Transseptal puncture in the dog utilizing three-dimensional transesophageal echocardiographic guidance.

Transseptal puncture is necessary to access the left atrium and mitral valve from a transvenous approach but is poorly described in veterinary medicine. The procedure is generally regarded as difficult and dangerous, particularly given the size of most small animal patients. Precise imaging is paramount to the procedure to ensure that puncture occurs within the desired location and to monitor for potential complications. Transesophageal echocardiography, including biplanar two-dimensional and particularly three-dimensional modalities, has great potential to improve the success and safety of transseptal puncture due to superior visualization of the fossa ovalis and other intracardiac structures. Here, we describe the use of transesophageal echocardiography to guide transseptal puncture based on our experience in 159 dogs, with an emphasis on three-dimensional echocardiography. We also detail how to perform transseptal puncture from a jugular approach, which we consider preferable in most patients. Complications from transseptal puncture are discussed, along with ways to limit those complications.

Outcomes of Preoperative Transophthalmic Artery Embolization of Meningiomas: A Systematic Review with a Focus on Embolization Agent.

BACKGROUND: Transophthalmic artery embolization of intracranial meningiomas is thought to be associated with a high complication risk. PURPOSE: With advances in endovascular techniques, we systematically reviewed the current literature to improve our understanding of the safety and efficacy of transophthalmic artery embolization of intracranial meningiomas. DATA SOURCES: We performed a systematic search using PubMed from inception until August 3, 2022. STUDY SELECTION: Twelve studies with 28 patients with intracranial meningiomas embolized through the transophthalmic artery were included. DATA ANALYSIS: Baseline and technical characteristics and clinical and safety outcomes were collected. No statistical analysis was conducted. DATA SYNTHESIS: The average age of 27 patients was 49.5 (SD, 13) years. Eighteen (69%) meningiomas were located in the anterior cranial fossa, and 8 (31%), in the sphenoid ridge/wing. Polyvinyl alcohol particles were most commonly (n = 8, 31%) used to preoperatively embolize meningiomas, followed by n-BCA in 6 (23%), Onyx in 6 (23%), Gelfoam in 5 (19%), and coils in 1 patient (4%). Complete embolization of the target meningioma feeders was reported in 8 (47%) of 17 patients; partial embolization, in 6 (32%); and suboptimal embolization, in 3 (18%). The endovascular complication rate was 16% (4 of 25), which included visual impairment in 3 (12%) patients. LIMITATIONS: Selection and publication biases were limitations. CONCLUSIONS: Transophthalmic artery embolization of intracranial meningiomas is feasible but is associated with a non-negligible complication rate.

Should Robotic Surgery Simulation Be Introduced in the Core Surgical Training Curriculum?

Introduction: The focus of this research is to qualitatively analyse the literature and address the knowledge gap between robotic surgery simulation (RoSS) and core surgical training curriculum. It will compare the effectiveness and the benefits of using robotic simulators in training as compared to the current standard training methods. Materials and Methods: A qualitative research of literature was carried out with the use of critical analysis formatting to expand the search. The inclusion criteria entailed selecting academic resources that focused on Robotic Surgery Simulation (RoSS) and core surgical curriculum. The Online databases used in the search took into account information retrieval from stakeholders. Evidence Synthesis: In this article, we compiled and scrutinized the available relevant literature comparing performance assessments, surgical skills transfer and assessment tools between robotic surgery simulation (RoSS) and current training platforms in open and minimal access surgery. Data that has been published underpins the authenticity of robotic Surgery Simulation (RoSS), based on a combination of observational evaluation and simulation scores. Conclusion: The introduction of robotic surgery simulation (RoSS) has the potential to bring major improvements in the surgical training curriculum. RoSS platforms are more robust in terms of ensuring rapid surgical skills transfer/ acquisition, assessment is standardized, unbiased and the training covers non-technical skills aspects.

Predictors of the need for an extracervical approach to intrathoracic goitre.

Background: Sternotomy and lateral thoracotomy are required infrequently to remove an intrathoracic goitre (ITG). As few studies have explored the need for an extracervical approach (ECA), the aim of this study was to examine this in a large cohort of patients. Methods: A prospective database of all patients who had surgery for ITG between 2004 and 2016 was interrogated. Patient demographics, preoperative characteristics and type of operation were analysed to identify factors associated with an ECA. Results: Of 237 patients who had surgery for ITG, 29 (12·2 per cent) required an ECA. ITGs below the aortic arch (odds ratio (OR) 10·84; P = 0·004), those with an iceberg shape (OR 59·30; P < 0·001) and revisional surgery (OR 4·83; P = 0·022) were significant preoperative predictors of an ECA. Conclusion: The extent of intrathoracic extension in relation to the aortic arch, iceberg goitre shape and revisional surgery were independent risk factors for ECA. Careful preoperative assessment should take these factors into consideration when determining the optimal surgical approach to ITG.

Evidence of Early Emergence of the Primary Dentition in a Northern Plains American Indian Population.

The purposes of this study were to describe primary tooth emergence in an American Indian (AI) population during the first 36 mo of life to compare 1) patterns of emergence between male and female children and 2) tooth emergence between these AI children and other U.S. ethnic groups. Data were derived from a birth cohort of 239 AI children from a Northern Plains tribe participating in a longitudinal study of early childhood caries, with examination data at target ages of 8, 12, 16, 22, 28, and 36 mo of age (±1 mo). Patterns of emergence in AI children were characterized and sex comparisons accomplished with interval-censored survival methodology. Numbers of erupted teeth in AI children at each age were compared via Kruskal-Wallis tests against those in children of the same age, as drawn from a cross-sectional study of dental caries patterns in Arizona; these comparisons were based on the dental examinations of 547 White non-Hispanic and 677 Hispanic children. Characterization of time to achievement of various milestones-including emergence of the anterior teeth, the first molars, and the complete primary dentition-provided no evidence of sex differences among AI children. AI children had significantly more teeth present at 8 mo (median, 3) than either White non-Hispanic (P < 0.0063) or Hispanic (P < 0.0001) children (median, 2 each). This was also true at 12 mo (P < 0.001; medians, 8 vs. 6 and 7, respectively) and 16 mo (P < 0.001; medians, 12 vs. 11 each). Less pronounced differences were seen at 22 mo (P < 0.0001). White non-Hispanic and Hispanic children did not differ at any time considered (P > 0.05). These results provide evidence of earlier tooth emergence in AI children than in the other 2 ethnicities. Although the underlying etiology of the severity of early childhood caries in AI children is likely to be multifactorial, earlier tooth emergence may be a contributing factor. Knowledge Transfer Statement: The findings of this study have practical implications for practitioners providing childhood oral health care to ethnic groups with early tooth emergence. It may be important to provide parents with information on toothbrushing, dentist visits, and other practices supportive of good oral health as early as possible to protect their children's primary dentition.

Stabilizing Dog Populations and Improving Animal and Public Health Through a Participatory Approach in Indigenous Communities.

Free-roaming dog populations are a global concern for animal and human health including transmission of infectious disease (e.g. rabies, distemper and parasites), dog bite injuries/mortalities, animal welfare and adverse effects on wildlife. In Saskatchewan (SK), Canada, veterinary care is difficult to access in the remote and sparsely inhabited northern half of the province, where the population is predominately Indigenous. Even where veterinary clinics are readily available, there are important barriers such as cost, lack of transportation, unique cultural perspectives on dog husbandry and perceived need for veterinary care. We report the effects of introducing a community action plan designed to improve animal and human health, increase animal health literacy and benefit community well-being in two Indigenous communities where a dog-related child fatality recently occurred. Initial door-to-door dog demographic surveys indicated that most dogs were sexually intact (92% of 382 dogs), and few had ever been vaccinated (6%) or dewormed (6%). Approximately three animal-related injuries requiring medical care were reported in the communities per 1000 persons per year (95% CL: 1.6-6.6), and approximately 86% of 145 environmentally collected dog faecal samples contained parasites, far above levels reported in other urban or rural settings in SK. Following two subsidized spay/neuter clinics and active rehoming of dogs, parasite levels in dog faeces decreased significantly (P < 0.001), and important changes were observed in the dog demographic profile. This project demonstrates the importance of engaging people using familiar, local resources and taking a community specific approach. As well, it highlights the value of integrated, cross-jurisdictional cooperation, utilizing the resources of university researchers, veterinary personnel, public health, environmental health and community-based advocates to work together to solve complex issues in One Health. On-going surveillance on dog bites, parasite levels and dog demographics are needed to measure the long-term sustainability of benefits to dog, human and wildlife health.

Effects of life-long fluoride intake on bone measures of adolescents: a prospective cohort study.

Controversy persists concerning the impact of community water fluoridation on bone health in adults, and few studies have assessed relationships with bone at younger ages. Ecological studies of fluoride's effects showed some increase in bone mineral density of adolescents and young adults in areas with fluoridated water compared with non-fluoridated areas. However, none had individual fluoride exposure measures. To avoid ecological fallacy and reduce bias, we assessed associations of average daily fluoride intake from birth to age 15 yr for Iowa Bone Development Study cohort members with age 15 yr dual-energy x-ray absorptiometry (DXA) bone outcomes (whole body, lumbar spine, and hip), controlling for known determinants (including daily calcium intake, average daily time spent in moderate-to-vigorous intensity physical activity, and physical maturity). Mean (SD) daily fluoride intake was 0.66 mg (0.24) for females and 0.78 mg (0.30) for males. We found no significant relationships between daily fluoride intake and adolescents' bone measures in adjusted models (for 183 females, all p values ≥ .10 and all partial R(2) ≤ 0.02; for 175 males, all p values ≥ .34 and all partial R(2) ≤ 0.01). The findings suggest that fluoride exposures at the typical levels for most US adolescents in fluoridated areas do not have significant effects on bone mineral measures.

A randomized trial of the Vein Viewer versus standard technique for placement of peripherally inserted central catheters (PICCs) in neonates.

OBJECTIVE: Peripherally inserted central catheters are important but can be difficult to place in neonates. Therefore, we compared a near-infrared device, the Vein Viewer, to determine if its use would increase successful line placement, with standard techniques. STUDY DESIGN: Randomized controlled trial in preterm and term neonates in a level 3 Neonatal Intensive Care Unit. RESULT: In all, 115 subjects were enrolled with 59 randomized to the Vein Viewer group and 56 to the control group. Overall, use of the Vein Viewer showed a trend to more successful placement 86 versus 75%; unadjusted odds ratio 2.33 (0.90, 6.04; P=0.08). Infants randomized to the Vein Viewer were more mature (30 ± 2 weeks gestational age (GA) versus 28 ± 2 weeks GA; P=0.08). After adjusting for GA, use of the Vein Viewer was significantly more likely to lead to successful line placement (adjusted odds ratio 3.05 (1.10, 1.82)). CONCLUSION: The Vein Viewer improved successful placement with the most benefit seen in infants of greater GA.

Post-traumatic stress symptoms in childhood brain tumour survivors and their parents.

OBJECTIVES: This study aimed to investigate post-traumatic stress symptoms (PTSS) in childhood brain tumour survivors and their parents. A further aim was to explore the relationship between objective illness parameters, parent-child interactions, coping styles and PTSS. METHODS: A cross-sectional correlational design was employed. Fifty-two childhood brain tumour survivors, aged 8-16, and 52 parents completed a battery of questionnaires designed to assess quality of parent-child interactions, monitoring and blunting attentional coping styles and PTSS. RESULTS: Over one-third (35%) of survivors and 29% of their parents reported severe levels of PTSS (suggestive of post-traumatic stress disorder 'caseness'). Increased parent-child conflict resolution for survivors and number of tumour recurrences for parents independently predicted the variance in PTSS. CONCLUSIONS: For a substantial proportion of brain tumour survivors and their parents the process of survivorship is a considerably distressing experience.

Sex steroids, periodontal health, and tooth loss in older men.

Sex steroids have a significant effect on skeletal biology in men, with reduced levels being associated with lower skeletal bone mass and cortical thickness. The purpose of this study was to determine if sex steroids are associated with periodontitis and tooth loss in a cohort of 1210 older dentate men followed for 3 years. Periodontal measures included attachment loss, pocket depth, gingival bleeding, and number of teeth. Baseline serum testosterone and estradiol were measured by radioimmunoassay. Severe periodontitis was common at baseline (38%), and progression occurred in 32% of the cohort. Incident tooth loss occurred in 22% of the cohort. Testosterone, estradiol, and sex hormone binding globulin (SHBG) concentrations were not related to baseline periodontal status or number of teeth. Moreover, there was no relationship between sex steroid levels and periodontitis progression or incident tooth loss. Although periodontitis, progression of periodontitis, and tooth loss are common in older men, they were not associated with sex steroids.

Is CSF cytology a useful diagnostic procedure in staging paediatric CNS tumours?

OBJECTIVES: To evaluate whether there are any factors that predict malignant cells being found in paediatric cerebrospinal fluid (CSF) samples. To determine whether CSF provides useful staging information not provided by magnetic resonance imaging (MRI) in paediatric patients with primary central nervous system (CNS) malignancy. METHODS: We compared the CSF cytology and spinal MRI staging results in paediatric patients with primary CNS malignancy at a UK tertiary referral centre, over a decade. RESULTS: Of 159 CSF samples, 72 samples were from 72 patients with primary CNS malignancy with spinal MRI available for comparison. Eight of these 72 had positive cytology (seven malignant and one suspicious). All had a high clinical suspicion of tumour at the time of sampling. Of the 72 patients, only two had evidence of CSF spread on MRI spinal staging and CSF cytology; ten had MRI without cytological evidence and six had cytological without MRI evidence. CONCLUSIONS: In paediatric patients with primary CNS tumours, CSF cytology provides useful staging information. Spinal MRI alone may miss some patients with CSF spread who would be identified with CSF cytology.

Astrocytoma derived short-term cell cultures retain molecular signatures characteristic of the tumour in situ.

The heterogeneity of tumours and uncertainties surrounding derived short-term cell cultures and established cell lines fundamentally challenge the research and understanding of tumour growth and development. When tumour cells are cultured, changes are inevitably induced due to the artificial growth conditions. Several recent studies have questioned how representative established cell lines or derived short-term cell cultures are of the tumour in situ. We have characterised gene expression changes induced by short-term culture in astrocytoma in order to determine whether derived short-term cell cultures are representative of the tumour in situ. In comparison to the majority of studies, paired biopsies and derived short-term cultures were investigated to reduce the effects of long-term culture and inter-tumour variability when comparing biopsies and derived cultures from tumours with the same histology from different individuals. We have used the Affymetrix GeneChip U133A to generate gene expression profiles of 6 paediatric pilocytic astrocytoma (PA) biopsies and derived short-term cell cultures and 3 adult glioblastoma multiforme (GBM) biopsies and derived short-term cultures. Significant differential gene expression is induced by short-term culture. However, when the biopsy and derived short-term cell culture samples were grouped according to tumour type (PA and GBM) a molecular signature of 608 genes showed significant differential expression between the groups. This gene cohort can distinguish PA and GBM tumours, regardless of the sample source, suggesting that astrocytoma derived short-term cultures do retain key aspects of the global tumour expression profile and are representative of the tumour in situ. Furthermore, these genes are involved in pathways and functions characteristic of adult GBM including VEGF signalling, hypoxia and TP53 signalling.

Relapsed intracranial ependymoma in children in the UK: patterns of relapse, survival and therapeutic outcome.

Relapsed ependymoma in children poses difficult dilemmas in management. Clinico-pathological and treatment data of 108 children with relapsed ependymoma in the United Kingdom (UK) treated between 1985 and 2002 were reviewed to identify prognostic factors affecting survival. The primary site was the most common site of relapse (84%). Overall 25% had metastatic relapse. Surgery at relapse was attempted in only 55%. Radiotherapy was delivered at relapse in 66% infants and 50% of older children were re-irradiated. Overall 5-year survival was 24% and 27% for children less than 3 years of age at initial diagnosis and older children, respectively. Multivariate analysis showed that, for infants, surgery (p=0.01) and radiotherapy (p=0.001) at relapse were independent predictors of survival. For older children regardless of the previous radiotherapy, repeat irradiation was associated with better outcome (p=0.05). Relapse was associated with poor outcome in both age groups. A survival advantage conferred by both radiotherapy and surgery at relapse is independently significant.

Longitudinal study of bone density and periodontal disease in men.

Bone loss is a feature of both periodontitis and osteoporosis, and periodontal destruction may be influenced by systemic bone loss. This study evaluated the association between periodontal disease and bone mineral density (BMD) in a cohort of 1347 (137 edentulous) older men followed for an average of 2.7 years. Participants were recruited from the Osteoporotic Fractures in Men Study. Random half-mouth dental measures included clinical attachment loss (CAL), pocket depth (PD), calculus, plaque, and bleeding. BMD was measured at the hip, spine, and whole-body, by dual-energy x-ray absorptiometry, and at the heel by ultrasound. After adjustment for age, smoking, race, education, body mass index, and calculus, there was no association between number of teeth, periodontitis, periodontal disease progression, and either BMD or annualized rate of BMD change. We found little evidence of an association between periodontitis and skeletal BMD among older men.

Tricalcium-phosphate and hydroxyapatite bone-graft extender for use in impaction grafting revision surgery. An in vitro study on human femora.

Impacted morsellised allografts have been used successfully to address the problem of poor bone stock in revision surgery. However, there are concerns about the transmission of pathogens, the high cost and the shortage of supply of donor bone. Bone-graft extenders, such as tricalcium phosphate (TCP) and hydroxyapatite (HA), have been developed to minimise the use of donor bone. In a human cadaver model we have evaluated the surgical and mechanical feasibility of a TCP/HA bone-graft extender during impaction grafting revision surgery. A TCP/HA allograft mix increased the risk of producing a fissure in the femur during the impaction procedure, but provided a higher initial mechanical stability when compared with bone graft alone. The implications of the use of this type of graft extender in impaction grafting revision surgery are discussed.

Posttraumatic mental and physical health correlates of forgiveness and religious coping in military veterans.

This study assessed mental and physical health correlates of dispositional forgiveness and religious coping responses in 213 help-seeking veterans diagnosed with PTSD. Controlling for age, socioeconomic status, ethnicity, combat exposure, and hostility, the results indicated that difficulty forgiving oneself and negative religious coping were related to depression, anxiety, and PTSD symptom severity. Difficulty forgiving others was associated with depression and PTSD symptom severity, but not anxiety. Positive religious coping was associated with PTSD symptom severity in this sample. Further investigations that delineate the relevance of forgiveness and religious coping in PTSD may enhance current clinical assessment and treatment approaches.

Enhanced antiviral effect in cell culture of type 1 interferon and ribozymes targeting HCV RNA.

We have recently shown that the replication of an HCV-poliovirus (PV) chimera that is dependent upon the hepatitis C virus (HCV) 5' untranslated region (UTR) can be inhibited by treatment with ribozymes targeting HCV RNA. To determine the antiviral effects of anti-HCV ribozyme treatment in combination with type 1 interferon (IFN), we analysed the replication of this HCV-PV chimera in HeLa cells treated with anti-HCV ribozyme and/or IFN-alpha2a, IFN-alpha2b, or consensus IFN. The anti-HCV ribozyme, or any of the IFNs alone have significant inhibitory effects on HCV-PV replication compared to control treatment (> or = 85%, P < 0.01). The maximal inhibition due to IFN treatment (94%, P < 0.01) was achieved with > or = 50 U/ml for either IFN-alpha2a or IFN-alpha2b compared to control treatment. A similar level of inhibition in viral replication could be achieved with a 5-fold lower dose of IFN if ribozyme targeting the HCV 5' UTR was given in combination. For consensus IFN, the dose could be reduced by > 12.5-fold if ribozyme targeting the HCV 5' UTR was given in combination. Conversely, the dose of ribozyme could be reduced 3-fold if given in combination with any of the IFN preparations. Moreover, treatment with low doses (1-25 U/mL) of IFN-alpha2a, IFN-alpha2b, or consensus IFN in combination with anti-HCV ribozyme resulted in > 98% inhibition of HCV-PV replication compared to control treatment (P < 0.01). These results demonstrate that IFN and ribozyme each have a beneficial antiviral effect that is augmented when given in combination.

Surveillance neuroimaging in childhood intracranial ependymoma: how effective, how often, and for how long?

OBJECT: The authors examined images obtained in 52 children with intracranial ependymomas to determine risk factors for tumor recurrence and to assess the impact of surveillance imaging on patient outcome. METHODS: Data obtained in all children with intracranial ependymomas were prospectively entered into a database from January 1987 to June 2000. The imaging and clinical details in all patients were reviewed. Fifty-two children with histologically proven intracranial ependymomas were treated at the authors' institution; recurrences developed in 28 (54%) of them, with a median time from surgery to first recurrence of 14.5 months (range 3-65 months). Of these tumor recurrences, 43% were asymptomatic and were noted on surveillance imaging. Seventeen children died, all of whom had recurrences. Incomplete excision of the primary tumor was significantly associated with reduced time to recurrence (p = 0.0144) and time to death (p = 0.0472). The age of the patient, location of the primary tumor, histological findings, and the presence or absence of spinal metastases on preoperative imaging were not significantly associated with outcome. The risk of death at any given time was 12-fold greater in patients in whom a recurrence was identified due to symptoms rather than on surveillance images (p = 0.016). CONCLUSIONS: Recurrent childhood ependymoma has a poor prognosis. The extent of the initial local tumor resection is the factor most closely associated with outcome. Surveillance imaging reveals a substantial number of asymptomatic recurrences, and survival appears to be improved in these patients compared with those identified by symptoms. The improvement in survival is thought to be greater than that expected just from earlier diagnosis.

Community water fluoridation, bone mineral density, and fractures: prospective study of effects in older women.

OBJECTIVE: To determine whether fluoridation influences bone mineral density and fractures in older women. DESIGN: Multicentre prospective study on risk factors for osteoporosis and fractures. SETTING: Four community based centres in the United States. PARTICIPANTS: 9704 ambulatory women without bilateral hip replacements enrolled during 1986-8; 7129 provided information on exposure to fluoride. MAIN OUTCOME MEASURES: Bone mineral density of the lumbar spine, proximal femur, radius, and calcaneus plus incident fractures (fractures that occurred during the study) of vertebrae, hip, wrist, and humerus. RESULTS: Women were classified as exposed or not exposed or having unknown exposure to fluoride for each year from 1950 to 1994. Outcomes were compared in women with continuous exposure to fluoridated water for the past 20 years (n=3218) and women with no exposure during the past 20 years (n=2563). In women with continuous exposure mean bone mineral density was 2.6% higher at the femoral neck (0.017 g/cm(2), P<0.001), 2.5% higher at the lumbar spine (0.022 g/cm(2), P<0.001), and 1.9% lower at the distal radius (0.007 g/cm(2), P=0.002). In women with continuous exposure the multivariable adjusted risk of hip fracture was slightly reduced (risk ratio 0.69, 95% confidence interval 0.50 to 0.96, P=0.028) as was the risk of vertebral fracture (0.73, 0.55 to 0.97, P=0.033). There was a non-significant trend toward an increased risk of wrist fracture (1.32, 1.00 to 1.71, P=0.051) and no difference in risk of humerus fracture (0.85, 0.58 to 1.23, P=0.378). CONCLUSIONS: Long term exposure to fluoridated drinking water does not increase the risk of fracture.

Management of choroid plexus tumours in children: 20 years experience at a single neurosurgical centre.

OBJECTIVE: Tumours of the choroid plexus are rare tumours of neuro-ectodermal origin, accounting for less than 1% of all intracranial tumours. Most cases present in children less than 2 years of age. While choroid plexus carcinomas (CPC) are reported to have an extremely poor prognosis, choroid plexus papillomas (CPP) are generally regarded as benign tumours with a very favourable long-term outcome. Management dilemmas are associated with the choice of surgical procedure, tumour vascularity, the treatment of hydrocephalus and the value of adjuvant therapy. The objective of this study was to review our experience with this rare tumour over a 20-year period. METHODS: Patients were identified from the Great Ormond Street Neurosurgical Brain Tumour Database. Over a 20-year period (1979-1999), 34 children were identified with a choroid plexus tumour. There were 25 cases of CPP and 9 cases of CPC. A retrospective review of case notes, radiological imaging, operation reports and pathology was performed. RESULTS: The median age at presentation was 17 months (1-138) for CPP and 13 months (2-102) for CPC. There was no sex difference for CPP. However, 8 of the 9 CPCs were male (89%). A complete surgical resection was achieved in all 25 cases of CPP and in 3 cases of CPC (33%). The median survival for CPPs was 75.5 months (2-228), with a median follow-up of 73.5 months (2-228). The median survival for CPCs was 6 months (1-90), with a median follow-up of 6 months (1-90). CONCLUSION: With modern neurosurgical practise, a cure should be the aim for all children with CPP. There is no evidence that adjuvant therapy has any role in the primary management of these children. However, CPC still has an extremely poor prognosis, and the efficacy of adjuvant therapy remains to be established.