The case for routine cervical mediastinoscopy prior to radical surgery for malignant pleural mesothelioma

Objectives: To assess whether cervical mediastinoscopy is necessary before radical resection of malignant pleural mesothelioma (MPM). Methods: Patients who underwent radical excision of MPM in a 48-month period were prospectively followed for evidence of disease recurrence and death. Histological evidence of extra pleural lymph node metastases was correlated with survival. Lymph node size at intraoperative lymphadenectomy was correlated with the presence of metastatic tumour. Results: The 55 patients who underwent radical resection (51 extra pleural pneumonectomies and 4 radical pleurectomies) comprised 50 men and 5 women with a median age of 58 years, range 41-70. Histological examination revealed 50 epithelioid, four biphasic and one sarcomatoid histology. Postoperative IMIG T stage was stage I 4, II 11, III 30 and IV 10. Postoperatively the 17 patients with metastases to the extra pleural lymph nodes had significantly shorter survival (median 4.4 months, 95% CI 3.2-5.4) than those without (median survival 16.3 months, 95% CI 11.6-21.0) P=0.012 Kaplan-Meier analysis. Seventy-seven extra pleural lymph nodes without metastases were measured with a mean long axis diameter of 16.9 mm (range 4-55) ; 22 positive nodes had a mean long axis diameter of 15.2 mm (range 6-30). In 15 of the 17 patients with positive extra pleural nodes, the nodes could have been biopsied at cervical mediastinoscopy. Conclusions: This study confirms that extra pleural nodal metastases are related to poor survival. Pathological nodal involvement cannot be predicted from nodal dimensions. These data suggest that all patients being considered for radical resection of MPM should preferentially undergo preoperative cervical mediastinoscopy irrespective of radiological findings. © 2003 Elsevier B.V. All rights reserved.

Alterations in cervical muscle activity in functional and stressful tasks in female office workers with neck pain

This study determined differences between computer workers with varying levels of neck pain in terms of work stressors, employee strain, electromyography (EMG) amplitude and heart rate response to various tasks. Participants included 85 workers (33, no pain; 38, mild pain; 14, moderate pain) and 22 non-working controls. Work stressors evaluated were job demands, decision authority, and social support. Heart rate was recorded during three tasks: copy-typing, typing with superimposed stress and a colour word task. Measures included electromyography signals from the sternocleidomastoid (SCM), anterior scalene (AS), cervical extensor (CE) and upper trapezius (UT) muscles bilaterally. Results showed no difference between groups in work stressors or employee strain measures. Workers with and without pain had higher measured levels of EMG amplitude in SCM, AS and CE muscles during the tasks than controls (all P < 0.02). In workers with neck pain, the UT had difficulty in switching off on completion of tasks compared with controls and workers without pain. There was an increase in heart rate, perceived tension and pain and decrease in accuracy for all groups during the stressful tasks with symptomatic workers producing more typing errors than controls and workers without pain. These findings suggest an altered muscle recruitment pattern in the neck flexor and extensor muscles. Whether this is a consequence or source of the musculoskeletal disorder cannot be determined from this study. It is possible that workers currently without symptoms may be at risk of developing a musculoskeletal disorder.

Performance measures for Australian laboratories reporting cervical cytology : a decade of data 1998–2008

Aim Performance measures for Australian laboratories reporting cervical cytology are a set of quantifiable measures relating to the profile and accuracy of reporting. This study reviews aggregate data collected over the ten years in which participation in the performance measures has been mandatory. Methods Laboratories submit annual data on performance measures relating to the profile of reporting, including reporting rates for technically unsatisfactory specimens, high grade or possible high grade abnormalities and abnormal reports. Cytology-histology correlation data and review findings of negative smears reported from women with histological high grade disease are also collected. Suggested acceptable standards are set for each measure. This study reviews the aggregate data submitted by all laboratories for the years 1998-2008 and examines trends in reporting and the performance of laboratories against the suggested standards. Results The performance of Australian laboratories has shown continued improvement over the study period. There has been a fall in the proportion of laboratories with data outside the acceptable standard range in all performance measures. Laboratories are reporting a greater proportion of specimens as definite or possible high grade abnormality. This is partly attributable to an increase in the proportion of abnormal results classified as high grade or possible high grade abnormality. Despite this, the positive predictive value for high grade and possible high grade abnormalities has continued to rise. Conclusion Performance measures for cervical cytology have provided a valuable addition to external quality assurance procedures in Australia. They have documented continued improvements in the aggregate performance, as well as providing benchmarking data and goals for acceptable performance for individual laboratories.

Flight-training effect on the cervical muscle isometric strength of trainee pilots

External stimulus/loading initiates adaptations within skeletal muscle. It has been previously found that the cervical area has the highest loading while performing flying maneuvers under +Gz. The first purpose of this study was to examine the neck muscle response to the physical environment associated with flight training, incorporating limited exposure to +Gz force, in a Pilatus PC-9 aircraft. The second purpose was to examine the short-term range of movement (ROM) response to flight training. Isometric cervical muscle strength and ROM was monitored in 9 RAAF pilots completing an 8-mo flight-training course at Pearce Airbase in Western Australia, and in 10 controls matched for gender, age, height, and weight. Isometric cervical muscle strength and ROM were measured at baseline and at 8 mo using the multi-cervical rehabilitation unit (Hanoun Medical, Downsview, Ontario, Canada). Results indicated that an increase in pilot neck strength was limited to flexion while in a neutral position. No strength changes were recorded in any other site in the pilots or for the controls. These findings suggest that short-term exposure to the physical environment associated with flight training had a limited significant effect on increasing isometric cervical muscle strength. No significant changes were observed in pilot ROM, indicating that short-term exposure to flight does not effect ROM.

Changes in cervical spine bone mineral density in response to flight training

BACKGROUND High magnitude loads and unusual loading regimes are two important determinants for increasing bone mass. Past research demonstrated that positive Gz-induced loading, providing high loads in an unaccustomed manner, had an osteogenic effect on bone. Another determinant of bone mass is that the bone response to loading is site specific. This study sought to further investigate the site specific bone response to loading, examining the cervical spine response, the site suspected of experiencing the greatest loading, to high performance flight. METHODS Bone mineral density (BMD) and bone mineral content (BMC) was monitored in 9 RAAF trainee fighter pilots completing an 8-mo flight training course on a PC-9 and 10 age-height-weight-matched controls. RESULTS At completion of the course, the pilots had a significant increase in cervical spine BMD and total body BMC. No significant changes were found for the control group. CONCLUSIONS This study demonstrated that the physical environment associated with flight training may have contributed to a significant increase in cervical spine bone mass in the trainee PC-9 pilots. The increase in bone mass was possibly a response to the strain generated by the daily wearing of helmet and mask assembly under the influence of positive sustained accelerative forces.

Identification of mechanism, PECARN risk factors and injury patterns in severe paediatric cervical spine injuries in Queensland

Introduction Canadian C spine rule and NEXUS criteria have identified risk factors for cervical spine injury in adults but not for children. PECARN has developed an 8 variable model for cervical spine injury in children. We sought to identify the mechanism, prevalence of PECARN risk factors, injury patterns, and management of severe Paediatric cervical spine injuries presenting to the major children’s hospitals in Brisbane, Australia. Methods This a retrospective study of the children with cervical spine injuries who presented directly or were referred to the major children’s hospitals in Brisbane over 5 years. Results There were 38 patients with 18 male and 20 female.The mean age was 8.6 years. They were divided into two groups according to their age, (Group 1 < =8 years had 18 (47%) patients, while group 2 (9-15 years) had 20 (53%) patients. Motor vehicle related injuries were the most common (61%) in Group 1 while it was sporting injuries (50%) in group 2. All patients in group 1 had upper cervical injury (C0-C2) while subaxial injuries were most common in group 2 (66.6%). 82% of the patients had 2 or more PECARN risk factors. 18 children (47%) had normal neurological assessment at presentation, 6 (16%) had radicular symptoms, 11 (29%) could not be assessed as they had already been intubated due to the severity of the injury, 3 (8%) had incomplete cord injury. 29 (69%) patients had normal neurological assessment at final follow up and 2 children died from their injuries. Conclusion Our study confirms that younger children sustain upper cervical injuries most commonly secondary to motor vehicle accidents, while the older sustain subaxial injuries from sporting activities. The significant prevalence of the PECARN risk factors among this cohort of patients have led to them being incorporated into a protocol at these hospitals used to assess patients with suspected cervical spinal injury.

How useful are x-rays in severe paediatric cervical spinal injuries?

INTRODUCTION Radiological evaluation of the paediatric cervical spine can be a challenge due to the normal anatomic variants and injuries that are unique to children. We aimed to identify the usefulness of plain X-rays in comparison with CT and MRI in diagnosing Paediatric cervical spinal injuries. METHODS Retrospective review of imaging studies of children diagnosed with paediatric cervical spine injuries who had presented to two tertiary hospitals in Queensland. RESULTS There were 38 patients with 18 male and 20 female .The mean age was 8.6 years. Plain Cervical Spine X-rays (3views, AP lateral and open mouth views) were done in 34 patients. The remaining 8 children had a suspected head injury and hence had CT scans of their neck done at the time of CT head scan. Of these images taken, X-rays were diagnostic in 28 (82%) patients. CONCLUSION X- Rays still have a role to play in the diagnosis of pediatric cervical spinal injuries and should be considered as the first line in fully conscious patients and their usefulness should not be overlooked in light of the newer imaging modalities.

Inertial sensor real-time feedback enhances the learning of cervical spine manipulation: A prospective study

Background Cervical Spinal Manipulation (CSM) is considered a high-level skill of the central nervous system because it requires bimanual coordinated rhythmical movements therefore necessitating training to achieve proficiency. The objective of the present study was to investigate the effect of real-time feedback on the performance of CSM. Methods Six postgraduate physiotherapy students attending a training workshop on Cervical Spine Manipulation Technique (CSMT) using inertial sensor derived real-time feedback participated in this study. The key variables were pre-manipulative position, angular displacement of the thrust and angular velocity of the thrust. Differences between variables before and after training were investigated using t-tests. Results There were no significant differences after training for the pre-manipulative position (rotation p = 0.549; side bending p = 0.312) or for thrust displacement (rotation p = 0.247; side bending p = 0.314). Thrust angular velocity demonstrated a significant difference following training for rotation (pre-training mean (sd) 48.9°/s (35.1); post-training mean (sd) 96.9°/s (53.9); p = 0.027) but not for side bending (p = 0.521). Conclusion Real-time feedback using an inertial sensor may be valuable in the development of specific manipulative skill. Future studies investigating manipulation could consider a randomized controlled trial using inertial sensor real time feedback compared to traditional training.

Cervical headgear in Class II division 1 correction in children : Academic Dissertation

Class II division 1 malocclusion occurs in 3.5 to 13 percent of 7 12 year-old children. It is the most common reason for orthodontic treatment in Finland. Correction is most commonly performed using headgear treatment. The aim of this study was to investigate the effects of cervical headgear treatment on dentition, facial skeletal and soft tissue growth, and upper airway structure, in children. 65 schoolchildren, 36 boys and 29 girls were studied. At the onset of treatment a mean age was 9.3 (range 6.6 12.4) years. All the children were consequently referred to an orthodontist because of Class II division 1 malocclusion. The included children had protrusive maxilla and an overjet of more than 2mm (3 to 11 mm). The children were treated with a Kloehn-type cervical headgear as the only appliance until Class I first molar relationships were achieved. The essential features of the headgear were cervical strong pulling forces, a long upward bent outer bow, and an expanded inner bow. Dental casts and lateral and posteroanterior cephalograms were taken before and after the treatment. The results were compared to a historical, cross-sectional Finnish cohort or to historical, age- and sex-matched normal Class I controls. The Class I first molar relationships were achieved in all the treated children. The mean treatment time was 1.7 (range 0.3-3.1) years. Phase 2 treatments were needed in 52% of the children, most often because of excess overjet or overbite. The treatment decreased maxillary protrusion by inhibiting alveolar forward growth, while the rest of the maxilla and mandible followed normal growth. The palate rotated anteriorly downward. The expansion of the inner bow of the headgear induced widening of the maxilla, nasal cavity, and the upper and lower dental arches. Class II malocclusion was associated with narrower oro- and hypopharyngeal space than in the Class I normal controls. The treatment increased the retropalatal airway space, while the rest of the airway remained unaffected. The facial profile improved esthetically, while the facial convexity decreased. Facial soft tissues masked the facial skeletal convexity, and the soft tissue changes were smaller than skeletal changes. In conclusion, the headgear treatment with the expanded inner bow may be used as an easy and simple method for Class II correction in growing children.

Fumarate Hydratase and Succinate Dehydrogenase in Neoplasia

Germline mutations in fumarate hydratase (FH) cause hereditary leiomyomatosis and renal cell cancer (HLRCC). FH is a nuclear encoded enzyme which functions in the Krebs tricarboxylic acid cycle, and homozygous mutation in FH lead to severe developmental defects. Both uterine and cutaneous leiomyomas are components of the HLRCC phenotype. Most of these tumours show loss of the wild-type allele and, also, the mutations reduce FH enzyme activity, which indicate that FH is a tumour suppressor gene. The renal cell cancers associated with HLRCC are of rare papillary type 2 histology. Other genes involved in the Krebs cycle, which are also implicated in neoplasia are 3 of the 4 subunits encoding succinate dehydrogenase (SDH); mutations in SHDB, SDHC, and SDHD predispose to paraganglioma and phaeochromocytoma. Although uterine leiomyomas (or fibroids) are very common, the estimations of affected women ranging from 25% to 77%, not much is known about their genetic background. Cytogenetic studies have revealed that rearrangements involving chromosomes 6, 7, 12 and 14 are most commonly seen in fibroids. Deletions on the long arm of chromosome 7 have been reported to be involved in about 17 to 34 % of leiomyomas and the small commonly deleted region on 7q22 suggests that there might be an underlying tumour suppressor gene in that region. The purpose of this study was to investigate the genetic mechanisms behind the development of tumours associated with HLRCC, both renal cell cancer and uterine fibroids. Firstly, a database search at the Finnish cancer registry was conducted in order to identify new families with early-onset RCC and to test if the family history was compatible with HLRCC. Secondly, sporadic uterine fibroids were tested for deletions on 7q in order to define the minimal deleted 7q-region, followed by mutation analysis of the candidate genes. Thirdly, oligonucleotide chips were utilised to study the global gene expression profiles of uterine fibroids in order to test whether 7q-deletions and FH mutations significantly affected fibroid biology. In the screen for early-onset RCC, 214 families were identified. Subsequently, the pedigrees were constructed and clinical data obtained. One of the index cases (RCC at the age of 28) had a mother who had been diagnosed with a heart tumour, which in further investigation turned out to be a paraganglioma. This lead to an alternative hypothesis that SDH, instead of FH, could be involved. SDHA, SDHB, SDHC and SDHD were sequenced from these individuals; a germline SDHB R27X mutation was detected with loss of the wild-type allele in both tumours. These results suggest that germline mutations in the SDHB gene predispose to early-onset RCC establishing a novel form of hereditary RCC. This has immediate clinical implications in the surveillance of patients suffering from early-onset RCC and phaeochromocytoma/paraganglioma. For the studies on sporadic uterine fibroids, a set of 166 fibroids from 51 individuals were collected. The 7q LOH mapping defined a commonly deleted region of about 3.2 mega bases in 11 of the 166 tumours. The deletion was consistent with previously reported allelotyping studies of leiomyomas and it therefore suggested the presence of a tumour suppressor gene in the deleted region. Furthermore, the high-resolution aCGH-chip analysis refined the deleted region to only 2.79Mb. When combined with previous data, the commonly deleted region was only 2.3Mb. The mutation screening of the known genes within the commonly deleted region did not reveal pathogenic mutations, however. The expression microarray analysis revealed that FH-deficient fibroids, both sporadic and familial, had their distinct gene expression profile as they formed their own group in the unsupervised clustering. On the other hand, the presence or absence of 7q-deletions did not significantly alter the global gene expression pattern of fibroids, suggesting that these two groups do not have different biological backgrounds. Multiple differentially expressed genes were identified between FH wild-type and FH-mutant fibroids, and the most significant increase was seen in the expression of carbohydrate metabolism-related and hypoxia inducible factor (HIF) target genes.

The role of AIP and CDKN1B/p27Kip1 in endocrine neoplasia

Identification of genes predisposing to tumor syndromes has raised general awareness of tumorigenesis. Genetic testing of tumor susceptibility genes aids the recognition of individuals at increased risk of tumors. Identification of novel predisposing genes enables further studies concerning the classification of potential associated tumors and the definition of target patient group. Pituitary adenomas are common, benign neoplasms accounting for approximately 15% of all intracranial tumors. Accurate incidence estimation is challenging since a great portion of these adenomas are small and asymptomatic. Clinically relevant adenomas, that cause symptoms due to the expansion of the cell mass or the over-secretion of normally produced hormones, occur in approximately one of 1 000 individuals. Although the majority of pituitary adenomas are sporadic, a minority occur as components of familial syndromes, such as Multiple Endocrine Neoplasia type 1 (MEN1) and Carney complex (CNC). MEN1 syndrome is caused by germ-line mutations in the MEN1 gene, whereas most of the CNC patients carry the mutated protein kinase A (PKA) regulatory subunit-1-α (PRKAR1A) gene. Recently, other conditions predisposing to endocrine tumors have been identified: Pituitary Adenoma Predisposition (PAP) and MEN type 4 (MEN4). PAP was originally identified in a genetically homogeneous Finnish population. In a population based cohort from Northern Finland, aryl hydrocarbon receptor-interacting protein (AIP) gene mutations were found in 16% of all patients diagnosed with growth hormone (GH) producing pituitary adenoma, and in 40% of the subset of patients who were diagnosed under the age of 35 years. Since AIP mutations were originally described in a defined, homogeneous population from Northern Finland, it was relevant to study whether mutations also occur in more heterogeneous populations. In patient cohorts with different ethnic origins and variable clinical phenotypes, germ-line AIP mutations were detectable at low frequencies (range 0.8-7.4%). AIP mutation-positive patients were often diagnosed with a GH-producing adenoma at a young age, and usually had no family history of endocrine tumors. The low frequency of AIP mutations in randomly selected patients, and the lack of any family history of pituitary adenomas create a challenge for the identification of PAP patients. Our preliminary study suggests that AIP immunohistochemistry may serve as a pre-screening tool to distinguish between the AIP mutation-negative and the mutation-positive tumors. Tumors of various endocrine glands are components of MEN1 and CNC syndromes. Somatic MEN1 and PRKAR1A mutations in sporadic pituitary adenomas are rare, but occur in some of the other tumors related to these syndromes. The role of AIP mutations in endocrine neoplasia was studied and our results indicated that somatic AIP mutations are rare or non-existent in sporadic tumors of endocrine glands (0 of 111). Furthermore, germ-line AIP mutations in prolactin producing adenomas (2 of 9) confirmed the role of this pituitary tumor type in the PAP phenotype. Thyroid disorders are common in the general population, and the majority of them are sporadic. Interestingly, it has been suggested that thyroid disorders might be more common in PAP families. For this reason we studied germ-line AIP mutations in 93 index cases from familial non-medullary thyroid cancer (NMTC) families. The underlying gene or genes for familial NMTC have not been identified yet. None of the patients had any potentially pathogenic AIP mutation. This suggests that AIP is unlikely to play a role in familial NMTCs. A novel multiple endocrine syndrome was originally described in rats with phenotypic features of human MEN type 1 and 2. Germ-line mutations of cyclin-dependent kinase inhibitor 1B (CDKN1B also known as p27Kip1) gene were reported later in these rats and a germ-line mutation was also identified in one human family with MEN1-like phenotype (later named MEN4). To confirm the importance of this gene’s mutations in humans, we performed a mutation screening in MEN-like patients and in patients with pituitary adenoma. Our results indicate that CDKN1B/p27Kip1 mutations appear in a small portion of MEN1-like patients (one of 36), and that such mutations are rare or non-existent in both familial (0 of 19) and sporadic pituitary adenoma patients (0 of 50). In conclusion, this work strengthens the tumor susceptibility role of AIP and CDKN1B/p27Kip1 in endocrine neoplasia. Clarifying the PAP phenotype facilitates the identification of potential AIP mutation carriers. Genetic counseling can be offered to the relatives and follow-up of the mutation carriers can be organized, hence an earlier diagnosis is feasible.

Diet, cell signalling, and tumourigenesis in multiple intestinal neoplasia mice

The incidence of colon cancer is high in Western societies, and in Finland it is among the three most common cancer types in both females and males. Environmental factors, including diet, affect colon cancer development. During the last few years, a vast amount of new, functional foods have been introduced to the consumers. Several products are already available that are marketed as promoting intestinal health. To be able to reliably call a dietary compound a chemopreventive substance it is of fundamental importance to understand the mechanism by which it affects tumour formation and the integrity of the epithelial cells. In this thesis, three different dietary compounds were studied in an experimental model of colon cancer. Inulin is a non-digestible fibre found naturally in chicory roots, artichokes and onions, amongst others. Nowadays it is widely used as an added dietary fibre in several food products. Conjugated linoleic acid (CLA) is a conjugated form of the fatty acid linoleic acid. CLA is formed by bacterial fermentation of linoleic acid in the rumen of cows and other ruminants. Concomitantly, it can naturally be found in milk and meat of ruminants. White currant is a colourless berry low in phenolic compounds that are believed to prevent cancer formation. Contrary to what was expected, inulin and the conjugated linoleic acid isomer trans-10, cis-12, were tumour growth promoting dietary constituents when fed to Min mice. Both diets decreased the NF-kappaB levels in the mucosa, but physiological adenoma development did not affect NF-kappaB. Diet altered beta-catenin and p53 signalling in the adenomas, confirming their involvement in adenoma growth. White currant, on the other hand, was chemopreventive, despite its low contents of phenolic compounds. The chemopreventive effect was accompanied by increased p53 levels in the mucosa, and decreased beta-catenin and NF-kappaB levels in the adenoma. This could explain the reduced adenoma number and size. The results underline the importance of carefully testing new dietary compounds in different settings to reliably confirm their health benefits. In this study two compounds that are consumed and believed to add to our health proved to be cancer promotive. A berry with low phenolic contents, on the other hand, was chemopreventive.

The relationship between forward head posture and cervical muscle performance in healthy individuals

Background Forward head postures (FHP) are proposed to adversely load cervical spine structures. Neck muscles provide support for the neck, and thus an imbalance in neck muscle performance could potentially contribute to the development of FHP. Previous studies have not considered the interaction of multiple muscle groups with regard to postural orientation. Given the interdependence of muscles along the cervical spine for optimal orientation and physical support of the vertebral column, the performance of a single muscle group may not accurately reflect the coordinated ability of the muscles to maintain a neutral neck posture. Purpose The purpose of this study was to investigate the relationship between FHP and the balance between the cervical extensor and flexor muscle groups in healthy individuals. We hypothesised that the magnitude of FHP would be associated with the strength and endurance performance ratios between the cervical extensor and flexor muscle groups. Methods Twenty male and 24 female volunteers were photographed in the sagittal plane wearing surface markers. The FHP of each participant was measured via the tragus-sternum marker distance over two conditions: (1)in relaxed standing and (2)during a sustained sitting task. Maximal strength (Nm) and endurance (s) performance of the extensor and flexor muscle groups were recorded at the upper (craniocervical flexion/extension (CCF/CCE)) and lower (cervicothoracic flexion/extension (CTF/CTE)) cervical regions. Muscle performance measures were expressed as extension:flexion ratios and their relation to FHP evaluated. A stepwise multiple regression analysis using backward elimination was utilised to examine the relationship between the postural measures and the muscle performance ratio measures. Separate models were used for the two different postural conditions (standing, sustained sitting). Gender was included as a constant correction factor in all regression models. Where gender was a significant variable in the model, analyses were repeated separately for males and females. Results Greater FHP in standing was significantly associated with reduced proportional CTE to CCF strength in females (R2 = 0.21, P = 0.03) and greater proportional CTE to CTF strength in males (R2 = 0.23, P = 0.03). A greater drift into FHP during sustained sitting was associated with a relative reduction in CCE endurance proportional to CTF endurance in females only (R2 = 0.27, P = 0.017). Conclusion(s) This initial study indicates that the balance in performance between the cervical flexor and extensor muscle groups may impact FHP in healthy individuals. However, the findings were inconsistent across different muscle performance ratios and gender. Larger scale studies are therefore now needed to further clarify the relationship between FHP and muscle performance. Implications The findings suggest that relative performance of the various cervical muscle groups needs to be accounted for when considering postural correction strategies in the clinical setting, as is often recommended.