 1st stage revision including radical debridement and removal of prosthesis. During the procedure an antibiotic-impregnated spacer (gentamycin/clindamycin with additional vancomycin added in house) was inserted. Antibiotic therapy with intravenous amoxicillin was continued for 2 weeks post-procedure and on discharge the patient was converted to oral amoxicillin for a further 8 weeks. The patient went on to have a 2nd stage revision, making a good recovery. An 85 year old woman presented with an 18 month history of discomfort and recurrent abscesses along the wound line of a left hip prosthesis, implanted over 20 years ago. She had a background of osteoarthritis and bullous phemphigoid, previously on steroid treatment. Fluid from the abscess was aspirated and isolated L. monocytogenes. Due to patient preference and frailty, radical revision was not thought a viable management option. Chronic suppressive therapy with oral amoxicillin was therefore instigated; one year on the infection remains well controlled and discomfort in the left hip has improved. L. monocytogenes has previously been infrequently implicated as a pathogen in prosthetic joint infection; however, there are reports of increasing numbers of cases particularly amongst immunosuppressed individuals. With an expanding at-risk population(1), its importance as a cause of prosthetic joint infection is set to rise in the future. Optimal management has not been well studied; it is likely that the best option combines antimicrobial therapy and prosthetic removal if possible

Aims

Surgical limb sparing for knee-bearing paediatric bone sarcoma is considered to have a clinically significant influence on postoperative function due to complications and leg-length discrepancies. However, researchers have not fully evaluated the long-term postoperative functional outcomes. Therefore, in this study, we aimed to elucidate the risk factors and long-term functional prognosis associated with paediatric limb-sparing surgery.

The purpose of the our study was to analyze prognostic factors characterizing biological behaviour of a tumour and specific features of the patient and to develop rational strategy of the combined treatment of malignant fibrous histiocytoma (MFH) in children. Between 1982 and 2008 fifty patients with MFH were observed and treated in our center. 24 (48%) were male and 26 (52%) were female. In all cases the diagnosis was confirmed by histological examination. We use polychemotherapy consist of alternating courses of CDDP, adriamicin, ifosfamide and etoposide and high-dose methotrexate (8–12 g/m. 2. ). Intensive polychemo-therapy allow us to expand indications for limb salvage treatment. Using growing (conventional and non-invasive types) endoprostesis improved the quality of life. 2-years RFS was 80,9±8,5% and 5-years RFS was 70,4±10,1% (Kaplan-Meier curves, p=0.03). The most significant prognostic factors were grade of histological response and type of polychemotherapy (conventional or intensive)

The aim of the our study was to analyze prognostic factors characterizing biological behaviour of a tumour and specific features of the patient and to develop rational strategy of the combined treatment of chondrosarcoma (CHS) in children. Between 1982 and 2008 seventy seven patients with CHS were observed and treated in our center. 38 (49,4%) were male and 39 (50,6%) were female. In all cases the diagnosis was confirmed by histological examination. In cases of high grade/mesenchymal or metastatic (into lungs) CHS we use polychemotherapy consist of alternating courses of CDDP, adriamicin, ifosfamide and etoposide and high-dose methotrexate (8–12 g/m. 2. ). Intensive polychemotherapy allow us to expand indications for limb salvage treatment. Using growing (conventional and non-invasive types) endoprostesis improved the quality of life. 5-years RFS was 75,4±7,8 % (Kaplan-Meier curves, p=0.02). The most significant prognostic factors were grade of histological response, morphological type of tumour and type of polychemotherapy (conventional or intensive)

Introduction. The systematic effects of joint replacement in rheumatoid arthritis (RA) patients are that inflamed synovium and pathological articular cartilage has dissipated. Expectations of total knee arthroplasty (TKA) are reduction of inflammatory cytokines, decreased disease activity and improvement of drug efficacy and ADL. Remission of rheumatoid arthritis is defined as having a Disease Activity Score DAS28 (ESR) of less than 2.6 and Health Assessment Questionnaire (HAQ) – Disability Index, less than 0.5. Purpose. We investigated whether TKA could reduce disease activity and improve ADL, and subsequent remission levels of DAS and HAQ or not. Material and Methods. We analyzed the Knee Society Score (KSS), KOOS score and DAS28 in 15 patients, 23 rheumatoid arthritic knees at pre-operation and 1 year after operation. Preoperatively patients had used non-steroidal anti-inflammatory drugs, prednisolone, disease-modifying anti-rheumatic drugs including methotrexate. TKA (Zimmer NexGen LPS Flex Knee implants and Stemmed Tibial component with stem) was performed with the modified gap technique or modified anatomical technique using original tensor with synovectomy. Results. Preoperative and postoperative KSS are 45.7±18.1 and 88.7±17.7 (P<0.01) respectively, and function scores were 40.1±21.7 and 74.8±24.0 (P<0.01) respectively (Figure 1). Preoperative and postoperative KOOS score (%) were ‘pain’ 50.6±37.8 and 95.4±19.3 (P<0.01), ‘symptom’ 56.6±32.8 and 94.7±18.6 (P<0.01), ‘ADL’ 60.6±27.9 and 89.5±32.4 (P<0.01), ‘QOL’ 28.4±32.1 and 63.6 ±22.9 (P<0.01) and ‘sport’ 20.56±29.52 and 47.10±33.9(P=0.06), respectively (Figure 2). Preoperative and postoperative DAS28(CRP) were 4.48±1.08 and 3.58±1.11(P<0.01), and DAS28 (ESR) were 4.90±1.02 and 4.13±0.99 (P=0.02) (Figure 3). Discussion. Each scores except ‘sport’ and DAS28 (ESR) improved statistically 1 year after operation. Function score, ‘ADL’ and ‘QOL’ scores also improved. HAQ score includes 2 categories related to walking ability and TKA was expected to improve the HAQ score, although the HAQ score is highly affected by upper arm function. The ‘sport’ score did not improve because almost all patients did not do sports preoperatively and postoperatively. DAS28 (ESR) and DAS28 (CRP) correlate strongly, but in this study there were statistical discrepancies in improvement. This might be because age, sex, disease duration, and existence of rheumatoid factors, anti-cyclic citrullinated peptide antibody and DLA-DRB1 shared epitope have been shown to influence ESR. DAS28 improved by a little less than 1.0, but there was limited control of disease activity. It was reported that the average DAS 28 didn't drop below 3.2 in 3 years follow-up after TKA. In this study we did not assess depending on preoperative disease activity, but it was reported that TKA had a systematic effect on severe or moderate RA activity, not low disease activity

Aims

To explore the synovial expression of mucin 1 (MUC1) and its role in rheumatoid arthritis (RA), as well as the possible downstream mechanisms.

Hyperactivation of the epidermal growth factor receptor (EGFR) by gene amplification, mutation as well as overexpression is a hallmark of multiple human carcinomas. However, in recent years data have accumulated that EGFR-mediated signals might also contribute to malignant progression and therapy resistance of human sarcomas. Consequently we have investigated if human osteosarcoma cell lines (n=9) express functional EGFR and its useability as therapeutic target. Osteosarcoma cells expressed distinctly differing level of EGFR reaching in some cases high amounts. However, even low expression levels were sufficient to activate both MAPK and PI3K pathways (determined by phosphorylation of ERK1/2 and S6, respectively) following EGF exposure of serum-starved cells. The EGFR-specific inhibitor gefitinib completely blocked EGF-mediated and attenuated serum-induced downstream signal activation. While gefitinib applied as single agent demonstrated only limited growth inhibiting activity in short term experiments (72h drug exposure), it led to reduced colony formation in long term experiments in the majority of cell lines. Importantly, gefitinb sensitized EGFR-expressing osteosarcoma cell lines against chemotherapy with doxorubicin and methotrexate, while it antagonised cisplatin-induced cell death. Summarizing, our data suggest that EGFR-mediated survival signals protect human osteosarcoma cells against the cytotoxic activity of several antineoplastic drugs. Consequently, combination approaches including EGFR inhibitors in addition to chemotherapy should be evaluated for treatment of high grade osteosarcoma patients

There have been marked changes in the management of Juvenile Idiopathic Arthritis (JIA) over recent decades, mainly with earlier use of methotrexate (MTX). Our aim was to describe orthopaedic interventions in a large group of adults with JIA followed up over several decades. This was a retrospective observational study of adult JIA patients attending a teaching hospital clinic, with information collated on JIA subtype, disease duration, orthopaedic interventions and exposure to MTX. The study included 144 patients with median disease duration of 19 years. Survival analysis showed that joint surgery was observed in the majority (75%) of patients with disease duration over 40 years with a trend for less joint surgery in patients with oligoarticular JIA. In total 41 patients (28.5%) had received joint surgery and 17/41(41%) have required multiple procedures. Of those who have required joint surgery, 20/41(48%) had started MTX in their adult years, with only 5/41 (12%), starting MTX prior to first joint replacement and none within five years of disease onset. Of the patients who have not had joint surgery to date, most (46/103, 45%) were receiving MTX or another immunosuppressive agent, in the majority of cases MTX was started within two years of disease onset. Many adults with JIA require joint replacement surgery and ongoing immunosuppressive treatments, emphasising that JIA is not a benign disease. Many patients who have had joint replacement surgery have had exposure to MTX albeit after many years after disease onset; it remains to be seen whether patients who have received MTX therapy early in their disease course will ultimately have less requirement for joint surgery

We attempted to investigate the incidence, the treatment modalities used and the outcome of Osteosarcoma (OS) patients treated at the two major Pediatric Oncology Hospitals in Singapore. A comprehensive list of patients with OS treated at the National University Hospital and KK Women’s and Children’s Hospital Singapore between April 1980 and May 2006 was generated. During the study interval, patients received neoadjuvant chemotherapy followed by definitive surgery consisting of either limb salvage or amputation followed by adjuvant chemotherapy. Chemotherapy was as per the European Osteosarcoma Intergroup (EOI) and as per the Memorial Sloan-Kettering Cancer Center’s (MSKCC) T12 protocols. Treatment of subsequent relapses consisted of various combinations of Methotrexate, ifosfamide, etoposide, other, and/or surgery. Of the total 49 patients with OS, 30% presented with metastatic OS. Median age of diagnosis of OS was 12.4 years. For the cohort, two and five-year overall survival were 71% and 55% respectively. The two-year overall survival was 73% for patients who were treated as per the MSKCC protocol. At last follow-up, median 4.3 years (range, 0.3 – 21.6 years), 25 were alive with no evidence of disease and 16 were dead of disease. Survival from OS in Singapore appears to be improving. Rarity and complexity of OS makes it crucial for patients to seek a centralized multi-disciplinary Musculoskeletal Oncology team involving surgeons and Pediatric Oncologists dedicated to the care of these young patients with the intent to cure