Management of lateral skull base cancer: United Kingdom National Multidisciplinary Guidelines.

This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. It provides recommendations on the work up and management of lateral skull base cancer based on the existing evidence base for this rare condition. Recommendations • All patients with more than one of: chronic otalgia, bloody otorrhoea, bleeding, mass, facial swelling or palsy should be biopsied. (R) • Magnetic resonance and computed tomography imaging should be performed. (R) • Patients should undergo audiological assessment. (R) • Carotid angiography is recommended in select patients. (G) • The modified Pittsburg T-staging system is recommended. (G) • The minimum operation for cancer involving the temporal bone is a lateral temporal bone resection. (R) • Facial nerve rehabilitation should be initiated at primary surgery. (G) • Anterolateral thigh free flap is the workhorse flap for lateral skull base defect reconstruction. (G) • For patients undergoing surgery for squamous cell carcinoma, at least a superficial parotidectomy and selective neck dissection should be carried out. (R).

The impact of delayed biliary decompression and anti-microbial therapy in 260 patients with cholangitis-associated septic shock.

BACKGROUND: Cholangitis-associated septic shock carries significant mortality. There is uncertainty regarding the most appropriate time to achieve biliary decompression. AIM: To determine whether the timing of biliary decompression and anti-microbial therapy affect the survival in cholangitis patients with septic shock. METHODS: Nested retrospective cohort study of all cholangitis-associated septic shock patients (hypotension requiring vasopressors) from an international, multi-centre database between 1996 and 2011. RESULTS: Among 260 patients (mean age 69 years, 57% male), overall mortality was 37%. Compared to nonsurvivors (n = 96), survivors (n = 164) had lower mean admission Acute Physiology And Chronic Health Evaluation (APACHE) II (22 vs. 28, P < 0.001) and lower median serum lactate on admission (3.4 vs. 4.6 mmol/L, P < 0.001). Survivors were more likely to receive appropriate anti-microbial therapy earlier (median 2.6 vs. 6.8 h from shock, P < 0.001). Survivors were also more likely to undergo successful biliary decompression earlier (median 8.8 vs. 22 h, P < 0.001). After adjusting for co-variates, APACHE II (odds ratio, OR 1.21 per increment (1.11-1.32), time delay to appropriate anti-microbial therapy [OR 1.15 per hour (1.07-1.25)] and delayed biliary decompression >12 h [OR 3.40 (1.12-10.31)] were all significantly associated with increased mortality (P < 0.04 for all; c-statistic 0.896). CONCLUSIONS: Patients with septic shock secondary to acute cholangitis have significant mortality. Endoscopic biliary decompression >12 h after the onset of shock and delayed receipt of appropriate anti-microbial therapy were both significantly associated with adverse hospital outcome. This might suggest that early initiation of anti-microbial therapy and urgent biliary decompression (within 12 h) could potentially improve outcomes in this high-risk patient population.

Lung cancer is associated with decreased expression of perforin, granzyme B and interferon (IFN)-γ by infiltrating lung tissue T cells, natural killer (NK) T-like and NK cells.

There is a limited understanding how of lung cancer cells evade cytotoxic attack. Previously, we have shown reduced production of the cytotoxic mediator granzyme B by CD8(+) T cells in lung cancer tissue. We hypothesized that lung cancer would be further associated with decreased production of granzyme B, perforin and proinflammatory cytokines by other cytotoxic lymphocytes, natural killer (NK) T-like and NK cells, and that this would result from soluble mediators released by the cancer cells. Lung cancer and non-cancer tissue from five patients was identified by experienced pathologists. Tumour necrosis factor (TNF)-α, interferon (IFN)-γ, granzyme B and perforin were measured in CD4 and CD8(+) T, NK T-like cells and NK cells by flow cytometry. Correlation between cancer stage and granzyme B was analysed retrospectively for 21 patients. The effects of soluble factors released by lung cancer cells on production of cytotoxic mediators and cytokines was assessed, and the role of prostaglandin E2 (PGE)2 /COX investigated using indomethacin inhibition. There were significantly decreased percentages of T, NK T-like and NK cells expressing perforin, TNF-α and IFN-γ in cancer versus non-cancer tissue, and of CD8(+) T cells and CD8(+) NK T-like cells expressing granzyme B (e.g. NK T-like cells: non-cancer 30% ± 7 versus cancer 6% ± 2·5). Cancer cells released soluble factors that inhibited granzyme B, perforin and IFN-γ production that was partially associated with the PGE2 /COX2 pathway. Thus, lung cancer is associated with decreased expression of granzyme B, perforin and IFN-γ by infiltrating T cells, NK T-like and NK cells, possibly as a result of soluble factors produced by the cancer cells including PGE2 . This may be an important immune evasion mechanism.

Factors affecting final facial nerve outcome following vestibular schwannoma surgery.

OBJECTIVE: To determine factors affecting facial nerve outcome of vestibular schwannoma surgery. METHODS: This retrospective cohort study comprised 652 patients. The outcome measure was House-Brackmann classification at two years post-operatively. Univariate and multivariate analyses were carried out to determine the factors affecting facial nerve outcome. The incidence rates of hemifacial spasm, metallic taste and crocodile tear syndrome were recorded. RESULTS: For tumours less than 1.5 cm, 95 per cent of outcomes were normal, 100 per cent were satisfactory (House-Brackmann grades I-III) and 0 per cent were unsatisfactory (grades IV-VI). For tumours 1.5-2.4 cm, 83 per cent of outcomes were normal, 99 per cent were satisfactory and 1 per cent were unsatisfactory. For tumours 2.5-3.4 cm, 68 per cent of outcomes were normal, 96 per cent were satisfactory and 4 per cent were unsatisfactory. For tumours 3.5-4.4 cm, 52 per cent of outcomes were normal, 80 per cent were satisfactory and 20 per cent were unsatisfactory. For tumours larger than 4.4 cm, 50 per cent of outcomes were normal, 72 per cent were satisfactory and 28 per cent were unsatisfactory. CONCLUSION: Tumour size and operation year were significant predictors of facial nerve outcome. The surgical learning curve was steepest for the first 50 patients.

Outcome of translabyrinthine surgery for vestibular schwannoma in neurofibromatosis type 2.

OBJECTIVES: To analyse the long-term outcome of translabyrinthine surgery for vestibular schwannoma (VS) in neurofibromatosis type 2 (NF2). RESEARCH TYPE: Retrospective cohort study. SETTING: Two tertiary referral NF2 units. PATIENTS: One hundred and forty eight translabyrinthine operations for patients with VS were performed. Preoperative stereotactic radiotherapy had been performed on 12(9.4%) patients. RESULTS: Mean tumour size was 3.1 cm. Total tumour excision was achieved in 66% of cases, capsular remnants were left in 24% of cases, and subtotal excision was achieved in 5% and partial removal was achieved in 5%. The radiological residual/recurrence rate was 13.9%. The perioperative mortality was 1.6%. At 2 years postoperatively, facial function was expressed in terms of House-Brackmann score (HB): HB 1 in 53.4%, HB 1/2 in 61.3%, HB 1-3 in 83.2% and HB 4-6 in 16.8%. All nine patients who underwent surgery following failed stereotactic radiotherapy had HB 3 function or better. Among 9.5% of the cases, 14 facial nerves were lost during surgery and repaired using direct anastomosis or grafting. There was no tinnitus present preoperatively in 27% of the cases, and 22% of patients developed tinnitus postoperatively. In patients with preoperative tinnitus, 61% remained the same, 17% got it resolved and only in 21% it worsened. The preoperative hydrocephalus rate was 26%, and among 15% of the cases five ventriculo-peritoneal (VP) shunts were performed. The cerebrospinal fluid leak rate was 2.5%. Fifty-six patients underwent auditory brainstem implantation (ABI) and two patients had cochlear implant (CI) sleepers inserted. CONCLUSIONS: The management of patients with NF2 presents the clinician with a formidable challenge with many patients still presenting themselves late with the neurological compromise and a large tumour load. There is still an argument for the management by observation until the neurological compromise dictates interventional treatment particularly with the option of hearing rehabilitation with ABI or CI. The translabyrinthine approach provides a very satisfactory means of reducing the overall tumour volume.

Antitumor activity of a small-molecule inhibitor of the histone kinase Haspin.

The approval of histone deacetylase inhibitors for treatment of lymphoma subtypes has positioned histone modifications as potential targets for the development of new classes of anticancer drugs. Histones also undergo phosphorylation events, and Haspin is a protein kinase the only known target of which is phosphorylation of histone H3 at Thr3 residue (H3T3ph), which is necessary for mitosis progression. Mitotic kinases can be blocked by small drugs and several clinical trials are underway with these agents. As occurs with Aurora kinase inhibitors, Haspin might be an optimal candidate for the pharmacological development of these compounds. A high-throughput screening for Haspin inhibitors identified the CHR-6494 compound as being one promising such agent. We demonstrate that CHR-6494 reduces H3T3ph levels in a dose-dependent manner and causes a mitotic catastrophe characterized by metaphase misalignment, spindle abnormalities and centrosome amplification. From the cellular standpoint, the identified small-molecule Haspin inhibitor causes arrest in G2/M and subsequently apoptosis. Importantly, ex vivo assays also demonstrate its anti-angiogenetic features; in vivo, it shows antitumor potential in xenografted nude mice without any observed toxicity. Thus, CHR-6494 is a first-in-class Haspin inhibitor with a wide spectrum of anticancer effects that merits further preclinical research as a new member of the family of mitotic kinase inhibitors.

Non echo planar, diffusion-weighted magnetic resonance imaging (periodically rotated overlapping parallel lines with enhanced reconstruction sequence) compared with echo planar imaging for the detection of middle-ear cholesteatoma.

OBJECTIVES: We evaluated use of the periodically rotated overlapping parallel lines with enhanced reconstruction diffusion-weighted imaging sequence, compared with conventional echo planar magnetic resonance imaging, in the detection of middle-ear cholesteatoma. MATERIAL AND METHODS: Sixteen patients awaiting second-stage combined approach tympanoplasty and three patients awaiting first-stage combined approach tympanoplasty underwent magnetic resonance imaging with both (1) the periodically rotated overlapping parallel lines with enhanced reconstruction sequence (i.e. non echo planar imaging) and (2) the array spatial sensitivity encoding technique sequence (i.e. echo planar imaging). Two neuroradiologists independently evaluated the images produced by both sequences. Radiology findings were correlated with surgical findings. RESULTS AND ANALYSIS: Seven cholesteatomas were found at surgery. Neither of the assessed imaging sequences were able to detect cholesteatoma of less than 4 mm. Rates for sensitivity, specificity, and positive and negative predictive values are presented. CONCLUSION: Decisions on whether or not to operate for cholesteatoma cannot be made based on the two imaging sequences assessed, as evaluated in this study. Other contributing factors are discussed, such as the radiological learning curve and technical limitations of the magnetic resonance imaging equipment.

Immunoglobulin G4 related systemic sclerosing disease involving the temporal bone.

OBJECTIVE: To report a rare condition affecting the temporal bone. Immunoglobulin G4 related systemic sclerosing disease is a recently described autoimmune condition with manifestations typically involving the pancreas, biliary system, salivary glands, lungs, kidneys and prostate. Histologically, it is characterised by T-cell infiltration, fibrosis and numerous immunoglobulin G4-positive plasma cells. This condition previously fell under the umbrella diagnosis of inflammatory pseudotumour and inflammatory myofibroblastic tumour. CASE REPORT: We present the case of a 58-year-old woman with multiple inflammatory masses involving the pharynx, gall bladder, lungs, pelvis, omentum, eyes and left temporal bone, over a seven-year period. We describe this patient's unusual clinical course and pathological features, which resulted in a change of diagnosis from metastatic inflammatory myofibroblastic tumour to immunoglobulin G4 related systemic sclerosing disease. We also review the literature regarding the management of inflammatory pseudotumours of the temporal bone, and how this differs from the management of immunoglobulin G4 related systemic sclerosing disease. CONCLUSION: We would recommend a full review of all histological specimens in patients with a diagnosis of temporal bone inflammatory pseudotumour or inflammatory myofibroblastic tumour. Consideration should be given to immunohistochemical analysis for anaplastic lymphoma kinase and immunoglobulin G4, with measurement of serum levels of the latter. Management of the condition is medical, with corticosteroids and immunosuppression, rather than surgical excision.

Cardiac injury markers in non-elite marathon runners.

An elevation of cardiac injury markers including creatinine kinase (CK), myoglobin (Myo) and cardiac troponin T (cTnT) has been observed in elite athletes following strenuous exercise. The mechanism and significance of this observation however have not been fully elucidated. The goals of this study were: 1) to determine whether these changes in biomarkers also occur in a large, heterogeneous group of non-elite athletes; and 2) to identify possible clinical or biochemical associations. We recruited 129 non-elite runners in 2006, 61 individuals who were taking part in the half (13.1 miles) marathon and 68 individuals participating in the full (26.2 miles) marathon. Demographic data and blood samples were collected for analysis of CK, Myo, cTnT, and Creatinine (Cr) levels within two hours of race start, at race completion, and 1-h post-race for both patient cohorts. In the 61 individuals (40 males, 40+/-12 yrs) completing the half marathon in a mean time of 150+/-20 min, 90.3%, 65.2%, and 30.6% of the subjects exhibited significant elevations in Myo, CK, and cTnT, respectively immediately post race and 100%, 74.9% and 45.9% in the same biomarkers one hour-post race. In the 68 individuals (44 males, 42+/-14 yrs) completing the full marathon in a mean time of 310+/-30 min, 95.3%, 70.2% and 35.7% exhibited significant elevations in Myo, CK and cTnT respectively immediately post race and 100%, 78.5% and 52.8% in the same biomarkers one hour-post race. The elevation in cTnT levels post-race were modestly associated with the time required to complete the race for the entire cohort of marathon runners. The serum levels of Cr, CK, and Myo post-race did not correlate however with age, sex, BMI, level of training, or prior marathon experience. Elevations of cardiac injury markers in non-elite athletes are extremely common following the completion of endurance events and correlate to the increased endurance time. Whether the increase in the levels of these enzymes represents true myocardial injury or a result of the release of cTnT from the myocytes requires further investigation.

Effect of chiropractic manipulations on the kinematics of back and limbs in horses with clinically diagnosed back problems.

REASON FOR PERFORMING STUDY: Although there is anecdotal evidence of clinical effectiveness of chiropractic in treatment of equine back pain, little scientific work has been reported on the subject. OBJECTIVES: To quantify the effect of chiropractic manipulations on back and limb kinematics in horse locomotion. METHODS: Kinematics of 10 Warmblood horses were measured over ground at walk and trot at their own, preferred speed before, and one hour and 3 weeks after chiropractic treatment that consisted of manipulations of the back, neck and pelvic area. Speed was the same during all measurements for each horse. RESULTS: Chiropractic manipulations resulted in increased flexion-extension range of motion (ROM) (P<0.05) at trot in the vertebral angular segments: T10-T13-T17 (0.3 degrees ) and T13-T17-L1 (0.8 degrees ) one hour after treatment, but decreased ROM after 3 weeks. The angular motion patterns (AMPs) of the same segments showed increased flexion at both gaits one hour after treatment (both angles 0.2 degrees at walk and 0.3 degrees at trot, P<0.05) and 3 weeks after treatment (1.0 degrees and 2.4 degrees at walk and 1.9 degrees and 2.9 degrees at trot, P<0.05). The lumbar (L3 and L5) area showed increased flexion after one hour (both angles 0.3 degrees at walk and 0.4 degrees at trot P<0.05), but increased extension after 3 weeks (1.4 degrees and 1.2 degrees , at trot only, P<0.05). There were no detectable changes in lateral bending AMPs. The inclination of the pelvis was reduced at trot one hour (1.6 degrees ) and 3 weeks (3 degrees ) after treatment (P<0.05). The mean axial rotation of the pelvis was more symmetrical 3 weeks after the treatment at both gaits (P<0.05). There were no changes in limb angles at walk and almost no changes at trot. CONCLUSIONS: The main overall effect of the chiropractic manipulations was a less extended thoracic back, a reduced inclination of the pelvis and improvement of the symmetry of the pelvic motion pattern. POTENTIAL RELEVANCE: Chiropractic manipulations elicit slight but significant changes in thoracolumbar and pelvic kinematics. Some of the changes are likely to be beneficial, but clinical trials with increased numbers of horses and longer follow-up are needed.

A critical evaluation of the evidence on a causal relationship between Helicobacter pylori and otitis media with effusion.

OBJECTIVE: There is growing interest in the presence of Helicobacter pylori in the upper aerodigestive tract, and in the middle ear in patients with otitis media with effusion. Some studies have reported detecting H pylori in the middle ear, although reports to the contrary exist. In this study, we critically evaluate the evidence for the theory that H pylori in the middle ear plays a role in otitis media with effusion. MATERIAL: We undertook a systematic review of all available studies investigating the presence of H pylori in the middle ear of patients with otitis media with effusion. The current literature was critically analysed using the key words and phrases 'Helicobacter pylori' 'otitis media with effusion', 'serous otitis media', 'glue ear' and 'middle ear'. Six original research papers were identified, studying a total of 203 patients and 27 controls; two of these papers were randomised, controlled studies and four were prospective, cohort studies. RESULTS: At present, there is poor evidence for the existence of H pylori-associated otitis media with effusion. CONCLUSIONS: Further research in the field is needed in order to delineate the presence of H pylori and its role in the pathogenesis of otitis media with effusion.

Unusual presentation of temporal bone involvement in Churg-Strauss syndrome.

OBJECTIVE: To present a case of a 60-year-old male with a history of sudden onset sensorineural hearing loss due to Churg-Strauss syndrome. CASE REPORT: The patient had a 20-year history of asthma and recurrent right otitis media and a nasal polypectomy four years prior to presenting with ear symptoms. Ear, nose and throat involvement is common in Churg-Strauss syndrome, usually manifesting as allergic rhinitis and chronic rhinosinusitis with or without polyps. CONCLUSIONS: Otolaryngologists play an important role in making an early diagnosis of this disease. To our knowledge this is the first case of Churg-Strauss syndrome primarily presenting with otological pathology: left sensorineural hearing loss and right otitis media.

Unusual otological manifestations in Camurati-Engelmann's disease.

Camurati-Engelmann's disease (CED) is a rare hereditary disorder affecting mainly the diaphysis of long bones but multiple cranial nerve deficits may also develop secondary to bony sclerosis of their foramina, including visual loss, facial palsy, deafness, vestibular disturbances and sensory deficits along the distribution of the trigeminal nerve. Deafness has been reported in about 18 per cent of these cases due to narrowing of the internal auditory canals caused by bony encroachment on nerves and vessels. We report an extremely rare case of a patient with CED who presented with deafness due to gross abnormalities affecting both middle ear and cochlea. The issues relating to the management of these patients with temporal bone involvement are discussed.

Surgical management of trigeminal neuromas: a report of eight cases.

OBJECTIVE: Trigeminal neuromas are rare tumours that may involve any part of the Vth nerve complex, including extracranial peripheral divisions of the nerve. A series of eight patients with intracranial trigeminal neuromas who underwent surgical management are presented. METHODS: The hospital records and radiological images were reviewed with regard to clinical presentation, surgical approach, operative findings, peri-operative morbidity and neurological outcome, and percentage of tumour recurrence. RESULTS: The principal presenting symptoms were those of involvement of the trigeminal nerve with sensory impairment in one or more of the three divisions. Tumour location was the prime determinant of surgical approach. Lateral skull base approaches were used as they are considered to be superior for identifying tumour origin, extension, and relationship to surrounding structures. Total excision of the tumour was carried out in three of the eight patients. In the remaining five patients some tumour was left purposely in order to minimize neurological deficit and optimize post-operative quality of life. There was no peri-operative mortality or major morbidity in our series. Five patients experienced symptomatic tumour recurrence and revision surgery was performed. CONCLUSION: Management of trigeminal neuromas is complex and requires a multidisciplinary approach. Pre-operative surgical planning allows tumour removal with preservation of important neural structures in the majority of cases. For large tumours occupying both the middle and posterior cranial fossae, the retrosigmoid/retrolabyrinthine/middle cranial fossa approach provides good exposure and results in minimal brain retraction. A Fisch type C approach is necessary for the largest tumours. Long-term follow up with interval imaging is mandatory to exclude long-term tumour recurrence.

Reproducibility of volume measurements of vestibular schwannomas - a preliminary study.

OBJECTIVE: A preliminary study to investigate the intra-observer and inter-observer variability of measurements of vestibular schwannoma volume using an area-tracing and linear dimension measurement method. DESIGN: Prospective blinded measurements by two observers (one a consultant and one a sub-specialty trainee in neuroradiology). SETTING: Ambulatory patients with known vestibular schwannoma attending a tertiary referral centre. PARTICIPANTS: Twenty-three patients with 26 vestibular schwannomas aged 29-80 years old. MAIN OUTCOME MEASURE: Quantification of the variability in measured volume due to intra- and inter-observer measurement differences, expressed as reliability coefficients within which 95% of repeated measurements are calculated to lie from each other in relative percentage terms. RESULTS: For the linear measurement method, intraobserver variability was calculated to have a reliability coefficient of 65% and for interobserver variability this was 155%. For the area tracing method, the corresponding coefficients were 26% for intraobserver variability and 44% for interobserver variability. CONCLUSIONS: Volume measurements in vestibular schwannoma are variable even when the measurements are made by the same observer on identical images. The area tracing method, commonly regarded as the gold standard, is less variable than a linear method but still introduces more variability than commonly realized (for 95% of patients, repeated measurements by the same observer lie within around 25% of each other). Manual area tracing is not widely used in practice because it is time consuming and reliable automated methods are eagerly awaited.

Outcome following retrosigmoid microvascular decompression of the facial nerve for hemifacial spasm.

This paper evaluates the outcome of retrosigmoid microvascular decompression of the facial nerve in a series of patients suffering from hemifacial spasm who had been referred to the skull-base team (comprising senior authors DAM and DGH). The paper is a retrospective review of 15 patients who underwent retrosigmoid microvascular decompression of the facial nerve at Addenbrooke's Hospital between 1985 and 1995. In this series it was possible to obtain complete resolution of hemifacial spasm in 93.3 per cent of cases in the short term and in 80 per cent in the long term. Twelve patients (80 per cent) were symptom-free post-operatively. Two patients had minor recurrence of symptoms occurring within six months of the procedure. One patient with no identifiable vascular impingement of the facial nerve had no improvement following surgery. Three patients suffered sensorineural hearing loss. Two patients complained of post-operative tinnitus, and transient facial palsy was noted in one patient. Retrosigmoid microvascular decompression of the facial nerve provides excellent long-term symptom control in a high percentage of patients with hemifacial spasm.

Management of the patient and family with neurofibromatosis 2: a consensus conference statement.

A consensus conference on neurofibromatosis 2 (NF2) was held in 2002 at the request of the United Kingdom (UK) Neurofibromatosis Association, with particular emphasis on vestibular schwannoma (VS) surgery. NF2 patients should be managed at specialty treatment centres, whose staff has extensive experience with the disease. All NF2 patients and their families should have access to genetic testing because presymptomatic diagnosis improves the clinical management of the disease. Some clinical manifestations of NF2, such as ocular abnormalities, can be detected in infancy; therefore, clinical screening for at-risk members of NF2 families can start at birth, with the first magnetic resonance (MRI) scan at 10-12 years of age. Minimal interference, maintenance of quality of life, and conservation of function or auditory rehabilitation are the cornerstones of NF2 management, and the decision points to achieve these goals for patients with different clinical presentations are discussed.

Team working to improve outcome in vestibular schwannoma surgery.

The concept of the 'learning curve' in the early years of consultant appointment is no longer acceptable and yet, for most complex operations, learning is a career-long process. Sub-specialization offers part of the solution to this problem by concentrating expertise, but there remains the question of how to introduce new team members without adversely affecting patient outcome. Shortened training and an increasingly aware public, who are more questioning of the experience and outcomes of those treating them, has required the surgical profession to move away from individual consultant practice and embrace team-working. When, in 1997, a second neurosurgeon joined the skull base team at Addenbrooke's Hospital, his introduction to acoustic neuroma surgery was mentored and operative cases were carefully selected at first. In this article, we discuss our experience with consultant mentoring, and compare the results of the first 100 translabyrinthine acoustic neuroma operations performed under this system with the first cohort of a similar number of patients published from Cambridge in 1989.