Anti-Ro52/TRIM21 is independently associated with pulmonary arterial hypertension and mortality in a cohort of systemic sclerosis patients.

Objective: We undertook a comprehensive cross-sectional analysis of a multicentred Australian cohort of systemic sclerosis (SSc) patients to evaluate the associations of anti-Ro52/TRIM21 with SSc pulmonary involvement.Method: The study included 596 patients from the Australian Scleroderma Cohort Study database whose anti-Ro52/TRIM21 status was known. Anti-Ro52/TRIM21 was measured via line immunoassay. Data on demographic variables, autoantibody profiles, presence of interstitial lung disease (ILD), presence of pulmonary arterial hypertension (PAH), oxygen saturation, Six-Minute Walk Test distance, Borg dyspnoea score, and lung function tests were extracted. SPSS software was used to examine associations using univariate and multivariate analyses.Results: Anti-Ro52/TRIM21 was present in 34.4% of SSc patients. In the cross-sectional analysis, anti-Ro52/TRIM21 was independently associated with PAH [odds ratio 1.75, 95% confidence interval (CI) 1.05-2.90], but not ILD or other surrogate measures of pulmonary involvement such as average patient oxygen saturation. The antibody, however, was also associated with a higher forced vital capacity/diffusing capacity of the lung for carbon monoxide ratio. Prospectively, anti-Ro52/TRIM21 was also associated with an increased risk of death in patients with SSc (hazard ratio 1.62, 95% CI 1.11-2.35), independent of confounding factors. The primary cause of death appeared to be related to PAH and/or ILD, and anti-Ro52/TRIM21 was associated with PAH-related complications.Conclusion: Anti-Ro52/TRIM21 was independently associated with PAH and mortality in SSc patients. Future longitudinal studies are recommended to investigate the timing and pathogenic mechanisms of this autoantibody in PAH.

Perspectives on oral squamous cell carcinoma prevention-proliferation, position, progression and prediction.

Squamous cell carcinoma arising from oral mucosal epithelium remains a lethal and deforming disease due to tumour invasion, oro-facial destruction, cervical lymph node metastasis and ultimate blood-borne dissemination. Worldwide, 300 000 new cases are seen each year, with a recent and significant rise in incidence affecting particularly the young. To rationalize perspectives on preventive strategies in oral cancer management, this study addresses a number of fundamental questions regarding carcinogenesis: proliferation-what epithelial cell changes precede tumour development? Position-why are certain oral sites so predisposed to cancer? Progression-why do some precursor lesions progress to invasive carcinoma and others do not? Prediction-how can we predict individual patient and/or lesion behaviour to prevent disease progression? By improving our understanding of oral carcinogenesis, can we thereby facilitate more effective primary, secondary and tertiary preventive strategies and ultimately reduce the global burden of oral squamous cell carcinoma (OSCC)?

Potentially malignant disorders-The case for intervention.

Potentially malignant disorders (PMD) are recognisable mucosal conditions preceding invasive squamous carcinoma development. Established oral cancer remains a lethal and deforming disease, with a rising incidence. Management techniques for identifiable oral precursor lesions have traditionally been polarised between observational and interventional surgical techniques. By defining salient management goals for treating potentially malignant disease, and examining the evidence supporting the efficacy of treatment intervention, this paper presents the case for interventional laser surgery as a definitive diagnostic and treatment modality.

Efficacy of oral brush biopsy in potentially malignant disorder management.

BACKGROUND: Oral potentially malignant disorders (PMD) harbour unpredictable risk for squamous cell carcinoma development. Current management requires tissue biopsy for histopathology characterisation, dysplasia grading and targeted intervention to "high-risk" lesions, although evidence-based guidelines are limited and diagnoses subjective. This study investigated the use of adjunctive oral brush biopsy techniques during the management of PMD in a UK hospital population. METHODS: Retrospective review of a 310 PMD patient cohort presenting to Maxillofacial Surgery in Newcastle upon Tyne with new, single-site lesions between December 2009 and May 2014. Patients underwent Orcellex® brush biopsy and liquid-based cytology examination in addition to conventional biopsy techniques, with management proceeding along established care pathways. Patient demographics, cytology data, most significant histopathology diagnoses and clinical outcome were all documented at the study census date (31.12.15). RESULTS: A total of 170 male & 140 female patients (age range 18-91 years), exhibiting primarily leukoplakia (86.5%) at floor of mouth and ventrolateral tongue sites (44.9%), were identified. Management comprised: observation (49.7%), laser surgery (44.9%), antifungal treatment (3.5%) and Head & Neck clinic referral following cancer diagnosis (1.9%). Clinical outcomes were as follows: disease free (51.3%), persistent PMD (42.3%) and malignant transformation (6.4%). Histology and cytology diagnoses strongly correlated (r = .305). Treatment modality, lesion site, histology and cytology diagnoses were the best predictors of clinical outcome. CONCLUSIONS: Orcellex® brush cytology provides reliable diagnoses consistent with conventional histopathology and offers less invasive, adjunctive assessment appropriate for long-term monitoring of patients in specialist clinics.

Profiling cancer risk in oral potentially malignant disorders-A patient cohort study.

BACKGROUND: Oral potentially malignant disorders harbour variable and unpredictable risk for squamous carcinoma development. Whilst current management strategies utilise histopathological diagnoses, dysplasia grading and targeted intervention for "high-risk" lesions, clinicians are unable to predict malignant potential. METHODS: Detailed, retrospective clinico-pathological analysis of potentially malignant lesions undergoing malignant transformation, from a 590 patient cohort treated by interventional laser surgery and followed for a mean of 7.3 years, was undertaken. Clinical outcome was documented at study census date (31 December 2014). RESULTS: A total of 99 patients (16.8%) developed cancer: 71 (12%) seen "unexpectedly" upon excision and 28 (4.8%) progressing to malignancy at a median of 87.3 months post-surgery. Thirty "unexpected" excisions were micro-invasive (42.3%) arising primarily in severely dysplastic precursors (75%) at ventro-lateral tongue and floor of mouth sites (54.5%); 1 patient (1.4%) had a cancer-related death, whilst 58 (81.7%) were disease free. A total of 19 of 28 "progressive" cancers (67.9%) arose at new sites, with erythroleukoplakia a significant predictor of malignancy (P = .0019). Nine (32.1%) developed at the same precursor site, with 6 (77.7%) on the ventro-lateral tongue and floor of mouth. Three (10.7%) were micro-invasive, 9 patients (32.1%) died from metastatic disease and 12 (42.9%) were disease free (P < .001). CONCLUSION: Squamous carcinoma may arise at the site of a precursor lesion as transformation or new-site development via field cancerisation. Whilst interventional surgery facilitates early diagnosis and treatment of occult disease, thus reducing risk from same-site transformation, new-site cancer is a significant long-term risk for patients with potentially malignant disorder.

Treatment resistance in potentially malignant disorders-'Nature' or 'Nurture' ?

BACKGROUND: Contemporary potentially malignant disorder management is based upon provisional histological diagnosis followed by interventional surgery to excise or ablate 'high-risk' mucosal lesions. Although the majority of patients achieve disease-free status post-treatment, others develop further or persistent disease unresponsive to intervention. METHODS: A detailed, retrospective clinico-pathological review of treatment resistant potentially malignant lesions, from a 590 patient cohort treated by CO2 laser surgery and followed for a mean of 7.3 years, was undertaken. Clinical outcome was determined at study census date (31 December 2014). RESULTS: A total of 87 patients (15%) exhibited PMD disease resistant to treatment: 34 (6%) became disease free following further treatment, whilst 53 (9%) had persistent disease despite intervention. Disease-free patients were younger, changed lesion appearance from erythroleukoplakia to leukoplakia (P = .004), developed further lesions at new sites, demonstrated reduction in dysplasia severity with time and required multiple treatments to achieve disease-free status (P = .0005). In contrast, persistent disease patients were older, male, often presented with proliferative verrucous leukoplakia (PVL) on gingival and alveolar sites, displayed less severe dysplasia initially and underwent laser ablation rather than excision (P = .027). CONCLUSION: Despite clinico-pathological profiling of treatment resistant patients, the precise inter-relationship between the inherent nature of potentially malignant disease and the external influence of treatment intervention remains obscure.

Stochastic processes in the aetiopathogenesis of scleroderma.

We review the aetiology of scleroderma from an epidemiological perspective examining genetic, environmental and stochastic risk factors. The presence of familial clustering (but with low twin concordance) suggests a genetic contribution, and this has been confirmed with recent candidate gene and genome-wide association screening demonstrating both major histocompatibility complex and non-major histocompatibility complex genetic linkage. In contrast, environmental associations are weak or inconsistent. An examination of the age-adjusted incidence curve of scleroderma is consistent with a stochastic process involving five to eight random events. In pathogenesis, scleroderma is best considered as an autoimmune disorder where genetic and environmental factors are both important variables, but random events are also likely to play a pivotal role. We suggest that these random events might result in acquired somatic mutations or epigenetic alterations involving genes coding for immune receptors, tolerogenic gates or proteins involved in immune regulation, inflammation and/or repair that, over time, might summate to form a requisite cassette (of genetic changes), which allows the initiation and progression of the autoimmune process.

Characterization and clinicopathological significance of circulating tumour cells in patients with oral squamous cell carcinoma.

Circulating tumour cells (CTCs) are cancer cells released by cancer into the peripheral circulation. Haematogenous tumour spread is a hallmark of metastatic malignancy and a key factor in cancer recurrence and prognosis. CTCs have diagnostic and prognostic significance for a number of adenocarcinomas and melanoma. A review of the published peer-reviewed literature was performed to determine the clinical relevance of CTCs as a biomarker in the management of oral squamous cell carcinoma (OSCC). Fourteen studies met the eligibility criteria. With regard to patients with OSCC, this review found the following: (1) CTCs have been detected using multiple techniques; (2) the presence of CTCs does not appear to be related to tumour differentiation or size; (3) CTCs may be detected without lymph node involvement; (4) the detection of CTCs may be prognostic for both disease-free survival and overall survival; (5) quantification of CTCs may reflect the efficacy of therapy; (6) CTCs may be of value for ongoing patient monitoring. Preliminary evidence suggests that CTCs have diagnostic and prognostic potential as a biomarker for oral cancer management and warrant further investigation to determine their appropriate place in the management of OSCC patients.

Clinical heterogeneity and prognostic features of South Australian patients with anti-synthetase autoantibodies.

AIM: To determine the clinical, serological and prognostic features of patients with autoantibodies against three aminoacyl-transfer RNA synthetases (ARS), namely Jo-1 (histidyl-tRNA synthetase), PL-7 (threonyl-tRNA synthetase) and PL-12 (alanyl-tRNA synthetase) in South Australia. METHODS: Patients with autoantibodies against ARS detected by line immunoassay (anti-Jo1, anti-PL7, anti-PL12) or enzyme-linked immunosorbent assay (anti-Jo1) were identified from existing laboratory databases for the period 1994-2009. Demographic, clinical and serological data were obtained by retrospective review of patients' medical records and laboratory databases. RESULTS: Forty-two patients with autoantibodies were identified (anti-Jo1 = 37, anti-PL7 = 4, anti-PL12 = 1). Females were more commonly affected than males (M : F = 12:30). Twenty-one patients had polymyositis (anti-Jo1 = 17, anti-PL7 = 4), seven dermatomyositis (anti-Jo1 = 6, anti-PL12 = 1), 10 overlap syndrome (anti-Jo1 = 10; lupus = 4, scleroderma = 3, Sjögren's syndrome = 2 and rheumatoid arthritis = 2) and four had interstitial lung disease (ILD) only (anti-Jo1 = 4). ILD was present in 69%, polyarthritis in 59% and positive anti-nuclear antibody (ANA) in 43% of patients. Concurrence of autoantibodies against Ro-52 with Jo-1 was seen in 12 patients. The mean follow-up period was 8.3 years (95% CI 5.8-10.8) with 12 deaths. Poor prognostic indicators were age of onset >60 years (P= 0.001), cancer (P= 0.002), negative ANA (P= 0.006) and negative autoantibodies to extractable nuclear antigens (P= 0.02). CONCLUSION: Patients with autoantibodies against ARS present with varied clinical features and occasionally with isolated lung involvement (amyopathic ILD). Older age of onset, malignancy and negative immunologic tests are predictors of poor prognosis. Concurrence of autoantibodies against Jo-1 and Ro-52 may reflect a coupling effect during generation of autoimmunity.

Survival in scleroderma: results from the population-based South Australian Register.

AIM: To ascertain the mortality risk and investigate clinical and serological factors influencing survival of patients listed on the South Australian Scleroderma Register (SASR). METHODS: The SASR is a population-based register, which was commenced in 1993 and has actively sought to recruit all scleroderma patients diagnosed in SA over a 15-year period. Clinical and serological details have been accessed from questionnaires or from clinical and laboratory files. Standardized mortality ratio (SMR) was calculated and survival analyses performed on all living and deceased patients listed on this SASR (n = 786). RESULTS: Patients with scleroderma had increased mortality compared with the general SA population (SMR 1.46 (95% confidence interval (CI) 1.28-1.69)). Factors that adversely altered survival included older age at onset, male gender, diffuse skin involvement, presence of scleroderma renal crisis, pulmonary fibrosis, pulmonary arterial hypertension, cancer and anti-topoisomerase (Scl-70) and anti-U1 RNP antibodies, while a trend was observed with increased nailfold capillary dropout. Mean age of death for patients with limited scleroderma was 74.1 years (95% CI 72.5-75.7), diffuse scleroderma 62.9 years (95% CI 59.4-66.4) and overlap disease 57.8 years (95% CI 48.7-66.9). Survival improved over the 15-year study period. CONCLUSIONS: Scleroderma substantially reduces life expectancy. Survival is influenced by age at onset, gender, diffuse involvement of skin fibrosis, visceral involvement, development of cancer, extent of microvascular capillary damage and by the presence of scleroderma-associated antibodies, Scl-70 and RNP. Scleroderma renal crisis continues to carry high mortality. Survival improved over the 15-year study period.

Idiopathic inflammatory myopathies.

The idiopathic inflammatory myopathies are a group of systemic autoimmune syndromes characterized by striated muscle inflammation. Here, we discuss the clinical features of this group of conditions and review the recent developments in the understanding of the pathogenesis and immunogenetics of the idiopathic inflammatory myopathies. The role of myositis-specific autoantibodies and their clinical significance and an overview of management are also provided.

Factors affecting carbon dioxide laser treatment for oral precancer: a patient cohort study.

BACKGROUND: Although the benefits of CO(2) laser surgery in oral precancer management have been evaluated, little consideration has been given to the factors which may influence treatment outcome, especially amongst patients developing recurrence or malignant transformation. STUDY DESIGN: Seventy eight patients (51 males, 27 females; mean age 57.8 years) undergoing CO(2) laser excision of single, new dysplastic oral precancer lesions (OPLs) were followed up for a minimum of 2 years and the influence of clinico-pathological parameters, socio-demographic factors and the presence or absence of residual dysplasia in excision margins upon clinical outcome were examined. RESULTS: Seventy three percent of patients were smokers and 78% consumed alcohol regularly. The majority of lesions were leukoplakias arising in the floor of mouth and ventro-lateral tongue and moderate or severe dysplasia accounted for 86% of histopathological diagnoses. Patient follow up ranged from 24 to 119 months (mean 58 months). Sixty four percent of patients were disease free at most recent clinical follow up, whilst 32% developed local recurrent dysplasia or new site dysplasia with 4% developing oral squamous cell carcinoma (but at sites distinct from their initial OPL). Excision margins were clear in 55% of cases, but 19% showed mild, 21% moderate and 5% severe dysplasia on histopathological examination. No statistically significant associations were seen between patients' age, gender, lesion appearance, site of origin, histopathological grading, presence of dysplasia in resection margins, or alcohol consumption and clinical outcome. Smokers, however, were at significantly higher risk of dysplasia recurrence compared to ex-smokers or non-smokers (P = 0.04). CONCLUSIONS: In the absence of agreed treatment protocols for OPLs, we recommend CO(2) laser surgery as an effective treatment modality offering precise lesion excision, full histopathological assessment, minimal post-operative morbidity and a 64% disease free clinical outcome. Regular patient follow up is encouraged due to the persistence of field cancerisation effects.

Familial scleroderma: nature, nurture or both?

BACKGROUND: The aim of the study was to investigate: (i) familial scleroderma (FS) risk factors, (ii) subtype concordance and (iii) relationship between dates (DSO) and ages (ASO) at scleroderma onset. METHODS: Forty-seven cases (23 families; 25 FS pairs) were identified. Scleroderma disease onset was defined by (i) Raynaud's onset, (ii) first symptom onset (1SxO), (iii) second symptom onset (2SxO) and (iv) scleroderma diagnosis (SDx). RESULTS: Female : male and limited : diffuse (L : D) ratios were 8.4:1 and 3.3:1. The Raynaud's onset - SDx interval was longer in limited disease (L : D = 14.6:3.1 years; P = 0.01). Raynaud's first occurred in 36% women > or =50 years. The median differences in ASO between affected family members were 10-12 years. Disease subtype concordance exceeded discordance (16:9 clusters; (P = 0.32) 16:7 families; (P = 0.17)). The observed/expected LL : LD : DD ratios were 14: 8:1/11:7:1 (P = 0.66). FS affected 34% (95% confidence interval 19-50) sister-sister and 44% (95% confidence interval 27-75) mother-daughter pairs. The second family member's SDx was made at the same (9%) or a younger age (80%) than the first family member. In 14 LL disease families ASO was closer between sisters than mothers-daughters (P = 0.07). There was a trend towards closer ages - than dates - at Raynaud's and 1SxO in scleroderma-affected family members (P = 0.054) and closer dates - than ages - at 2SxO (P = 0.02) and SDx. CONCLUSION: FS showed female predominance, relatively late onset Raynaud's, subtype ratios similar to idiopathic scleroderma and earlier SDx in younger family members. Familial L scleroderma has a longer prediagnostic latency than familial D scleroderma. FS is likely under-ascertained. In LL scleroderma, Raynaud's/1SxO is possibly more genetically determined and 2SxO/SDx more environmentally determined.

Prevalence of sicca symptoms in a South Australian cohort with systemic sclerosis.

BACKGROUND: The presence of sicca symptoms is a frequent finding in patients with systemic sclerosis (SSc). The aim of this study was to examine the prevalence of sicca symptoms in a South Australian cohort of SSc patients and correlate this to a number of parameters, including autoantibody status, use of anticholinergic medication, age and the presence of functional anti-muscarinic-3 receptor (M3R)-blocking antibodies. METHODS: A screening questionnaire was sent out to all patients on the South Australian Scleroderma Register from the years 1998-2006 to determine the prevalence of sicca symptoms. A subset of patients on the register had ocular sicca symptoms tested by use of Schirmer's strips to validate the accuracy of the questionnaire. Eight patients were tested for anti-M3R-blocking antibodies using a functional physiological assay. RESULTS: One hundred and ninety-three SSc patients took part in this study. Sicca symptoms were present in 59% of patients with the limited form of SSc, compared with 49% of patients with the diffuse form and 40% of patients with the overlap syndrome. The use of anticholinergic medication or thyroxine was associated with higher sicca scores in SSc patients. SS-A and SS-B autoantibodies (seen in Sjögren's syndrome) were detected in eight patients in this study. The detection of anti-M3R-blocking antibodies correlated well to presence of sicca. CONCLUSION: This study confirmed that sicca symptoms are found in a high proportion of patients with SSc, especially those with the limited variant. Further testing of larger numbers of SSc patients with sicca for anti-M3R-blocking antibodies will be needed before more definitive conclusions can be drawn. Physicians should be made aware that sicca symptoms are a frequent cause of morbidity for SSc patients*.

Predictors of oropharyngeal cancer survival in Europe.

OBJECTIVES: HPV16-positive oropharyngeal cancer (OPC) patients experience better outcomes compared to HPV16-negative patients. Currently, strategies for treatment de-escalation are based on HPV status, smoking history and disease stage. However, the appropriate cut-point for smoking and the role of other non-clinical factors in OPC survival remains uncertain. MATERIALS AND METHODS: We examined factors associated with OPC outcome in 321 patients recruited in a large European multi-center study. Seropositivity for HPV16 E6 was used as a marker of HPV16 positive cancer. Hazard ratios (HR) and confidence intervals (CI) were estimated using Cox proportional models adjusted for potential confounders. RESULTS: Overall 5-year survival following OPC diagnosis was 50%. HPV16-positive OPC cases were at significantly lower risk of death (aHR = 0.51, 95% CI: 0.32-0.80). A significant effect on OPC survival was apparent for female sex (aHR 0.50: 95% CI: 0.29-0.85) and being underweight at diagnosis (aHR: 2.41, 95% CI: 1.38-4.21). A 10 pack year smoking history was not associated with overall survival. Higher stage at diagnosis appeared as the only factor significantly associated with OPC recurrence (aHR: 4.88, 95% CI: 2.12-11.21). CONCLUSION: This study confirms that HPV16 status is an independent prognostic factor for OPC survival while female sex lowers risk of death and being underweight at diagnosis increases the risk of death. Smoking was not an independent predictor of OPC survival.

Cancerisation within the oral cavity: the use of 'field mapping biopsies' in clinical management.

Field cancerisation within the oral cavity risks multiple primary tumour development. Whilst multi-focal disease may ultimately affect up to 24% of oral cancer patients, a particular management problem is encountered with those patients presenting with pan-oral dysplasia. In an attempt to characterise the extent of dysplasia and to quantify the risk of malignant change, examination under anaesthesia (EUA) and multiple, 'field mapping biopsies' were carried out for 16 consecutive patients presenting with pan-oral disease. Seventy lesions, predominantly homogenous leukoplakias, were biopsied primarily showing hyperkeratosis or mild dysplasia histologically. More significant dysplasia was seen to affect the faucial pillars, floor of mouth and ventral tongue. Interventional CO(2) laser surgery was used to excise 11 severely dysplastic lesions in six patients. Field mapping appears effective in the initial identification and treatment of the most significant areas of dysplasia in patients with multi-focal precancer. Longitudinal, multi-centre trials are now required.

Effects of active non-smoking programmes on smoking behaviour in oral precancer patients.

Smoking is the commonest risk factor for oral cancer and precancer. The objective of this study was to characterize smoking behaviour and attitude in a cohort of oral precancer patients in Newcastle upon Tyne, UK, and to determine changes in behaviour during diagnosis, treatment and follow-up. Twenty-seven consecutive, smoking patients with dysplastic oral lesions were recruited to the study and a detailed smoking history obtained, quantifying types and numbers of cigarettes smoked, length of smoking history, and changes in smoking behaviour during treatment episodes and long-term follow-up. All patients underwent an interventional management protocol comprising risk-factor education, histopathological diagnosis by incisional biopsy and laser excision of lesions. Patients were followed up for 5 years. Whilst there was a significant decrease in the number of cigarettes smoked at patients' most recent follow-up compared with initial presentation (p<0.001), 74% continued to smoke. Patients received advice from a smoking cessation adviser on support available to them from the local NHS (National Health Service) Stop Smoking services. Six out of 10 patients who set a 'quit date' and attended a programme had quit at the 4-week follow-up but only 5 remained non-smokers. Smoking remains a considerable problem in oral precancer patients even after interventional treatment, with the risk of further precancerous lesions and malignant transformation.

Interventional laser surgery for oral potentially malignant disorders: a longitudinal patient cohort study.

Oral squamous cell carcinoma (OSCC) is a lethal disease, with rising incidence. There were 6767 new OSCC cases and 2056 deaths in the UK in 2011. Cancers are preceded by oral potentially malignant disorders (PMDs), recognizable mucosal diseases harbouring increased SCC risk, offering clinicians a 'therapeutic window' to intervene. Contemporary practice remains unable to predict lesion behaviour or quantify malignant transformation risk. No clear management guidelines exist and it is unclear from the literature whether early diagnosis and intervention prevents cancer. Between 1996 and 2014, 773 laser treatments were performed on 590 PMD patients in Newcastle maxillofacial surgery departments. The efficacy of the intervention was examined by review of the clinicopathological details and clinical outcomes of the patients (mean follow-up 7.3 years). Histopathology required up-grading in 36.1% on examining excision specimens. Seventy-five percent of patients were disease-free, mostly younger patients with low-grade dysplasia; 9% exhibited persistent disease and were generally older with proliferative verrucous leukoplakia. Disease-free status was less likely for erythroleukoplakia (P=0.022), 'high-grade' dysplasia (P<0.0001), and with lichenoid inflammation (P=0.028). Unexpected OSCC was identified in 12.0%, whilst 4.8% transformed to malignancy. Interventional laser surgery facilitates definitive diagnosis and treatment, allows early diagnosis of OSCC, identifies progressive disease, and defines outcome categories. Evidence is lacking that intervention halts carcinogenesis. Multicentre, prospective, randomized controlled trials are needed to confirm the efficacy of surgery.