Factor VIII activity of BAY 94-9027 is accurately measured with most commonly used assays: Results from an international laboratory study.

INTRODUCTION: Discrepancies in the measurement of modified factor VIII (FVIII) products have been recognized, highlighting the need for adjustments in clinical laboratory practices to ensure effective monitoring of patients treated with these products, particularly using the one-stage (activated partial thromboplastin time [aPTT]) assay. AIM: To assess the ability of clinical laboratories to measure the activity of BAY 94-9027, a PEGylated extended half-life FVIII product, using routine (predominantly one-stage) assays in clinical laboratories METHODS: Blinded samples of FVIII-deficient plasma spiked with defined levels of BAY 94-9027 and a recombinant FVIII product comparator were provided to 52 clinical laboratories that routinely conduct FVIII testing. Samples were provided at 3 concentrations (low, medium and high), and laboratories analysed the samples using routine in-house one-stage and, when available, chromogenic assays. Acceptable spiked recovery (accuracy) of the local laboratory methods to measure BAY 94-9027 was the primary endpoint of the study. RESULTS: Accurate FVIII measurements were obtained at all concentrations for both products using the chromogenic assay and most of the commonly used one-stage reagents, both ellagic acid and silica based. Two specific silica-based reagents, APTT-SP and PTT-A, underestimated BAY 94-9027 levels at all concentrations, consistent with previous findings. CONCLUSIONS: FVIII activity of BAY 94-9027 was accurately measured with most commonly used one-stage assays used in routine clinical practice. The chromogenic assay was also accurate. It is recommended that clinical laboratories identify and avoid specific inappropriate reagents, such as the APTT-SP and PTT-A, in their one-stage assays for FVIII monitoring.

BAY 94-9027, a PEGylated recombinant factor VIII, exhibits a prolonged half-life and higher area under the curve in patients with severe haemophilia A: Comprehensive pharmacokinetic assessment from clinical studies.

INTRODUCTION: Recombinant factor VIII (rFVIII) products with extended half-lives, such as BAY 94-9027, can potentially maintain higher FVIII levels for longer periods of time, thus providing improved bleeding protection vs standard-acting FVIII products. AIM: To characterize the pharmacokinetic (PK) profile of BAY 94-9027 from phase 1, phase 2/3 (PROTECT VIII) and phase 3 (PROTECT VIII Kids) clinical trials in adults, adolescents and children with severe haemophilia A METHODS: Patients with severe haemophilia A (FVIII <1%) with >50 FVIII exposure days (EDs) and no history of inhibitors were included in the phase 1 (18-65 years, ≥150 EDs), PROTECT VIII (12-65 years, ≥150 EDs) and PROTECT VIII Kids (<12 years, >50 EDs) trials. PK parameters were assessed following a 25-IU/kg or 60-IU/kg BAY 94-9027 dose in the phase 1 study after the first and repeated infusion, in PROTECT VIII after the first and repeated 60-IU/kg infusion and in PROTECT VIII Kids after a single 60-IU/kg infusion. The chromogenic assay was used to assess FVIII activity. RESULTS: Compared with sucrose-formulated rFVIII, BAY 94-9027 had reduced clearance that resulted in a ~1.4-fold increase in half-life and dose-normalized area under the curve (AUC). The BAY 94-9027 PK profile was comparable after single- and repeated-dose administrations. Dose-proportional increases were observed between 25- and 60-IU/kg administrations. BAY 94-9027 PK characteristics were age dependent, consistent with other FVIII products. CONCLUSIONS: BAY 94-9027 shows an extended half-life and increased AUC vs standard-acting FVIII products. These PK characteristics will result in higher FVIII levels for longer duration.

Safety and efficacy of BAY 94-9027, a prolonged-half-life factor VIII.

Essentials Recombinant factor VIII BAY 94-9027 conjugates in a site-specific manner with polyethylene glycol. BAY 94-9027 was given to patients with severe hemophilia A as prophylaxis and to treat bleeds. BAY 94-9027 prevented bleeds at dose intervals up to every 7 days and effectively treated bleeds. BAY 94-9027 treatment was mainly well tolerated and no patient developed factor VIII inhibitors. Click to hear Dr Tiede's perspective on half-life extended factor VIII for the treatment of hemophilia A SUMMARY: Background BAY 94-9027 is a B-domain-deleted prolonged-half-life recombinant factor VIII (FVIII) that conjugates in a site-specific manner with polyethylene glycol. Objective Assess efficacy and safety of BAY 94-9027 for prophylaxis and treatment of bleeds in patients with severe hemophilia A. Patients/methods In this multinational, phase 2/3, partially randomized, open-label trial, men aged 12-65 years with FVIII < 1% and ≥ 150 exposure days to FVIII received BAY 94-9027 for 36 weeks on demand or prophylactically at intervals determined following a 10-week run-in period on 25 IU kg-1 body weight two times per week. Patients with > 1 bleed during the run-in subsequently received 30-40 IU kg-1 two times per week; patients with ≤ 1 bleed were eligible for randomization to every-5-days (45-60 IU kg-1 ) or every-7-days (60 IU kg-1 ) prophylaxis (1 : 1) for 26 additional weeks until randomization arms were filled. Patients who were eligible but not randomized continued twice-weekly prophylaxis. The primary efficacy outcome was annualized bleeding rate (ABR). Results The intent-to-treat population included 132 patients (prophylaxis, n = 112; on demand, n = 20). Median ABR (quartile [Q1; Q3]) for patients treated two times per week who were not eligible for randomization (n = 13) improved after dose increase (17.4 [14.3; 26.0] to 4.1 [2.0; 10.6]). Median ABR for patients randomized to every-5-days treatment (n = 43) was 1.9 (0; 4.2), similar to patients eligible for randomization but who continued treatment two times per week (n = 11). Median ABR for 32/43 patients (74%) who continued every-7-days prophylaxis until study end was 0.96 (0.0; 4.3). Six hundred and thirty-six of 702 bleeds (90.6%) were controlled with ≤ 2 infusions. No patient developed a FVIII inhibitor. Conclusions BAY 94-9027 prevented bleeding across three individually tailored dose regimens and was effective for treatment of bleeds.

BAY 81-8973 safety and efficacy for prophylaxis and treatment of bleeds in previously treated children with severe haemophilia A: results of the LEOPOLD Kids Trial.

INTRODUCTION: BAY 81-8973, a full-length, unmodified, recombinant factor VIII (FVIII) in development for treatment of haemophilia A, has the same primary amino acid sequence as Bayer's sucrose-formulated recombinant FVIII but is produced with more advanced manufacturing technologies. AIM: To demonstrate safety and efficacy of BAY 81-8973 for prophylaxis and treatment of bleeds in previously treated children. METHODS: In this phase III, multicentre, open-label, nonrandomized study, boys aged ≤12 years with severe haemophilia A and ≥50 exposure days (EDs) to FVIII products received prophylaxis with BAY 81-8973 25-50 IU kg(-1) ≥2 times weekly for ≥50 EDs. The efficacy endpoint was annualized number of total bleeds. Adverse events (AEs) and immunogenicity were assessed. RESULTS: Fifty-one patients were treated (age: <6 years, n = 25; 6-<12 years, n = 26) with a 2× per week (43%) or >2× per week (57%) regimen at study start. Median [quartile 1; quartile 3 (Q1; Q3)] annualized number of bleeds for the combined age groups was 1.90 (0; 6.02) for total bleeds, 0 (0; 2.01) for joint bleeds and 0 (0; 0) for spontaneous bleeds. Median (Q1; Q3) annualized number of total bleeds within 48 h of previous prophylaxis infusion was 1.88 (0; 3.97) for children aged <6 years and 0 (0; 1.96) for children aged 6-<12 years. No drug-related serious AEs or inhibitors were reported. CONCLUSIONS: Prophylaxis with BAY 81-8973 using individualized prophylaxis regimens of 2× per week, 3× per week and every-other-day infusions was efficacious in prevention and treatment of bleeds in children with severe haemophilia A. Treatment with BAY 81-8973 was well tolerated.

Is day-1 postoperative review necessary after pars plana vitrectomy?

PURPOSE: This study aimed to determine the proportion of patients requiring alteration in management based on the findings of the day-1 postoperative visit after pars plana vitrectomy, and to identify clinical characteristics that predict the need for unexpected intervention. PATIENTS AND METHODS: A retrospective case note review was conducted of all patients who underwent pars plana vitrectomy and who then attended for review on the first postoperative day. All patients received routine prophylactic anti-glaucoma medication. RESULTS: Two hundred and seventy-three patients examined on day 1 following vitrectomy were studied. Indications for surgery included retinal detachment, epiretinal membrane, macular hole, vitreous haemorrhage, diabetic eye disease, and floaters. Twenty-gauge (20G) vitrectomy was performed in 124 eyes (45%); 23-gauge (23G) vitrectomy was performed in 149 eyes (55%). Phacoemulsification was performed concurrently in 51/273 (19%) eyes. Ten patients (3.7%) required unexpected intervention on day 1 owing to intraocular pressure (IOP) >30 (2/273), IOP <6 (5/273), or unexpected return to theatre for anterior chamber washout (3/273). There was no difference in intervention rate or day-1 IOP between 20G and 23G cases. Hypotony was less common if gas tamponade was used (χ(2)-test, P<0.001). Patients undergoing combined phacoemulsification and 20G vitrectomy were significantly more likely to require intervention on day 1 than patients undergoing 20G vitrectomy alone (15.0 vs 1.9%, P=0.029, Fisher's exact test) but this was not the case for patients undergoing 23G vitrectomy (0 vs 4.2%, Fisher's exact test, P=0.58). CONCLUSIONS: The intervention rate on the first day after vitrectomy is low and day-1 postoperative review can be safely omitted in the majority of patients undergoing vitrectomy.

Phase I study of BAY 94-9027, a PEGylated B-domain-deleted recombinant factor VIII with an extended half-life, in subjects with hemophilia A.

BACKGROUND: BAY 94-9027 is a B-domain-deleted recombinant factor VIII (rFVIII) with site-specific attachment of poly(ethylene glycol) that has shown an extended half-life in animal models of hemophilia. OBJECTIVES: To assess the pharmacokinetics and safety of BAY 94-9027 after single and repeated administration in subjects with severe hemophilia A. PATIENTS/METHODS: This 8-week, prospective, multicenter, open-label, phase I trial was conducted in 14 subjects aged 21­58 years with FVIII of < 1%, ≥ 150 days of exposure to FVIII, and no history of FVIII inhibitors. After a ≥ 3-day washout, subjects received a single dose of sucrose-formulated rFVIII (rFVIII-FS) (cohort 1 [n = 7], 25 IU kg−1; cohort 2 [n = 7], 50 IU kg−1) for a 48-h pharmacokinetic (PK) study. After another ≥ 3-day washout, cohort 1 received twice-weekly BAY 94-9027 at 25 IU kg−1 (16 doses), and cohort 2 received once-weekly BAY 94-9027 at 60 IU kg−1 (nine doses). A 168-h PK study was performed after the first and last BAY 94-9027 doses. RESULTS: BAY 94-9027 showed equivalent recovery and an improved PK profile vs. rFVIII-FS, with a half-life of ~ 19 h (vs. ~ 13.0 h for rFVIII-FS). BAY 94-9027 was well tolerated, and no immunogenicity was observed. CONCLUSIONS: This phase I study demonstrates that BAY 94-9027 has an extended half-life in subjects with hemophilia A and, after multiple dosing, was well tolerated with no immunogenicity during the 8-week trial. A phase III study in a larger number of subjects is underway to fully characterize how this prolonged half-life will permit less frequent prophylaxis dosing for patients with hemophilia.

Estimation of genetic diversity using SSR markers in sunflower.

Microsatellites or simple sequence repeats (SSRs) were used for the estimation of genetic diversity among a group of 40 sunflower lines developed at the research area of Department of Plant Breeding and Genetics, University of Agriculture, Faisalabad. Total numbers of alleles amplified by 22 polymorphic primers were 135 with an average of 6.13 alleles per locus, suggesting that SSR is a powerful technique for assessment of genetic diversity at molecular level. The expected heterozygosity (PIC) ranged from 0.17 to 0.89. The highest PIC value was observed at the locus C1779. The genetic distances ranged from 9 to 37%. The highest genetic distance was observed between the lines L50 and V3. Genetic distances were low showing lesser amount of genetic diversity among the sunflower lines.

PEGylated therapeutic proteins for haemophilia treatment: a review for haemophilia caregivers.

PEGylation is the technology involving the covalent attachment of polyethylene glycol (PEG) to a protein-, peptide- or small-molecule drug to improve their pharmacokinetic, pharmacodynamic and immunological profiles, and thus, enhance the therapeutic effect. Today, PEGylation of proteins is a well-established technology and is being used in the treatment of a variety of clinical disorders. Several PEGylated coagulation proteins for haemophilia A and B are under development with the goal of prolonging the circulation half-life of factor VIII (FVIII) or factor IX. The prolongation of half-life, resulting in less frequent injections can provide significant benefits in improving the quality of life of subjects with haemophilia and improvement in adherence to treatment. A review of published literature on PEGylated therapeutic products currently approved for human use and a discussion of a PEGylated recombinant FVIII molecule (BAY 94-9027, Bayer HealthCare, Berkeley, CA, USA) currently being investigated in the pivotal clinical trial prior to registration is provided. Available safety information of PEGylated proteins containing high molecular weight PEG does not indicate any safety concerns to date, following long-term (chronic) use in animal models or patients. Chronic use of currently available PEGylated products has been shown to be safe, paving the way for chronic use of PEGylated coagulation products in persons with haemophilia.

Nasopharyngeal cylindrical cell papilloma.

INTRODUCTION: Cylindrical cell papillomas are rare tumours which usually arise in the sinonasal region. CASE REPORT: We report a case of a nasopharyngeal cylindrical cell papilloma in a 56-year-old man who presented with a four-month history of right-sided hearing loss, otalgia, vertigo and tinnitus. Investigation revealed a soft, nodular lesion obstructing the pharyngeal opening of the right eustachian tube; this was treated by wide endoscopic excision. CONCLUSION: Cylindrical cell papilloma is a possible cause of eustachian tube obstruction in adults. Effective treatment of these lesions usually requires wide endoscopic excision, in order not to miss coexistent carcinoma.

Psychosocial correlates of physical activity in adolescents with haemophilia.

Boys with haemophilia are now encouraged to exercise and take part in physical activities, but actual measures of time spent in active participation is lacking. The aim of this study was to obtain an objective measure of daily physical activity in boys with haemophilia as compared with healthy controls. The study also aimed to ascertain the social and cognitive factors associated with exercise in this population. Seventeen patients (aged 11-18 years) with haemophilia were studied and compared with 44 healthy controls (aged 10-16.5 years). Physical activity was measured by accelerometry. Psychosocial correlates were assessed using validated questionnaires. Measured physical activity levels in subjects with haemophilia were slightly higher than for the control group. Both groups spent 70% of the day inactive, with similar proportions of time in moderate and vigorous activity. Subjects with haemophilia had a favourable self-image and similar levels of anxiety as peers without a bleeding disorder. Self-efficacy scores were lower than for controls suggesting increased sensitivity to barriers and lack of acceptance of alternatives. Health beliefs did not influence physical activity, but a negative correlation of time spent in high or vigorous activity with scores for support-seeking was observed. The data demonstrate that in the appropriate social environment and with medical support, patients with haemophilia may be as physically active as their peers without a bleeding disorder. Further investigation into the psychosocial barriers of physical activity in patients with haemophilia is needed to more effectively encourage healthy behaviours.

Advances in the understanding of chondrodermatitis nodularis chronica helices: the perichondrial vasculitis theory.

OBJECTIVES: Chondrodermatitis nodularis chronica helicis (CNCH) usually presents as a painful nodule affecting the pinna. The aetiology of the disease is unknown. Several theories have been suggested. We suggest a possible explanation based upon pathophysiological treatment correlations to new histopathological evidence. DESIGN: A detailed histopathological review of 16 confirmed cases of CNCH was undertaken by two pathologists, independently and together, using a qualitative grading of arteriolar narrowing. RESULTS: Review of cases revealed arteriolar narrowing in perichondrium region of pinna most remote from arterial blood supply, i.e. helix. This has lead to ischaemic changes and death of the metabolically active underlying cartilage with necrosis and extrusion. CONCLUSION: This is the first report of specific perichondrial arteriolar changes as the possible cause of underlying cartilage necrosis resulting in CNCH.

The intravestibular source of the vestibular aqueduct: Its structure and pathology in Ménière's disease.

CONCLUSION: We describe a thin, highly vascular layer of mineralized cartilage, which surrounds most of the endolymphatic duct. In the normal ear this may act in helping to control the chemical composition of endolymph. In Ménière's disease (MD) there is a marked apoptotic change among the mineralized cartilage cells of this layer, which seems to be associated also with the deposition of a pathological substance in the walls of many blood vessels. This may lead to serious chemical change in the nearby endolymph and so provoke the symptoms of MD. OBJECTIVES: Endolymphatic hydrops is found in all cases of MD, but is not specific for that condition. We sought a cellular change in the vicinity of the saccule that might be more specific than the lesion of endolymphatic hydrops and thus lead to a more successful management of the disease. MATERIALS AND METHODS: We examined stained step sections of 33 autopsy temporal bones from 20 cases of MD, particularly in the region of the vestibule, and compared the changes with those found in a similar region of 65 temporal bones taken from randomly selected cases of non-Ménière conditions. RESULTS: In all temporal bones there was a well-demarcated region of the posterior vestibule, which formed a skeletal arch around the opening of the tunnel of the vestibular aqueduct into which the endolymphatic duct entered from the vestibule. This 'vestibular arch' was composed mainly of blood vessels and mineralized chondrocytes. The inner skeletal layer surrounding the course of most of the endolymphatic duct in the tunnel of the vestibular aqueduct was composed of the same tissue and was in fact continuous with the vestibular arch. In the non-Ménière temporal bones the mineralized chondrocytes were congregated around normal thin-walled blood vessels and small numbers of them seemed to be undergoing apoptosis in this vicinity. In all of the MD temporal bones, except five in which the vestibular arch was either absent or atrophic, we found pronounced changes of apoptosis among the mineralized cartilage cells and these were associated with proliferative changes in blood vessels in which a bluish-staining translucent deposit, possibly mineralization of the vascular wall, was prominent.

Temporal bone study of development of the organ of Corti: correlation between auditory function and anatomical structure.

OBJECTIVE: To study the development of the organ of Corti in the human cochlea, and to correlate our findings with the onset of auditory function. MATERIAL AND METHODS: Step sections of 81 human fetal temporal bones were studied, from eight weeks of gestation to full term. RESULTS: By the end of the 10th week, the tectorial membrane primordium could be traced even in the most apical turns. Individual hair cells became identifiable at the basal turn at 14 weeks. At the same time, a small but well formed oval space was observed between the inner and outer hair cells in the basal turn. This does not correspond to the tunnel of Corti, as is erroneously quoted in the literature, as the individual pillar cells develop at later stages. Between 14 and 15 weeks, Hensen's cells were recognised for the first time. Individual pillar cells were identifiable at 17 weeks and the tunnel of Corti opened at 20 weeks. By 25 weeks, the cochlea had reached its adult size, but continued to develop until full term. DISCUSSION AND CONCLUSIONS: A temporal coincidence of different developmental events is responsible for early fetal audition at 20 weeks, including growth of pillar cells, opening of the tunnel of Corti and regression of Kollicker's organ, with the subsequent formation of the inner spiral sulcus and then separation of the tectorial membrane. The fine structures of the organ of Corti continue to develop well after the 25th week, and this may well alter the mechanical properties of the vibrating parts of the cochlea, which may in turn account for the frequency shift observed in preterm infants. These changes will have to be taken into account in the development of prenatal hearing screening tests.

Prevalence of histologic otosclerosis: an unbiased temporal bone study in Caucasians.

BACKGROUND: 'Histologic otosclerosis' refers to a disease process without clinical symptoms or manifestations that can only be discovered by sectioning of the temporal bone at autopsy. 'Clinical otosclerosis' concerns the presence of otosclerosis at a site where it causes conductive hearing loss by interfering with the motion of the stapes or of the round window membrane. Various authors have studied the prevalence of histologic otosclerosis on laboratory collections of temporal bones. Some 12-15% of the temporal bones with histologic otosclerosis have demonstrated stapedial fixation. Using these figures for calculating the prevalence of clinical otosclerosis gives an extrapolated clinical prevalence of 0.99-1.2%. This does not correlate well with the clinical data on otosclerotic families from which a clinical prevalence of 0.3% has been estimated. OBJECTIVE: To study the prevalence of histologic otosclerosis in an unselected series of temporal bones. STUDY DESIGN: During a 1-year period, 118 consecutive pairs of temporal bones of deceased patients at a tertiary center were collected to determine the prevalence of otosclerosis. Although histology remains the gold standard for evaluation of otosclerosis, the gross observation of temporal bone slices combined with microradiography was used to screen for otosclerotic lesions more rapidly and with a lower cost-benefit ratio. The temporal bones with suspected otosclerosis shown with these techniques were further analyzed by conventional histology. RESULTS: 2.5% of the 236 temporal bones (or 3.4% of patients) studied demonstrated histologic otosclerosis. CONCLUSIONS: Although the prevalence of 2.5% is much lower than previously published figures on histologic otosclerosis, the extrapolated data (extrapolated clinical prevalence = 0.30-0.38%) correlate well with clinical studies of otosclerotic families. The previous studies based on laboratory collections were likely biased by the presence of hearing loss or other otological diseases.

The U.S. Thrombosis and Hemostasis Centers pilot sites program.

Venous thromboembolism (VTE) is a common disorder associated with significant morbidity and mortality. Despite important advances in understanding the etiology of VTE, delivery of care to patients with thrombosis and thrombophilia is frequently incomplete and highly variable. A comprehensive model of health care has been used successfully to treat and prevent complications for people with hemophilia and other chronic disorders. The effectiveness of an integrated healthcare model for patients with all coagulation disorders has yet to be evaluated. The Division of Hereditary Blood Disorders of the Centers for Disease Control and Prevention (CDC) is collaborating with eight Thrombosis and Hemostasis Centers (pilot sites) to provide health-related services and conduct research directed toward the reduction or prevention of complications of thrombosis and thrombophilia. The initial objectives of the collaboration are to (1) determine the efficacy of integrated multidisciplinary care and prevention services for people with hemostatic disorders, (2) assess unmet needs for service delivery and identify outreach strategies to improve access to care, (3) develop effective messages aimed at disease management and prevention, and (4) foster the development of training programs to enhance provider skills for the delivery of patient care. To address these objectives, the investigators and CDC have developed and implemented a web-based patient registry to follow prospectively service allocation and patient outcomes. Funding for the program began in October 2001. All eight funded centers are affiliated with U.S. medical schools. Principal investigators at the centers are hematologists (five adult, two pediatric) or cardiologists. Faculty in obstetrics-gynecology, surgery, and multiple other specialties are integral to the model of care at the centers. Other critical components at the centers are clinical laboratory services, training programs, research networks, and education and outreach programs. From August 2003 to March 2006, over 2,600 patients were enrolled in the registry, accounting for a total of more than 5,000 visits to the centers. Immediate goals of the data collection at the centers are to characterize patients receiving care at centers and document the state of health services provided. Long-term goals are to evaluate prospectively clinical outcomes for patients receiving multidisciplinary care and prevention services at centers. The network of data collection across centers will facilitate future collaborative clinical and epidemiologic investigations and enhance collective expertise in hemostasis and coagulation disorders.

The uncertainty of the surgical margin in the treatment of head and neck cancer.

We discuss our surgical philosophy concerning the subtle interplay between the size of the surgical margin taken and the resultant morbidity from ablative oncological procedures, which is ever more evident in the treatment of head and neck malignancy. The extent of tissue resection is determined by the "trade off" between cancer control and the perioperative, functional and aesthetic morbidity and mortality of the surgery. We also discuss our dilemmas concerning recent minimally invasive endoscopic microsurgical techniques for the trans-oral laser removal or co-ablation of aero-digestive tract tumours, which result in a minimal surgical margin of oncological clearance. By a process of inductive argument as to the nature of the surgical margin, we consider whether the risks of taking a lesser margin with adjuvant therapy is justified by the attendant gain in reduced surgical morbidity and the possible costs in tumour control.

Metastasizing pleomorphic salivary adenoma.

OBJECTIVE: To address questions about the etiology, behavior, optimal treatment, and prognosis of metastasizing pleomorphic adenoma (MPA), we undertook a review of the literature (1953-2005) and constructed a virtual series of all identified cases of MPA, metastatic lesions that are very occasionally identified in patients with a history of pleomorphic salivary adenoma and, on detailed pathological evaluation, found to exhibit all the histological hallmarks of the preceding benign lesions. DATA SOURCES: A review of the English-language literature between 1953 and 2005 using MEDLINE, secondary references identified from bibliographies of pertinent articles, and a further case from one of our institutions. DATA SYNTHESIS: A virtual case series was constructed and quantitatively analyzed. Forty-two patients with an average age of 33 years were identified. There were 20 male and 22 female patients. There was an overwhelming history of incomplete surgery for pleomorphic salivary adenoma. Most patients had locoregional recurrences before metastasis, and the mean presentation-to-metastasis latency was 16 years. Bone was the most common site for metastases (45%), followed by the head and neck (43%) and lung (36%). There was significant morbidity and mortality from distant disease, with 5-year disease-specific and disease-free survival of 58% and 50%, respectively. Developing distant lesions within 10 years of the primary tumor and presence of metastases in multiple sites were independent predictors of survival on Cox regression analysis. Metastasectomy conferred significant survival advantage over nonoperative treatment (log-rank analysis, P<.02). Chemotherapy and radiotherapy were of limited value. CONCLUSIONS: Meticulous surgery is crucial in preventing MPA. Metastatic disease carries significant morbidity and mortality and should be treated surgically when feasible.

The development of the spiral ganglion in the human foetus.

The development of the spiral ganglion was studied in steps sections of 81 human temporal bones. By the 8th week, the spiral ganglion has already separated from the vestibular ganglion. At 13 weeks two distinct populations are observed that correspond to neuron and Schwann cells. At 15 weeks the spiral ganglion has increased its distance from the cochlear duct and is surrounded by mesenchyme near the scala tympani. At 14 weeks a gradual decrease in the nucleus-to-cell area ratio was observed in spiral ganglion neurons that may reflect a morphological adaptation to function. By the 23rd week the modiolus begins to ossify and the spiral ganglion is surrounded by bony trabeculae. The time course of spiral ganglion development follows that of the stria vascularis and organ of Corti, although maturation changes are still observed in the neuronal population even beyond 20 weeks.