An ovine knee simulator: description and proof of concept.

Aims: The ovine stifle is an established model for evaluation of knee treatments, such as meniscus replacement. This study introduces a novel ovine gait simulator for pre-testing of surgical treatments prior to in vivo animal trials. Furthermore, we describe a pilot study that assessed gait kinematics and contact pressures of native ovine stifle joints and those implanted with a novel fiber-matrix reinforced polyvinyl alcohol-polyethylene glycol (PVA-PEG) hydrogel meniscus to illustrate the efficacy of the simulator. Methods: The gait simulator controlled femoral flexion-extension and applied a 980N axial contact force to the distal tibia, whose movement was guided by the natural ligaments. Five right ovine stifle joints were implanted with a PVA-PEG total medial meniscus replacement, fixed to the tibia via transosseous tunnels and interference screws. Six intact and five implanted right ovine stifle joints were tested for 500 k gait cycles at 1.55 Hz. Implanted stifle joint contact pressures and kinematics in the simulator were compared to the intact group. Contact pressures were measured at 55° flexion using pressure sensitive film inserted sub-meniscally. 3D kinematics were measured optically across two 30-s captures. Results: Peak contact pressures in intact stifles were 3.6 ± 1.0 MPa and 6.0 ± 2.1 MPa in the medial and lateral condyles (p < 0.05) and did not differ significantly from previous studies (p > 0.4). Medial peak implanted pressures were 4.3 ± 2.2 MPa (p > 0.4 versus intact), while lateral peak pressures (9.4 ± 0.8 MPa) were raised post medial compartment implantation (p < 0.01). The range of motion for intact joints was flexion/extension 37° ± 1°, varus/valgus 1° ± 1°, external/internal rotation 5° ± 3°, lateral/medial translation 2 ± 1 mm, anterior/posterior translation 3 ± 1 mm and distraction/compression 1 ± 1 mm. Ovine joint kinematics in the simulator did not differ significantly from published in vivo data for the intact group, and the intact and implanted groups were comparable (p > 0.01), except for in distraction-compression (p < 0.01). Conclusion: These findings show correspondence of the ovine simulator kinematics with in vivo gait parameters. The efficacy of the simulator to evaluate novel treatments was demonstrated by implanting a PVA-PEG hydrogel medial meniscal replacement, which restored the medial peak contact pressures but not lateral. This novel simulator may enable future work on the development of surgical procedures, derisking subsequent work in live animals.

Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging.

Clonal hematopoiesis (CH) arises when hematopoietic stem cells (HSCs) acquire mutations, most frequently in the DNMT3A and TET2 genes, conferring a competitive advantage through mechanisms that remain unclear. To gain insight into how CH mutations enable gradual clonal expansion, we used single-cell multi-omics with high-fidelity genotyping on human CH bone marrow (BM) samples. Most of the selective advantage of mutant cells occurs within HSCs. DNMT3A- and TET2-mutant clones expand further in early progenitors, while TET2 mutations accelerate myeloid maturation in a dose-dependent manner. Unexpectedly, both mutant and non-mutant HSCs from CH samples are enriched for inflammatory and aging transcriptomic signatures, compared with HSCs from non-CH samples, revealing a non-cell-autonomous effect. However, DNMT3A- and TET2-mutant HSCs have an attenuated inflammatory response relative to wild-type HSCs within the same sample. Our data support a model whereby CH clones are gradually selected because they are resistant to the deleterious impact of inflammation and aging.

Cementation in total hip arthroplasty: history, principles, and technique.

Total hip arthroplasty (THA) is a remarkably successful operation that has grown rapidly its utilization. Early modern THA constructs as developed by Sir John Charnley featured cemented femoral stems and acetabular components. The technique of cementing components for THA has evolved over time. Modern acetabular preparation requires exposure of the subchondral bone with appropriate cement penetration into the trabecular bone, whereas femoral preparation requires cleaning of the canal, cement restrictor placement, retrograde filling, and pressurization of the cement. When used appropriately, these techniques result in excellent long-term survivorship of implants and are also widely considered to be the ideal method of fixation for hip fractures. The purpose of this article to review the history, properties, techniques, and outcomes of bone cement utilization in THA.

Prevention of Periprosthetic Joint Infection in Total Hip and Knee Replacement: One European Consensus.

Periprosthetic joint infection (PJI) is a devastating complication in total hip and knee replacement. Its prevention is key to decrease the incidence and avoid some consequences that seriously impact patients and health systems. In view of the variety of recommendations and guidelines, we decided to conduct an expert, peer-reviewed European consensus analysis about the pre-, intra-, and postoperative prevention of PJI. A multinational group of practicing orthopedic experts developed a series of 47 consensus statements in 6 main groups of intervention, and a 2-stage Delphi approach was launched with a threshold for agreement at 75% and for very high agreement at more than 90%. A total of 306 orthopedic surgeon responses were gathered from 9 countries. Consensus was reached for 42/47 statements, 31/47 of which achieved a very high consensus. Many preoperative actions gathered strong consensus, although areas like the use of alcoholic chlorhexidine or the timing of hair removal did not attain strong consensus, despite available evidence. Intra- and postoperative actions showed more variability regarding incise drapes, skin suturing techniques, and wound follow-up. This study confirms an important consensus among orthopedic surgeons across Europe in many areas well known to contribute to the prevention of PJI; however, there are still grounds for improvement.

A longitudinal cohort study of adolescent elite footballers and controls investigating the development of cam morphology.

Cam morphology describes an asphericity of the femoral head that develops during adolescence, is highly prevalent in athletes, and predisposes individuals to future osteoarthritis. However, it's aetiology remains poorly understood. The aim of this study was to perform 3-year longitudinal follow-up of a control population and football club academy cohort to compare the change in hip and growth plate anatomy between athletes and controls. MRI and questionnaires were used to characterise change in hip and growth plate anatomy and quantify activity levels. 121 male academy footballers and 107 male and female controls participated at baseline. Footballers experienced significantly greater increases in femoral head asphericity (4.83 degrees (95% CI: 2.84 to 6.82), p < 0.001) than controls. A positive correlation existed between activity levels and change in femoral head morphology (coefficient 0.79, p ≤ 0.001). Greatest morphological change occurred in individuals aged 11-12 years at baseline, with no significant change in individuals aged 14 years and older at baseline. Cam morphology development was secondary to soft tissue hypertrophy and lateral growth plate extension. In conclusion, excessive loading of the hip joint through exercise prior to 14 years of age may result in growth plate adaptations causing cam morphology. Potential interventions may include training type and load modification in young adolescent football players.

Primary stability of a proximally coated and tapered stem.

AIMS: The aim of this prospective cohort study was to evaluate the early migration of the TriFit cementless proximally coated tapered femoral stem using radiostereometric analysis (RSA). METHODS: A total of 21 patients (eight men and 13 women) undergoing primary total hip arthroplasty (THA) for osteoarthritis of the hip were recruited in this study and followed up for two years. Two patients were lost to follow-up. All patients received a TriFit stem and Trinity Cup with a vitamin E-infused highly cross-linked ultra-high molecular weight polyethylene liner. Radiographs for RSA were taken postoperatively and then at three, 12, and 24 months. Oxford Hip Score (OHS), EuroQol five-dimension questionnaire (EQ-5D), and adverse events were reported. RESULTS: At two years, the mean subsidence of the head and tip for the TriFit stem was 0.38 mm (SD 0.32) and 0.52 mm (SD 0.36), respectively. The total migration of the head and tip was 0.55 mm (SD 0.32) and 0.71 mm (SD 0.38), respectively. There were no statistically significant differences between the three to 12 months' migration (p = 0.105) and 12 to 24 months' migration (p = 0.694). The OHS and EQ-5D showed significant improvements at two years. CONCLUSION: The results of this study suggest that the TriFit femoral stem achieves initial stability and is likely to be stable in the mid and long term. A long-term outcome study is required to assess late mechanisms of failure and the effects of bone mineral density (BMD) related changes. Cite this article: Bone Joint J 2021;103-B(4):644-649.

Trends and developments in hip and knee arthroplasty technology.

The developments in hip and knee arthroplasty over recent years have aimed to improve outcomes, reduce complications and improve implant survival. This review describes some of the most interesting trends and developments in this important and fast-moving field. Notable developments have included ceramic hip resurfacing, mini hip stems, cementless knee replacement and the wider adoption of the dual mobility articulation for hip arthroplasty. Advances in additive manufacturing and the surface modification of joint replacements offer increasing options for more challenging arthroplasty cases. Robotic assisted surgery is one of the most interesting developments in hip and knee surgery. The recent growth in the use of this technology is providing data that will help determine whether this approach should become the standard of care for hip and knee arthroplasty in the future.

The Response of Hip Joint Cartilage to Exercise in Children: An MRI Study Using T2-Mapping.

OBJECTIVE: The aim of this study was to determine the effects of activity and cam morphology on cartilage composition during adolescence and investigate the development of cartilage composition with age. DESIGN: Cross-sectional observational cohort study of individuals from football club academies and an age-matched control population, aged 9 to 18 years. Assessments included questionnaires and T2-mapping of hips. Primary imaging outcome measures were T2 relaxation time of acetabular and femoral cartilage, average alpha angle, and lateral epiphyseal extension. RESULTS: The cohort consisted of 109 elite male footballers, 49 male controls, and 51 female controls. Elite male footballers had an acetabular cartilage T2 value 4.85 ms greater than male controls (P < 0.001). A significant positive correlation existed between Physical Activity Questionnaire Score and acetabular cartilage T2 value (coefficient 1.07, P < 0.001) and femoral cartilage T2 value (coefficient 0.66, P = 0.032). Individuals with a closed physis had an acetabular cartilage T2 value 7.86 ms less than individuals with an open physis. Acetabular cartilage T2 values decreased with age in elite footballers. No correlation existed between alpha angle and anterosuperior acetabular cartilage T2 value and no difference in T2 value existed between individuals with and without cam morphology. CONCLUSIONS: This study demonstrates that high activity levels may significantly affect acetabular cartilage composition during adolescence, but cam morphology may not detrimentally affect cartilage composition until after adolescence.

Are multiple views superior to a single view when teaching hip surgery? A single-blinded randomized controlled trial of technical skill acquisition.

PURPOSE: Surgical education videos currently all use a single point of view (POV) with the trainee locked onto a fixed viewpoint, which may not deliver sufficient information for complex procedures. We developed a novel multiple POV video system and evaluated its training outcome compared with traditional single POV. METHODS: We filmed a hip resurfacing procedure performed by an expert attending using 8 cameras in theatre. 30 medical students were randomly and equally allocated to learn the procedure using the multiple POV (experiment group [EG]) versus single POV system (control group [CG]). Participants advanced a pin into the femoral head as demonstrated in the video. We measured the drilling trajectories and compared it with pre-operative plan to evaluate distance of the pin insertion and angular deviations. Two orthopedic attendings expertly evaluated the participants' performance using a modified global rating scale (GRS). There was a pre-video knowledge test that was repeated post-simulation alongside a Likert-scale questionnaire. RESULTS: The angular deviation of the pin in EG was significantly less by 29% compared to CG (p = 0.037), with no significant difference in the entry point's distance between groups (p = 0.204). The GRS scores for EG were 3.5% higher than CG (p = 0.046). There was a 32% higher overall knowledge test score (p<0.001) and 21% improved Likert-scale questionnaire score (p = 0.002) after video-learning in EG than CG, albeit no significant difference in the knowledge test score before video-learning (p = 0.721). CONCLUSION: The novel multiple POV provided significant objective and subjective advantages over single POV for acquisition of technical skills in hip surgery.

Implications of anticoagulant and antiplatelet therapy in patients presenting with hip fractures: a current concepts review.

The increasing use of anticoagulant and antiplatelet therapy for the prevention of thromboembolic disease poses a significant challenge to orthopaedic surgeons treating elderly patients presenting with proximal femoral fractures. Early surgical intervention is known to be beneficial from a clinical perspective and has been encouraged in the UK through the introduction of best practice tariffs providing increased remuneration for prompt treatment. An understanding of the necessary delay to surgery or reversal options for each type of antiplatelet or anticoagulant agent is therefore important. A number of professional bodies have recently produced guidelines that help clinicians manage these patients during the peri-operative period. We review the guidelines relating to antiplatelet and anticoagulant agents during the perioperative period with respect to hip fracture surgery. Antiplatelet agents should not interfere with timing of surgery, but may affect the choice of anaesthetic performed. The action of warfarin should be reversed to expedite surgery. Newer direct oral anticoagulants are more problematic and surgical delay may be necessary, though reversal agents are becoming available.

Corrective Osteotomies for Complex Intra-Articular Tibial Plateau Malunions using Three-Dimensional Virtual Planning and Novel Patient-Specific Guides.

Corrective osteotomy of intra-articular tibial plateau malunions is technically demanding for orthopaedic surgeons. The aim of our study was to evaluate the feasibility of the combination of three-dimensional (3D) virtual planning and novel patient-specific guides for assisting correction of complex intra-articular tibial plateau malunions. Six patients with posttraumatic intra-articular tibial plateau malunions were included. Preoperatively 3D models of the tibias were reconstructed using the computed tomography scan data. Virtual surgical planning was performed, and patient-specific guides for osteotomy and reduction were designed, which were then 3D printed. Intraoperatively they were applied to guide the osteotomy and reduction. After surgery, radiographs were taken to evaluate the knee joint surface. The operating surgeons were asked to complete the Likert scale questionnaire to assess their attitude to the novel technology. The guides were successfully used for guiding osteotomy correction of malunion in all patients. Postoperative radiographs showed the articular step-off was considerably reduced and the articular congruency was satisfactory in all patients. The results of the questionnaire demonstrated a high level of surgeon satisfaction and acceptance to the technology. For selective patients with complex intra-articular tibial plateau malunions, the novel technique could serve as a valuable option for guiding precise malunion correction.

Up to 10 year follow-up of the Oxford Domed Lateral Partial Knee Replacement from an independent centre.

BACKGROUND: The Oxford Domed Lateral Partial Knee Replacement (ODLPKR) was designed specifically for the lateral compartment in response to the unacceptable dislocation rate seen with the Oxford Partial Knee. This paper presents the up to 10-year follow-up of an independent, single surgeon series using this implant. The aim of this study is to assess the medium term outcome of the ODLPKR. The primary outcome measures were 13 revision surgery, re-operation and functional outcome. METHODS: Sixty-four knees in 58 patients were performed between 2005 and 2009. Patients were interviewed by telephone to determine whether further surgery had been conducted on their knee and to complete an Oxford Knee Score (OKS) questionnaire. RESULTS: The status of 61 knees was confirmed with a median follow-up period of 84months. One patient sustained two bearing dislocations ultimately requiring an elective bearing exchange. Two knees underwent revision to TKR and five other patients reported further operations. Median OKS was 26 (range nine to 36) pre-operatively and 42 (10-48) at final follow-up. CONCLUSION: The ODLPKR offers an effective and safe treatment for lateral compartment osteoarthritis. Bearing dislocation does not appear to be a significant issue with this implant and implant retention is similar to that achieved by medial unicompartmental knee replacements in the medium term.

Patient-specific instrumentation improves alignment of lateral unicompartmental knee replacements by novice surgeons.

PURPOSE: Patient-specific instrumentation (PSI) has the potential to offer numerous benefits-not least of all, improved resection accuracy; but its potential has not been realised in clinical studies. An explanation may be the focus of such studies on the total knee replacement (TKR-a common procedure, with which surgeons are generally very familiar. Consequently, we sought to investigate the potential role of PSI in guiding novice surgeons to perform the more technically demanding and less familiar lateral unicondylar knee replacement (LUKR). METHODS: Twelve orthopaedic trainees naive to LUKR were instructed to perform the procedure according to a pre-operative plan. These were carried out on synthetic sawbones and were completed once with conventional instrumentation alone and once with the adjunct of PSI, allowing a comparison of the plan adherence achieved by the two sets of instrumentation. RESULTS: There was a tendency for PSI to demonstrate improved plan adherence, though a statistically significant improvement was only seen in compound rotational error of the femoral implant (p = 0.004). PSI was, however, able to produce narrower standard deviations in the mean translational displacement of the femoral implant and also the mean rotational displacement of both implants, suggesting a higher degree of precision. CONCLUSIONS: Our study provides some evidence that PSI can improve the ability of novice surgeons to replicate a pre-operative plan, but our results suggest the need for larger-scale clinical studies to establish the role of PSI in this procedure.

Application of an innovative computerized virtual planning system in acetabular fracture surgery: A feasibility study.

INTRODUCTION: Acetabular fracture surgery is amongst the most challenging tasks in the field of trauma surgery and careful preoperative planning is crucial for success. The aim of this paper is to describe the preliminary outcome of the utilization of an innovative computerized virtual planning system for acetabular fractures. METHODS: 3D models of acetabular fractures and surrounding soft tissues from six patients were constructed from preoperative CT scans. A novel highly-automatic segmentation technique was performed on the 3D model to separate each fracture fragment, then 3D virtual reduction was performed. Additionally, the models were used to assess potential surgical approaches with reference to both the fracture and the surrounding soft tissues. The time required for virtual planning was recorded. After surgery, the virtual plan was compared to the real surgery with respect to surgical approach and reduction sequence. A Likert scale questionnaire was completed by the surgeons to evaluate their satisfaction with the system. RESULTS: Virtual planning was successfully completed in all cases. The planned surgical approach was followed in all cases with the planned reduction sequence followed completely in five cases and partially in one. The mean time required for virtual planning was 38.7min (range 21-57, SD=15.5). The mean time required for planning of B-type fractures was 25.0min (range 21-30, SD=4.6), of C-type fracture 52.3min (range 49-57, SD=4.2). The results of the questionnaire demonstrated a high level of satisfaction with the planning system. CONCLUSION: This study demonstrates that the virtual planning system is feasible in clinical settings with high satisfaction and acceptability from the surgeons. It provides a viable option for the planning of acetabular fracture surgery.

Increase in quality and quantity of orthopaedic studies from 2002 to 2012.

PURPOSE: To compare the level of evidence of orthopaedic studies published in 2002 and 2012 to determine whether the quality and quantity of studies have increased. METHODS: The top 10 orthopaedic journals in 2002 and 2012 were identified, according to the Thomson Reuters impact factor. The level of evidence of each clinical article between January and June in 2002 and 2012 were determined by 2 senior orthopaedic trainees, according to the Oxford Centre for Evidence-based Medicine 2011 Levels of Evidence. Basic science articles, case reports, and non-systematic reviews were excluded. The proportions of papers designated to each level of evidence in 2002 and 2012 were compared, as was the mean level of evidence of studies in 2002 and 2012. RESULTS: In 2002, 379 clinical articles were identified and their level of evidence was level 1 (n=3), level 2 (n=67), level 3 (n=71), and level 4 (n=238). In 2012, 642 clinical articles were identified and their level of evidence was level 1 (n=26), level 2 (n=113), level 3 (n=167), and level 4 (n=336). The proportion of level 4 articles decreased from 62.8% in 2002 to 52.3% in 2012 (p=0.001), whereas the proportion of level 1 articles increased from 0.8% to 4.1% (p=0.002) and level 3 articles increased from 18.7% to 26.0% (p=0.008). The mean level of evidence improved from 3.44 in 2002 to 3.27 in 2012 (p=0.002). CONCLUSION: The quality and quantity of orthopaedic studies have increased from 2002 to 2012, but most studies remained of a low level of evidence.

The In Vitro and In Vivo Activity of the Microtubule Disruptor STX140 Is Mediated by Hif-1 Alpha and CAIX Expression.

Tumor neo-angiogenesis is regulated, in part, by the hypoxia-inducible gene HIF1. Evidence suggests HIF1 associates with polymerized microtubules and traffics to the nucleus. This study investigated the role of HIF1 in mediating the antitumor activity of two steroid-based sulfamate ester microtubule disruptors, STX140 and STX243, in vitro and in vivo. The effects of STX140, STX243 and the parental compound 2-methoxyestradiol (STX66) on HIF1α and HIF2α protein expression were assessed in vitro in MCF-7 and MDA-MB-231 cells cultured under hypoxia. More pertinently, their effects were examined on HIF1-regulated genes in vivo in mice bearing MCF-7 or MDA-MB-231 tumors. The level of mRNA expression of vascular endothelial growth factor (VEGF), glucose transporter 1 (GLUTI), phosphoglycerate kinase (PGK), ATP-binding cassette sub-family B member 1 (ABCB1) and carbonic anhydrase IX (CAIX) was quantified by Real-time Polymerase Chain Reaction (RT-PCR). Despite inhibiting nuclear HIF1α protein accumulation under hypoxia in vitro, STX140 and STX243 did not significantly regulate the expression of four out of five HIF1α-regulated genes in vitro and in vivo. Only CAIX mRNA expression was down-regulated both in vitro and in vivo. Immunoblot analysis showed that STX140 and STX243 reduced CAIX protein expression in vitro. These compounds had no effect on HIF2α translocation. The potential for inhibition of CAIX by STX140 and STX243 was examined by docking the ligands to the active site in comparison with a known sulfamate-based inhibitor. Microtubule disruption and antitumor activity of STX140 and STX243 is most likely HIF1-independent and may, at least in part, be mediated by inhibition of CAIX expression and activity.

Synthesis, anti-tubulin and antiproliferative SAR of steroidomimetic dihydroisoquinolinones.

A SAR translation strategy adopted for the discovery of tetrahydroisoquinolinone (THIQ)-based steroidomimetic microtubule disruptors has been extended to dihydroisoquinolinone (DHIQ)-based compounds. A steroid A,B-ring-mimicking DHIQ core was connected to methoxyaryl D-ring mimics through methylene, carbonyl, and sulfonyl linkers, and the resulting compounds were evaluated against two cancer cell lines. The carbonyl-linked DHIQs in particular exhibit significant in vitro antiproliferative activities (e.g., 6-hydroxy-7-methoxy-2-(3,4,5-trimethoxybenzoyl)-3,4-dihydroisoquinolin-1(2H)-one (16 g): GI50 51 nM in DU-145 cells). The broad anticancer activity of DHIQ 16 g was confirmed in the NCI 60-cell line assay giving a mean activity of 33 nM. Furthermore, 6-hydroxy-2-(3,5-dimethoxybenzoyl)-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (16 f) and 16 g and their sulfamate derivatives 17 f and 17 g (2-(3,5-dimethoxybenzoyl)-7-methoxy-6-sulfamoyloxy-3,4-dihydroisoquinolin-1(2H)-one and 7-methoxy-2-(3,4,5-trimethoxybenzoyl)-6-sulfamoyloxy-3,4-dihydroisoquinolin-1(2H)-one, respectively) show excellent activity against the polymerization of tubulin, close to that of the clinical combretastatin A-4, and bind competitively at the colchicine binding site of tubulin. Compounds 16 f and 17 f were also shown to demonstrate in vitro anti-angiogenic activity. Additionally, X-ray and computational analyses of 17 f reveal that electrostatic repulsion between the two adjacent carbonyl groups, through conformational biasing, dictates the adoption of a "steroid-like" conformation that may partially explain the excellent in vitro activities.

Enhanced osseous implant fixation with strontium-substituted bioactive glass coating.

The use of endosseous implants is firmly established in skeletal reconstructive surgery, with rapid and permanent fixation of prostheses being a highly desirable feature. Implant coatings composed of hydroxyapatite (HA) have become the standard and have been used with some success in prolonging the time to revision surgery, but aseptic loosening remains a significant issue. The development of a new generation of more biologically active coatings is a promising approach for tackling this problem. Bioactive glasses are an ideal candidate material due to the osteostimulative properties of their dissolution products. However, to date, they have not been formulated with stability to devitrification or thermal expansion coefficients (TECs) that are suitable for stable coating onto metal implants while still retaining their bioactive properties. Here, we present a strontium-substituted bioactive glass (SrBG) implant coating which has been designed to encourage peri-implant bone formation and with a TEC similar to that of HA. The coating can be successfully applied to roughened Ti6Al4V and after implantation into the distal femur and proximal tibia of twenty-seven New Zealand White rabbits for 6, 12, or 24 weeks, it produced no adverse tissue reaction. The glass dissolved over a 6 week period, stimulating enhanced peri-implant bone formation compared with matched HA coated implants in the contralateral limb. Furthermore, superior mechanical fixation was evident in the SrBG group after 24 weeks of implantation. We propose that this coating has the potential to enhance implant fixation in a variety of orthopedic reconstructive surgery applications.

Synthesis, antitubulin, and antiproliferative SAR of C3/C1-substituted tetrahydroisoquinolines.

The syntheses and antiproliferative activities of novel substituted tetrahydroisoquinoline derivatives and their sulfamates are discussed. Biasing of conformational populations through substitution on the tetrahydroisoquinoline core at C1 and C3 has a profound effect on the antiproliferative activity against various cancer cell lines. The C3 methyl-substituted sulfamate (±)-7-methoxy-2-(3-methoxybenzyl)-3-methyl-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline (6 b), for example, was found to be ∼10-fold more potent than the corresponding non-methylated compound 7-methoxy-2-(3-methoxybenzyl)-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline (4 b) against DU-145 prostate cancer cells (GI50 values: 220 nM and 2.1 µM, respectively). Such compounds were also found to be active against a drug-resistant MCF breast cancer cell line. The position and nature of substitution of the N-benzyl group in the C3-substituted series was found to have a significant effect on activity. Whereas C1 methylation has little effect on activity, introduction of C1 phenyl and C3-gem-dimethyl substituents greatly decreases antiproliferative activity. The ability of these compounds to inhibit microtubule polymerisation and to bind tubulin in a competitive manner versus colchicine confirms the mechanism of action. The therapeutic potential of a representative compound was confirmed in an in vivo multiple myeloma xenograft study.