3D distribution of perlecan within intervertebral disc chondrons suggests novel regulatory roles for this multifunctional modular heparan sulphate proteoglycan.

Perlecan is a modular, multifunctional heparan sulphate-proteoglycan (HS-PG) that is present in the pericellular and wider extracellular matrix of connective tissues. In the present study, confocal microscopy was used to study perlecan distribution within intervertebral disc chondrons. Perlecan immunolabel was demonstrated intracellularly and in close association with the cell nucleus within chondrons of both the annulus fibrosus (AF) and nucleus pulposus (NP). This observation is consistent with earlier studies that have localised HS-PGs with nuclear cytoskeletal components. Nuclear HS-PGs have been proposed to transport fibroblast growth factor (FGF)-1, FGF-2 and FGFR-1 into the cell nucleus, influencing cell proliferation and the cell-cycle. Perlecan has well-known interactive properties with FGF family members in the pericellular and extracellular matrix. Perinuclear perlecan may also participate in translocation events with FGFs. The glycosaminoglycan side chains of HS-PGs can modulate chromatin structure by regulating the access of transcription factors to DNA. These mechanisms are consistent with the distribution patterns identified here and previously reported for other HS-PGs, introducing a potentially-novel arena for perlecan in gene regulation. Whilst much is known of the structure and function of perlecan in the pericellular and extracellular matrix, very little is known of any intracellular forms of perlecan. The perlecan labelling patterns described here suggest the possibility of involvement of this HS-PG in an intracrine regulatory system. Future studies should further explore this possibility and the potential for this HS-PG as a novel therapeutic target.

Management of meningeal solitary fibrous tumors/hemangiopericytoma; surgery alone or surgery plus postoperative radiotherapy?

INTRODUCTION: A meningeal solitary fibrous tumor (SFT), also called hemangiopericytoma, is a rare mesenchymal malignancy. Due to anatomic constrains, even after macroscopic complete surgery with curative intent, the local relapse risk is still relatively high, thus increasing the risk of dedifferentiation and metastatic spread. This study aims to better define the role of postoperative radiotherapy (RT) in meningeal SFTs. PATIENTS AND METHODS: A retrospective study was performed across seven sarcoma centers. Clinical information was retrieved from all adult patients with meningeal primary localized SFT treated between 1990 and 2018 with surgery alone (S) compared to those that also received postoperative RT (S + RT). Differences in treatment characteristics between subgroups were tested using independent samples t-test for continuous variables and chi-square tests for proportions. Local control (LC) and overall survival (OS) rates were calculated as time from start of treatment until progression or death from any cause. LC and OS in groups receiving S or S + RT were compared using Kaplan-Meier survival curves. RESULTS: Among a total of 48 patients, 7 (15%) underwent S and 41 (85%) underwent S + RT. Median FU was 65 months. LC was significantly associated with treatment. LC after S at 60 months was 60% versus 90% after S + RT (p = 0.052). Furthermore, R1 resection status was significantly associated with worse LC (HR 4.08, p = 0.038). OS was predominantly associated with the mitotic count (HR 3.10, p = 0.011). CONCLUSION: This retrospective study, investigating postoperative RT in primary localized meningeal SFT patients, suggests that combining RT to surgery in the management of this patient population may reduce the risk for local failures.

ESMO consensus conference recommendations on the management of locoregional melanoma: under the auspices of the ESMO Guidelines Committee.

The European Society for Medical Oncology (ESMO) held a consensus conference on melanoma on 5-7 September 2019 in Amsterdam, The Netherlands. The conference included a multidisciplinary panel of 32 leading experts in the management of melanoma. The aim of the conference was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where available evidence is either limited or conflicting. The main topics identified for discussion were: (i) the management of locoregional disease; (ii) targeted versus immunotherapies in the adjuvant setting; (iii) targeted versus immunotherapies for the first-line treatment of metastatic melanoma; (iv) when to stop immunotherapy or targeted therapy in the metastatic setting; and (v) systemic versus local treatment of brain metastases. The expert panel was divided into five working groups in order to each address questions relating to one of the five topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the results relating to the management of locoregional melanoma, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.

ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee.

The European Society for Medical Oncology (ESMO) held a consensus conference on melanoma on 5-7 September 2019 in Amsterdam, The Netherlands. The conference included a multidisciplinary panel of 32 leading experts in the management of melanoma. The aim of the conference was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where available evidence is either limited or conflicting. The main topics identified for discussion were (i) the management of locoregional disease; (ii) targeted versus immunotherapies in the adjuvant setting; (iii) targeted versus immunotherapies for the first-line treatment of metastatic melanoma; (iv) when to stop immunotherapy or targeted therapy in the metastatic setting; and (v) systemic versus local treatment for brain metastases. The expert panel was divided into five working groups to each address questions relating to one of the five topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the results relating to the management of metastatic melanoma, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.

Diagnostic performance of MRI and histology in assessment of deep lipomatous tumours.

BACKGROUND: Deep lipomatous tumours can be benign lipomas or intermediate/locally recurring atypical lipomatous tumours (ALTs). Differentiating between these two entities clinically and radiologically is difficult. The aims of this study were to report a series of deep lipomatous tumours, comparing the clinical, radiological and pathological features of ALTs and lipomas; and to predict the likelihood of a lipomatous tumour being ALT based on anatomical site and MRI characteristics. METHODS: This was a retrospective review of patients with deep lipomatous tumours presenting over 6 years to a tertiary sarcoma centre, with preoperative MRI, and preoperative or postoperative histology including MDM2 gene analysis. Sensitivity, specificity, predictive values and accuracy in diagnosing ALT were calculated for MRI and histopathological features. RESULTS: Some 248 patients were included; 81 (32·7 per cent) had a final diagnosis of ALT. ALTs were larger than lipomas (median 19 versus 10 cm; P < 0·001); there was no ALT smaller than 5 cm. A tumour presenting in the lower limb was more likely to be an ALT than a lesion at any other site (48·4 versus 13·5 per cent; P < 0·001). In patients with lipomatous tumours at sites other than the lower limbs, MRI had a negative predictive value of 95 per cent for excluding ALT. CONCLUSION: Despite concern, most deep lipomatous tumours (nearly 70 per cent) are benign lipomas. Certain features imply that tumours are almost never ALT: smaller than 5 cm or located outside the lower limb with no suspicious characteristics on MRI. Tumours with these features might safely and confidently be managed outside tertiary sarcoma centres.

ANTECEDENTES: Los tumores lipomatosos profundos pueden ser lipomas benignos o tumores lipomatosos atípicos (atypical lipomatous tumour, ALT) con potencial de recidiva local/intermedia. Diferenciar estas dos entidades desde el punto de vista clínico es difícil. Los objetivos de este estudio fueron presentar una gran serie de tumores lipomatosos profundos, comparando las características clínicas, radiológicas y patológicas de los ALT y de los lipomas y predecir la probabilidad de que un tumor lipomatoso sea ALT según su localización anatómica y las características de la RNM. MÉTODOS: Revisión retrospectiva de pacientes con tumores lipomatosos profundos tratados en un centro terciario de sarcoma durante un período de 6 años, en los que se dispusiese de RNM preoperatoria y análisis MDM2 en el preoperatorio o postoperatorio. Se calculó la sensibilidad, la especificidad, el valor predictivo y la precisión diagnóstica de la RNM y de las características histopatológicas para el diagnóstico de ALT. RESULTADOS: Se incluyeron 248 pacientes, de los que en solo 81 (32,7%) se estableció un diagnóstico final de ALT. Los ALT fueron más grandes que los lipomas (19 versus 10 cm, P < 0,001) y no hubo ningún ALT de tamaño menor de 5 cm. Hubo una mayor probabilidad de que un tumor fuera ALT si se presentaba en las extremidades inferiores en comparación con cualquier otra localización (48,4% versus 13,5%, P < 0,001). En pacientes con tumores lipomatosos localizados en otros lugares que no fueran las extremidades inferiores, la RMN tuvo un valor predictivo negativo del 95,5% para excluir la ALT. CONCLUSIÓN: A pesar del recelo tradicional, la mayoría (70%) de los tumores lipomatosos profundos son lipomas benignos. Algunas características, como los tumores de menos de 5 cm y aquellos ubicados fuera de las extremidades inferiores sin características sospechosas por RNM, indican que los tumores casi nunca son ALT. Los tumores con esas características pueden tratarse de manera segura y con solvencia fuera de los centros de sarcomas terciarios. En casos seleccionados, puede ser útil la prueba genética MDM2 en la biopsia.

Prospective cohort study of ultrasound surveillance of regional lymph nodes in patients with intermediate-risk cutaneous melanoma.

BACKGROUND: For patients with intermediate-thickness melanoma, surveillance of regional lymph node basins by clinical examination alone has been reported to result in a larger number of lymph nodes involved by melanoma than if patients had initial sentinel node biopsy and completion dissection. This may result in worse regional control. A prospective study of both regular clinical examination and ultrasound surveillance was conducted to assess the effectiveness of these modalities. METHODS: Between 2010 and 2014, patients with melanoma of thickness 1·2-3·5 mm who had under-gone wide local excision but not sentinel node biopsy were recruited to a prospective observational study of regular clinical and ultrasound nodal surveillance. The primary endpoint was nodal burden within a dissected regional lymph node basin. Secondary endpoints included locoregional or distant relapse, progression-free and overall survival. RESULTS: Ninety patients were included in the study. After a median follow-up of 52 months, ten patients had developed nodal relapse as first recurrence, four had locoregional disease outside of an anatomical nodal basin as the first site of relapse and six had relapse with distant disease. None of the patients who developed relapse within a nodal basin presented with unresectable nodal disease. The median number of involved lymph nodes in patients undergoing lymphadenectomy for nodal relapse was 1 (range 1-2; mean 1·2). CONCLUSION: This study suggests that ultrasound surveillance of regional lymph node basins is safe for patients with melanoma who undergo a policy of nodal surveillance.

Modelling obesity trends in Australia: unravelling the past and predicting the future.

BACKGROUND/OBJECTIVES: Modelling is increasingly being used to predict the epidemiology of obesity progression and its consequences. The aims of this study were: (a) to present and validate a model for prediction of obesity among Australian adults and (b) to use the model to project the prevalence of obesity and severe obesity by 2025. SUBJECTS/METHODS: Individual level simulation combined with survey estimation techniques to model changing population body mass index (BMI) distribution over time. The model input population was derived from a nationally representative survey in 1995, representing over 12 million adults. Simulations were run for 30 years. The model was validated retrospectively and then used to predict obesity and severe obesity by 2025 among different aged cohorts and at a whole population level. RESULTS: The changing BMI distribution over time was well predicted by the model and projected prevalence of weight status groups agreed with population level data in 2008, 2012 and 2014.The model predicts more growth in obesity among younger than older adult cohorts. Projections at a whole population level, were that healthy weight will decline, overweight will remain steady, but obesity and severe obesity prevalence will continue to increase beyond 2016. Adult obesity prevalence was projected to increase from 19% in 1995 to 35% by 2025. Severe obesity (BMI>35), which was only around 5% in 1995, was projected to be 13% by 2025, two to three times the 1995 levels. CONCLUSIONS: The projected rise in obesity severe obesity will have more substantial cost and healthcare system implications than in previous decades. Having a robust epidemiological model is key to predicting these long-term costs and health outcomes into the future.

Cost-effectiveness analysis of telephone-based support for the management of pressure ulcers in people with spinal cord injury in India and Bangladesh.

OBJECTIVE: To determine from a societal perspective the cost-effectiveness and cost-utility of telephone-based support for management of pressure ulcers. STUDY DESIGN: Cost-effectiveness and cost-utility analysis of a randomised clinical trial. SETTING: Tertiary centre in India and Bangladesh. METHODS: An economic evaluation was conducted alongside a randomised clinical trial comparing 12 weeks of telephone-based support (intervention group) with usual care (control group). The analyses evaluated costs and health outcomes in terms of cm2 reduction of pressure ulcers size and quality-adjusted life years (QALYs) gained. All costs were in Indian Rupees (INR) and then converted to US dollars (USD). RESULTS: The mean (95% confidence interval) between-group difference for the reduction in size of pressure ulcers was 0.53 (-3.12 to 4.32) cm2, favouring the intervention group. The corresponding QALYs were 0.027 (0.004-0.051), favouring the intervention group. The mean total cost per participant in the intervention group was INR 43 781 (USD 2460) compared to INR 42 561 (USD 2391) for the control group. The per participant cost of delivering the intervention was INR 2110 (USD 119). The incremental cost-effectiveness ratio was INR 2306 (USD 130) per additional cm2 reduction in the size of the pressure ulcer and INR 44 915 (USD 2523) per QALY gained. CONCLUSION: In terms of QALYs, telephone-based support to help people manage pressure ulcers at home provides good value for money and has an 87% probability of being cost-effective, based on 3 times gross domestic product. Sensitivity analyses were performed using the overall cost data with and without productivity costs, and did not alter this conclusion.

Telephone-based management of pressure ulcers in people with spinal cord injury in low- and middle-income countries: a randomised controlled trial.

STUDY DESIGN: A multicentre, prospective, assessor-blinded, parallel randomised controlled trial. OBJECTIVES: The objective of the trial was to determine the effectiveness of telephone-based management of pressure ulcers in people with spinal cord injury (SCI) in low- and middle-income countries. METHODS: One hundred and twenty people with SCI living in the community were recruited through three hospitals in India and Bangladesh between November 2013 and March 2016. Participants had sustained an SCI >3 months prior and had a pressure ulcer. Participants were randomly allocated (1:1) to a control or intervention group. Participants in the control group received no intervention. Participants in the intervention group received weekly advice by telephone for 12 weeks about the management of their pressure ulcers from a trained health-care professional. Outcomes were measured by a blinded assessor at baseline and 12 weeks. There was one primary outcome, namely, the size of the pressure ulcer and 13 secondary outcomes. RESULTS: The mean between-group difference for the size of the pressure ulcer at 12 weeks was 2.3 cm2 (95% confidence interval -0.3 to 4.9; favouring the intervention group). Eight of the 13 secondary outcomes were statistically significant. CONCLUSION: The results of our primary outcome (that is, size of pressure ulcer) do not provide conclusive evidence that people with SCI can be supported at home to manage their pressure ulcers through regular telephone-based advice. However, the results from the secondary outcomes are sufficiently positive to provide hope that this simple intervention may provide some relief from this insidious problem in the future.

Patterns of disease relapse in primary extremity soft-tissue sarcoma.

BACKGROUND: Extremity soft-tissue sarcomas comprise a range of distinct histological subtypes. This study aimed to characterize the patterns of disease relapse in patients undergoing resection of primary extremity soft-tissue sarcoma. METHODS: All patients who had resection of primary extremity soft-tissue sarcoma at the Royal Marsden Hospital between January 2004 and January 2014 were identified from an institutional database. RESULTS: In the period examined, 556 patients underwent resection. The most common histological subtypes were undifferentiated pleomorphic sarcoma (169 patients, 30·4 per cent), well differentiated liposarcoma (63, 11·3 per cent), myxoid liposarcoma (62, 11·2 per cent), myxofibrosarcoma (54, 9·7 per cent) and leiomyosarcoma (39, 7·0 per cent). Local recurrence-free survival (LRFS) did not differ significantly between histological subtypes (P = 0·222). Distant metastasis-free survival (DMFS) and disease-specific survival (DSS) were found to differ significantly between subtypes (P < 0·001 for both DMFS and DSS), with the worst outcomes in patients with undifferentiated pleomorphic sarcoma (5-year survival rate: 56·8 (95 per cent c.i. 52·5 to 61·1) per cent for DMFS; 60·1 (55·6 to 64·6) per cent for DSS). However, on multivariable analysis, histological subtype was not found to be independently prognostic for LRFS, DMFS or DSS. Metastatic disease developed in 149 patients, with the lungs being the most common site of first metastasis (120 patients, 80·5 per cent). The site of first metastasis differed between subtypes, with extrapulmonary metastases predominant in myxoid liposarcoma (11 of 13 patients; P < 0·001). CONCLUSION: Although histological subtype was not found to be an independent prognostic factor for oncological outcomes, the site of first metastasis differed significantly between subtypes.

Pericellular colocalisation and interactive properties of type VI collagen and perlecan in the intervertebral disc.

The aim of this study was to immunolocalise type VI collagen and perlecan and determine their interactive properties in the intervertebral disc (IVD). Confocal laser scanning microscopy co-localised perlecan with type VI collagen as pericellular components of IVD cells and translamellar cross-bridges in ovine and murine IVDs. These cross-bridges were significantly less abundant in the heparin sulphate deficient Hspg2 exon 3 null mouse IVD than in wild type. This association of type VI collagen with elastic components provides clues as to its roles in conveying elastic recoil properties to annular tissues. Perlecan and type VI collagen were highly interactive in plasmon resonance studies. Pericellular colocalisation of perlecan and type VI collagen provides matrix stabilisation and cell-matrix communication which allows IVD cells to perceive and respond to perturbations in their biomechanical microenvironment. Perlecan, at the cell surface, provides an adhesive interface between the cell and its surrounding extracellular matrix. Elastic microfibrillar structures regulate tensional connective tissue development and function. The 2010 Global Burden of Disease study examined 291 disorders and identified disc degeneration and associated low back pain as the leading global musculoskeletal disorder emphasising its massive socioeconomic impact and the need for more effective treatment strategies. A greater understanding of how the IVD achieves its unique biomechanical functional properties is of great importance in the development of such therapeutic measures.

A telephone-based version of the spinal cord injury-secondary conditions scale: a reliability and validity study.

OBJECTIVE: The objective of this study was to determine the inter-rater reliability and validity of using a telephone-based version of the spinal cord injury-secondary conditions scale (SCI-SCS). TRIAL DESIGN: A psychometric study was conducted. SETTING: The study was conducted in Royal North Shore Hospital, Sydney, Australia. PARTICIPANTS: Forty people with a complete or an incomplete spinal cord injury. METHODS: Inter-rater reliability was tested by comparing the telephone-based version of the SCI-SCS administered on two different days by two different telephone assessors. Validity was tested by comparing the telephone-based version of the SCI-SCS with the paper-based version of the SCI-SCS. RESULTS: The median (interquartile range) age and time since injury were 54 (48-63) years and 28 (14-35) years, respectively. The intraclass correlation coefficient (95% confidence interval) reflecting the agreement between the telephone-based version of the SCI-SCS administered on two different days by two different assessors was 0.96 (0.93-0.98). The corresponding value reflecting agreement between the telephone-based assessment and the paper-based assessment was 0.90 (0.83-0.95). CONCLUSION: The telephone-based version of the SCI-SCS is a simple and a quick questionnaire to administer that has both inter-rater reliability and validity. It may be useful as a way to screen for secondary health conditions in low- and middle-income countries where it is not always feasible to provide routine face-to-face follow-ups and where literacy may be a problem.

Isolated Limb Perfusion with Melphalan and Tumour Necrosis Factor α for In-Transit Melanoma and Soft Tissue Sarcoma.

BACKGROUND: Isolated limb perfusion (ILP) is indicated in locally advanced melanoma and soft tissue sarcoma of the extremities. This series reports the outcome of patients undergoing ILP with melphalan and tumour necrosis factor α (TNFα) at a single centre. METHODS: All patients undergoing ILP from January 2005 to January 2015 were identified from a prospectively maintained database. Those undergoing ILP for in-transit melanoma (ITM) were grouped according to disease burden: low volume and bulky (>2 cm diameter). RESULTS: A total of 143 perfusions were attempted: 9 and 134 in the upper and lower limbs, respectively. A response was assessable in 129 patients with overall response rates for ITM and sarcoma of 81.8 and 61.1 %, respectively. No difference was found in response rates between low-volume and bulky ITM. Limb salvage rates in these cohorts were 97 and 62 %. Regional toxicity following ILP was minimal with 7 grade III (5.4 %), and 1 grade V (0.8 %) reactions. Median progression-free survival was 11 months in the ITM cohort and 12 months in the sarcoma cohort. In the ITM cohort, complete responses were significantly more durable than partial responses (p = 0.0004). Median disease-specific survival was 21 months in the ITM cohort and was not reached in the sarcoma cohort. CONCLUSIONS: TNFα-based ILP is safe and provides excellent palliation of ITM due to rapid progression of systemic disease. It is less effective in sarcoma due to lower initial response rates and a lower incidence of disease dissemination.

Percutaneous core needle biopsy in retroperitoneal sarcomas does not influence local recurrence or overall survival.

BACKGROUND: Tumours within the retroperitoneum can cause a diagnostic dilemma. A preoperative core needle biopsy often is required to establish a histological diagnosis. Preoperative core needle biopsy for extremity soft-tissue sarcoma is oncologically safe and biopsy site recurrence is extremely rare, attributed to placing the biopsy site within the planned resection field. This study investigates whether preoperative core needle biopsy affects oncological outcomes in retroperitoneal sarcomas. METHODS: Patients undergoing resection of intermediate- and high-grade primary retroperitoneal sarcoma from 1990 until 2011 were included. Primary endpoints were immediate biopsy-related complications, local recurrence, and overall survival. RESULTS: A total of 150 patients were included in the analysis. Of these, 90 patients underwent resection after a preoperative biopsy. Median follow-up was 48 months. One patient required hospital admission postbiopsy for an abdominal wall rectus sheath haematoma. No patient developed intra-abdominal complications that required hospitalisation or early operation related to core needle biopsy. No patient developed a biopsy site recurrence. There was no significant increase in either local recurrence (p = 0.101) or overall survival (p = 0.191) after core needle biopsy. CONCLUSIONS: Preoperative core needle biopsy for retroperitoneal sarcomas is safe and does not affect oncological outcome.

Outcome following resection of retroperitoneal sarcoma.

BACKGROUND: Retroperitoneal sarcoma comprises a range of different histological subtypes with dissimilar behaviour and biology. This study sought to characterize the morbidity and mortality associated with multivisceral resection and oncological outcomes according to subtype. METHODS: All patients undergoing resection of primary retroperitoneal sarcoma at the Royal Marsden Hospital between January 2005 and December 2014 were identified from a database. RESULTS: Some 362 patients underwent resection, with 292 requiring multivisceral resection. The 30-day mortality rate was 1·4 per cent (5 patients), the 30-day morbidity rate was 15·7 per cent (57 patients), and 27 patients required a return to theatre. Age over 75 years was predictive of 30-day mortality (hazard ratio 1·37, 95 per cent c.i. 1·13 to 1·65). The overall disease-specific survival rate at 3 years was 81·2 per cent. For well differentiated liposarcoma, dedifferentiated liposarcoma and leiomyosarcoma, 3-year local recurrence-free survival rates were 98 (95 per cent c.i. 83 to 99), 56·7 (45·7 to 66·2) and 80 (67 to 89) per cent respectively. At 3 years the distant metastasis-free survival rate was 100, 85·9 (77·4 to 91·4) and 65 (49 to 77) per cent, and the disease-specific survival rate was 97 (89 to 99), 78·5 (74·6 to 82·4) and 79 (63 to 85) per cent for well differentiated liposarcoma, dedifferentiated liposarcoma and leiomyosarcoma respectively. CONCLUSION: Resection of retroperitoneal sarcoma was associated with a 30-day mortality rate of less than 2 per cent and a morbidity rate of 15·7 per cent. The overall 3-year disease-specific survival rate was 81·2 per cent.

Surgical treatment of gastrointestinal stromal tumour of the rectum in the era of imatinib.

BACKGROUND: Gastrointestinal stromal tumours (GISTs) of the rectum often require radical surgery to achieve complete resection. This study investigated the management and outcome of surgery for rectal GISTs and the role of imatinib. METHODS: A cohort study was undertaken of patients identified from a database at one tertiary sarcoma referral centre over a continuous period, from January 2001 to January 2013. RESULTS: Over 12 years, 19 patients presented with a primary rectal GIST. Median age was 57 (range 30-77) years. Neoadjuvant imatinib was used in 15 patients, significantly reducing mean tumour size from 7·6 (95 per cent c.i. 6·1 to 9·0) to 4·1 (2·8 to 5·3) cm (P < 0·001). Nine of these patients underwent surgical resection. Imatinib therapy enabled sphincter-preserving surgery to be undertaken in seven patients who would otherwise have required abdominoperineal resection or pelvic exenteration for tumour clearance. Neoadjuvant imatinib treatment also led to a significant reduction in mean(s.d.) tumour mitotic count from 16(16) to 4(9) per 50 high-power fields (P = 0·015). Imatinib was used only as adjuvant treatment in two patients. There were three deaths, all from unrelated causes. Eleven of the 13 patients who underwent resection were alive without evidence of recurrence at latest follow-up, with a median disease-free survival of 38 (range 20-129) months and overall survival of 62 (39-162) months. CONCLUSION: The use of neoadjuvant imatinib for rectal GISTs significantly decreased both tumour size and mitotic activity, which permitted less radical sphincter-preserving surgery.

The transmembrane heparan sulphate proteoglycan syndecan-4 is involved in establishment of the lamellar structure of the annulus fibrosus of the intervertebral disc.

The annulus fibrosus of the intervertebral disc unites adjacent vertebral bodies along the length of the spine and provides tensile resistance towards compressive, twisting and bending movements arising through gait. It consists of a nested series of oriented collagenous lamellae, arranged in cross-ply circumferentially around the nucleus pulposus. The organisation of oriented collagen in the annulus is established during foetal development by an identical arrangement of oriented fibroblasts that are precisely organised into cell sheets, or laminae. These provide a template for ordered deposition of extracellular matrix material on cell surfaces, by means of a poorly understood mechanism involving the actin cytoskeleton. In this study, we investigate the role of two cell surface heparan sulphate proteoglycans (HSPGs), glypican-6 and syndecan-4, in the matrix assembly process in the developmental rat intervertebral disc. We compare their expression patterns with those of heparan sulphate and the interactive, cell-surface adhesive glycoprotein, fibronectin, and relate these to the stage-specific collagenous architectures present within the annulus at both light and electron microscopic levels. We show that both proteoglycans are strongly associated with the development, growth and aging of the intervertebral disc. Furthermore, the immunohistochemical labelling patterns suggest that syndecan-4, in particular, plays a potentially-significant role in annulus formation. We propose that this HSPG mediates interaction between the actin cytoskeleton and nascent extracellular matrix in the lamellar organisation of annulus tissue. These data add considerably towards an understanding of how cells organise and maintain complex, oriented extracellular matrices and has particular clinical relevance to the fields of tissue engineering and repair.

Outcomes of routine ilioinguinal lymph node dissection for palpable inguinal melanoma nodal metastasis.

BACKGROUND: Patients who present with palpable inguinal melanoma nodal metastasis have two surgical options: inguinal or ilioinguinal lymph node dissection. Indications for either operation remain controversial. This study examined survival and recurrence outcomes following ilioinguinal dissection for patients with palpable inguinal nodal metastasis, and assessed the incidence and preoperative predictors of pelvic nodal metastasis. METHODS: This was a retrospective clinicopathological analysis of consecutive surgical patients with stage III malignant melanoma. All patients underwent a standardized ilioinguinal dissection at a specialist tertiary oncology hospital over a 12-year period (1998-2010). RESULTS: Some 38.9 per cent of 113 patients had metastatic pelvic nodes. Over a median follow-up of 31 months, the 5-year overall survival rate was 28 per cent for patients with metastatic inguinal and pelvic nodes, and 51 per cent for those with inguinal nodal metastasis only (P = 0.002). The nodal basin control rate was 88.5 per cent. Despite no evidence of pelvic node involvement on preoperative computed tomography (CT), six patients (5.3 per cent) with a single metastatic inguinal lymph node had metastatic pelvic lymph nodes. Logistic regression analysis showed that the number of metastatic inguinal nodes (odds ratio 1.56; P = 0.021) and suspicious CT findings (odds ratio 9.89; P = 0.001) were both significantly associated with metastatic pelvic nodes. The specificity of CT was good (89.2 per cent) in detecting metastatic pelvic nodes, but the sensitivity was limited (57.9 per cent). CONCLUSION: Metastatic pelvic nodes are common when palpable metastatic inguinal nodes are present. Long-term survival can be achieved following their resection by ilioinguinal dissection. As metastatic pelvic nodes cannot be diagnosed reliably by preoperative CT, patients presenting with palpable inguinal nodal metastasis should be considered for ilioinguinal dissection.

Predicting mortality in people with type 2 diabetes mellitus after major complications: a study using Swedish National Diabetes Register data.

AIM: To predict mortality risk and life expectancy for patients with type 2 diabetes after a major diabetes-related complication. METHODS: The study sample, taken from the Swedish National Diabetes Register, consisted of 20 836 people with type 2 diabetes who had their first major complication (myocardial infarction, stroke, heart failure, amputation or renal failure) between January 2001 and December 2007. A Gompertz proportional hazards model was derived which determined significant risk factors associated with mortality and was used to estimate life expectancies. RESULTS: Risk of death changed over time according to type of complication, with myocardial infarction initally having the highest initial risk of death, but after the first month, the risk was higher for heart failure, renal failure and amputation. Other factors that increased the risk of death were male gender (hazard ratio 1.06, 95% CI 1.02-1.12), longer duration of diabetes (hazard ratio 1.07 per 10 years, 95% CI 1.04-1.10), smoking (hazard ratio 1.51, 95% CI 1.40-1.63) and macroalbuminuria (hazard ratio 1.14, 95% CI 1.06-1.22). Low BMI, low systolic blood pressure and low estimated GFR also increased mortality risk. Life expectancy was highest after a stroke, myocardial infarction or heart failure, lower after amputation and lowest after renal failure. Smoking and poor renal function were the risk factors which had the largest impact on reducing life expectancy. CONCLUSIONS: Risk of death and life expectancy differs substantially among the major complications of diabetes, and factors significantly increasing risk included smoking, low estimated GFR and albuminuria.

UKPDS outcomes model 2: a new version of a model to simulate lifetime health outcomes of patients with type 2 diabetes mellitus using data from the 30 year United Kingdom Prospective Diabetes Study: UKPDS 82.

AIMS/HYPOTHESIS: The aim of this project was to build a new version of the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model (UKPDS-OM1), a patient-level simulation tool for predicting lifetime health outcomes of people with type 2 diabetes mellitus. METHODS: Data from 5,102 UKPDS patients from the 20 year trial and the 4,031 survivors entering the 10 year post-trial monitoring period were used to derive parametric proportional hazards models predicting absolute risk of diabetes complications and death. We re-estimated the seven original event equations and estimated new equations for diabetic ulcer and some second events. The additional data permitted inclusion of new risk factor predictors such as estimated GFR. We also developed four new equations for all-cause mortality. Internal validation of model predictions of cumulative incidence of all events and death was carried out and a contemporary patient-level dataset was used to compare 10 year predictions from the original and the new models. RESULTS: Model equations were based on a median 17.6 years of follow-up and up to 89,760 patient-years of data, providing double the number of events, greater precision and a larger number of significant covariates. The new model, UKPDS-OM2, is internally valid over 25 years and predicts event rates for complications, which are lower than those from the existing model. CONCLUSIONS/INTERPRETATION: The new UKPDS-OM2 has significant advantages over the existing model, as it captures more outcomes, is based on longer follow-up data, and more comprehensively captures the progression of diabetes. Its use will permit detailed and reliable lifetime simulations of key health outcomes in people with type 2 diabetes mellitus.