Identification and survival outcomes of a cohort of patients with cancer of unknown primary in Ontario, Canada.

BACKGROUND: Cancer of unknown primary origin (CUP) is defined by the presence of pathologically identified metastatic disease without clinical or radiological evidence of a primary tumour. Our objective was to identify incident cases of CUP in Ontario, Canada, and determine the influence of histology and sites of metastases on overall survival (OS). MATERIAL AND METHODS: We used the Ontario Cancer Registry (OCR) and the Same-Day Surgery and Discharge Abstract Database (SDS/DAD) to identify patients diagnosed with CUP in Ontario between 1 January 2000, and 31 December 2005. Patient diagnostic information, including histology and survival data, was obtained from the OCR. We cross-validated CUP diagnosis and obtained additional information about metastasis through data linkage with the SDS/DAD database. OS was assessed using Cox regression models adjusting for histology and sites of metastases. RESULTS: We identified 3564 patients diagnosed with CUP. Patients without histologically confirmed disease (n = 1821) had a one-year OS of 10.9%, whereas patients with confirmed histology (n = 1743) had a one-year OS of 15.6%. The most common metastatic sites were in the respiratory or digestive systems (n = 1603), and the most common histology was adenocarcinoma (n = 939). Three-year survival rates were 3.5%, 5.3%, 41.6% and 3.6% among adenocarcinoma, unspecified carcinoma, squamous cell carcinoma and undifferentiated histology, respectively. Three-year survival rates were 40%, 2.4%, 8.0% and 4.6% among patients with metastases localised to lymph nodes, the respiratory or digestive systems, other specified sites, and unspecified sites, respectively. CONCLUSION: CUP patients in Ontario have a poor prognosis. Some subgroups may have better survival rates, such as patients with metastases localised to lymph nodes and patients with squamous cell histology.

Lung function and inflammatory responses in healthy young adults exposed to 0.06 ppm ozone for 6.6 hours.

RATIONALE: Exposure to ozone causes a decrease in spirometric lung function and an increase in airway inflammation in healthy young adults at concentrations as low as 0.08 ppm, close to the National Ambient Air Quality Standard for ground level ozone. OBJECTIVES: To test whether airway effects occur below the current ozone standard and if they are more pronounced in potentially susceptible individuals, such as those deficient in the antioxidant gene glutathione S-transferase mu 1 (GSTM1). METHODS: Pulmonary function and subjective symptoms were measured in 59 healthy young adults (19-35 yr) immediately before and after exposure to 0.0 (clean air, CA) and 0.06 ppm ozone for 6.6 hours in a chamber while undergoing intermittent moderate exercise. The polymorphonuclear neutrophil (PMN) influx was measured in 24 subjects 16 to 18 hours postexposure. MEASUREMENTS AND MAIN RESULTS: Subjects experienced a significantly greater (P = 0.008) change in FEV(1) (± SE) immediately after exposure to 0.06 ppm ozone compared with CA (-1.71 ± 0.50% vs. -0.002 ± 0.46%). The decrement in FVC was also greater (P = 0.02) after ozone versus CA (-2.32 ± 0.41% vs. -1.13 ± 0.34%). Similarly, changes in %PMN were greater after ozone (54.0 ± 4.6%) than CA (38.3 ± 3.7%) exposure (P < 0.001). Symptom scores were not different between ozone versus CA. There were no significant differences in changes in FEV(1), FVC, and %PMN between subjects with GSTM1-positive and GSTM1-null genotypes. CONCLUSIONS: Exposure of healthy young adults to 0.06 ppm ozone for 6.6 hours causes a significant decrement of FEV(1) and an increase in neutrophilic inflammation in the airways. GSTM1 genotype alone appears to have no significant role in modifying the effects.

Prediction of lung function response for populations exposed to a wide range of ozone conditions.

CONTEXT: A human exposure-response (E-R) model previously demonstrated to accurately predict population mean FEV1 response to ozone exposure has been proposed as the foundation for future risk assessments for ambient ozone. OBJECTIVE: Fit the original and related models to a larger data set with a wider range of exposure conditions and assess agreement between observed and population mean predicted values. MATERIALS AND METHODS: Existing individual E-R data for 23 human controlled ozone exposure studies with a wide range of concentrations, activity levels, and exposure patterns have been obtained. The data were fit to the original model and to a version of the model that contains a threshold below which no response occurs using a statistical program for fitting nonlinear mixed models. RESULTS: Mean predicted FEV1 responses and the predicted proportions of individuals experiencing FEV1 responses greater than 10, 15, and 20% were found to be in agreement with observed responses across a wide range of exposure conditions for both models. The threshold model, however, provided a better fit to the data than the original, particularly at the lowest levels of exposure. CONCLUSION: The models identified in this manuscript predict population FEV1 response characteristics for 18-35-year-old individuals exposed to ozone over a wide range of conditions and represent a substantial improvement over earlier E-R models. Because of its better fit to the data, particularly at low levels of exposure, the threshold model is likely to provide more accurate estimates of risk in future risk assessments of ozone-induced FEV1 effects.

Physiological Factors Affecting Lung Deposition.

Ventilation and mechanics of breathing are an integral part of respiratory physiology that directly affect aerosol transport and deposition in the lung. Although natural breathing pattern varies widely among individuals, breathing pattern is controllable, and by using an appropriate breathing pattern, aerosol deposition can be substantially modified for desired purposes. Effects of breathing pattern have been investigated under carefully controlled inhalation conditions covering a wide range of tidal volumes (VT) and breathing frequencies (f) or respiratory times (T = 1/f). The studies have shown that lung deposition can increase or decrease as much as two times by changing the breathing pattern. Specific functional relationships have been found between lung deposition and breathing pattern parameters such that lung deposition can be estimated for any given breathing pattern. Both VT and T have shown strong effects on lung deposition, but their influence is variable depending on particle size, particularly, ultrafine vs. micron-sized particles. VT is more influential than T for micron-sized particles whereas VT and T are equally influential for ultrafine particles. Although effects of lung morphology are difficult to study systematically, comparison between normals and patients with obstructive airway disease has shown that lung deposition is closely related with the degree of airways obstruction and can be 2-3 times greater in patients with obstructive airway disease compared to normals. Thus, breathing pattern and the status of airways obstruction should be carefully considered in designing aerosol delivery and estimating deposition dose.

Deposition of aerosol particles in human lungs: in vivo measurement and modelling.

The deposition dose and site of inhaled particles within the lung are the key determinants in health risk assessment of particulate pollutants. Accurate dose estimation, however, is a formidable task because aerosol transport and deposition in the lung are governed by many factors whose precise workings are often not fully understood. In vivo human data obtained under controlled environment are most important and provide the primary basis of estimating lung doses. The existing database, however, is not sufficient to cover widely varying exposure conditions encountered during daily activities. Mathematical models thus are used to fill the gap or to extend the range of experimental data and are further used as a tool for analysing the exposure-dose relationship under varying inhalation conditions. In this report we briefly review and discuss our recent studies of in vivo measurement of inhaled particles in normal subjects, subsequent analysis of the data for empirical modelling and an improved mathematical model that can be used for a wide range of applications.

An intraatrial thrombus and pulmonary thromboembolism as a late complication of percutaneous vertebroplasty.

Although percutaneous vertebroplasty is a simple and generally safe method for the management of vertebral compression fractures, cement leakage outside the vertebral body is a potential source of serious complications. We report a patient who presented with dyspnea and edema five years after percutaneous vertebroplasty and underwent open-heart surgery. This case demonstrates an intraatrial thrombus and pulmonary thromboembolism caused by venous leakage of polymethylmethacrylate as a late complication of the procedure.

Mathematical analysis of particle deposition in human lungs: an improved single path transport model.

A dynamic single-path mathematical model was developed that is capable of analyzing detailed deposition patterns of inhaled particles in human lungs. Weibel's symmetric lung morphology was adopted as the basic lung structure, and detailed transport processes were evaluated numerically using the fully implicit procedure. Deposition efficiencies by specific mechanisms were individually examined for accuracy and new empirical formulas were incorporated whenever appropriate. Deposition in the alveolar region was divided into deposition fractions in the alveolar duct and alveoli, considering active transport processes between the two regions. The deposition fractions were obtained for each airway generation, serial lung volumetric compartments, and conventional three-compartment anatomic lung regions. In addition, the surface dose and cumulative deposition with time were analyzed. The results showed excellent agreement with available experimental data. The present model provides an improvement from the previously reported models and can be used as a tool in assessing internal dose of inhaled particles under various inhalation conditions.

The safety of reused endotracheal tubes sterilized according to Centers for Disease Control and Prevention guidelines.

STUDY OBJECTIVE: To investigate safety issues associated with the reuse of sterilized endotracheal tubes (ETTs). DESIGN: Prospective, randomized study. SETTING: Laboratory in vivo testing. INTERVENTION: Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa were inoculated onto ETT cuffs. Following inoculation, ETTs were sterilized with either ethylene oxide or glutaraldehyde. Cuffs were then swabbed and cultured for 24 hours. To examine changes in the physical integrities of sterilized ETT cuffs, ETTs were sterilized with ethylene oxide gas once, twice, or three times (the E1, E2, and E3 groups, respectively). Alternatively, ETTs were soaked in glutaraldehyde for 150, 300, 450, or 600 minutes (the G1, G2, G3, and G4 groups, respectively). MEASUREMENTS: Endotracheal tube cuffs were considered nonsterile if a visible colony of test organisms was cultured, and sterile if no colony was cultured. Changes in the physical integrity of sterilized ETT cuffs were determined by measuring changes in intracuff pressure or tensile strength. MAIN RESULTS: No growth of bacteria was observed in sterilized tubes. Endotracheal tube cuffs of the E1 and E2 groups showed almost the same physical integrity as those of the control group, whereas E3 group cuffs were softer than those of the untreated controls. Endotracheal tube cuffs of the G1 and G2 groups were harder than untreated controls; than of those of the G3 and G4 groups were similar to the controls. CONCLUSIONS: Endotracheal tubes can be reused sterilized safely. The physical integrity of ETT cuffs may be compromised by glutaraldehyde or ethylene oxide sterilization treatments.

Total respiratory tract deposition of fine micrometer-sized particles in healthy adults: empirical equations for sex and breathing pattern.

Accurate dose estimation under various inhalation conditions is important for assessing both the potential health effects of pollutant particles and the therapeutic efficacy of medicinal aerosols. We measured total deposition fraction (TDF) of monodisperse micrometer-sized particles [particle diameter (Dp) = 1, 3, and 5 microm in diameter] in healthy adults (8 men and 7 women) in a wide range of breathing patterns; tidal volumes (Vt) of 350-1500 ml and respiratory flow rates (Q) of 175-1,000 ml/s. The subject inhaled test aerosols for 10-20 breaths with each of the prescribed breathing patterns, and TDF was obtained by monitoring inhaled and exhaled aerosols breath by breath by a laser aerosol photometer. Results show that TDF varied from 0.12-0.25, 0.26-0.68, and 0.45-0.83 for Dp = 1, 3, and 5 microm, respectively, depending on the breathing pattern used. TDF was comparable between men and women for Dp = 1 microm but was greater in women than men for Dp = 3 and 5 microm for all breathing patterns used (P < 0.05). TDF increased with an increase in Vt regardless of Dp and Q used. At a fixed Vt TDF decreased with an increase in Q for Dp = 1 and 3 microm but did not show any significant changes for Dp = 5 microm. The varying TDF values, however, could be consolidated by a single composite parameter (omega) consisting of Dp, Vt, and Q. The results indicate that unifying empirical formulas provide a convenient means of assessing deposition dose of particles under varying inhalation conditions.

Transport and uptake of MTBE and ethanol vapors in a human upper airway model.

Potential human exposure to vapors of methyl tertiary-butyl ether (MTBE) and ethanol is of increasing concern because these materials are widely used as gasoline additives. In this study we analyzed numerically the transport and deposition of MTBE and ethanol vapors in a model of the human upper respiratory airway, consisting of an oral airway and the first four generations of the tracheobronchial tree. Airflow characteristics and mass transfer processes were analyzed at different inspiratory flow conditions using a three-dimensional computational fluid and particle dynamics method. The deposition data were analyzed in terms of regional deposition fractions (DF = regional uptake/mouth concentration) and deposition enhancement factors (DEF = local DF/average DF) at local micro surface areas. Results show that DF in the entire upper airway model is 21.9%, 12.4%, and 6.9% for MTBE and 67.5%, 51.5%, and 38.5% for ethanol at a flow rate of 15, 30, and 60 L/min, respectively. Of the total DF, 65-70% is deposited in the oral airway for both vapors. Deposition is localized at various sites within the upper airway structure, with a maximum DEF of 1.5 for MTBE and 7.8 for ethanol. Local deposition patterns did not change with inhalation conditions, but DF and the maximum DEF increased with diffusivity, solubility, and the degree of airway wall absorption of vapors, as shown by a greater deposition of ethanol than MTBE. The vapor deposition efficiency as expressed by the dimensionless mass transfer coefficient correlated well with a product of Reynolds (Re) and Schmidt (Sc) numbers. In conclusion, MTBE and ethanol vapors deposit substantially in the upper airway structure with a marked enhancement of dose at local sites, and the deposition dose may be reasonably estimated by a functional relationship with dimensionless fluid flow and diffusion parameters.

Isotonic and hypertonic saline droplet deposition in a human upper airway model.

The evaporative and hygroscopic effects and deposition of isotonic and hypertonic saline droplets have been simulated from the mouth to the first four generations of the tracheobronchial tree under laminar-transitional-turbulent inspiratory flow conditions. Specifically, the local water vapor transport, droplet evaporation rate, and deposition fractions are analyzed. The effects of inhalation flow rates, thermodynamic air properties and NaCl-droplet concentrations of interest are discussed as well. The validated computer simulation results indicate that the increase of NaCl-solute concentration, increase of inlet relative humidity, or decrease of inlet air temperature may reduce water evaporation and increase water condensation at saline droplet surfaces, resulting in higher droplet depositions due to the increasing particle diameter and density. However, solute concentrations below 10% may not have a very pronounced effect on droplet deposition in the human upper airways.

Airflow and nanoparticle deposition in a 16-generation tracheobronchial airway model.

In order to achieve both manageable simulation and local accuracy of airflow and nanoparticle deposition in a representative human tracheobronchial (TB) region, the complex airway network was decomposed into adjustable triple-bifurcation units, spreading axially and laterally. Given Q(in) = 15 and 30 L/min and a realistic inlet velocity profile, the experimentally validated computer simulation model provided some interesting 3-D airflow patterns, i.e., for each TB-unit they depend on the upstream condition, local geometry and local Reynolds number. Directly coupled to the local airflow fields are the convective-diffusive transport and deposition of nanoparticles, i.e., 1 nm < or = d(p) < or = 100 nm. The CFD modeling predictions were compared to experimental observations as well as analytical modeling results. The CFD-simulated TB deposition values agree astonishingly well with analytical modeling results. However, measurable differences can be observed for bifurcation-by-bifurcation deposition fractions obtained with these two different approaches due to the effects of more realistic inlet conditions and geometric features incorporated in the CFD model. Specifically, while the difference between the total TB deposition fraction (DF) is less than 16%, it may be up to 70% for bifurcation-by-bifurcation DFs. In addition, it was found that fully developed flow and uniform nanoparticle concentrations can be assumed beyond generation G12. For nanoparticles with d(p) > 10 nm, the geometric effects, including daughter-branch rotation, are minor. Furthermore, the deposition efficiencies at each individual bifurcation in the TB region can be well correlated as a function of an effective diffusion parameter.

Total lung deposition of ultrafine particles in elderly subjects during controlled breathing.

Ultrafine particulate matter (PM) in the air may be harmful to health, particularly in elderly subjects. From the dosimetry point of view, it is not known if the elderly subjects are more susceptible to exposure to ultrafine PM. We measured the total deposition fraction (TDF) of ultrafine PM (NMD = 0.04-0.1 microm in number median diameter) in the lungs of healthy, elderly subjects (age = 69 +/- 5 yr) and compared the results with those obtained from young adults (age = 31 +/- 4 yr) in an earlier study. Subjects inhaled the aerosols with six different breathing patterns: three different tidal volumes (V(t) = 500, 750, and 1000 ml) and two flow rates (Q) for each V(t). TDF was measured breath by breath in situ by measuring aerosol concentrations on inhalation and exhalation using an ultrafine condensation particle counter. Mean TDF (+/-SD) of the elderly subjects was 0.43 +/- 0.03, 0.36 +/- 0.04, 0.31 +/- 0.03, and 0.27 +/- 0.02 for NMD = 0.04, 0.06, 0.08, and 0.1 microm, respectively, for V(t) = 500 ml and Q = 250 ml/s. These and all other results were very similar to those of young adults. The results suggest that healthy, elderly subjects are not subjected to a greater respiratory dose of ultrafine PM than young adults under the same exposure conditions.

Pathology and physiology of auditory neuropathy with a novel mutation in the MPZ gene (Tyr145->Ser).

We studied a family with hereditary sensory motor neuropathy and deafness accompanying a missense mutation in the MPZ gene. Pathological examination of the cochlea in one of the family members revealed marked loss of auditory ganglion cells and central and peripheral auditory nerve fibres within the cochlea. The inner hair cells were of normal number with preserved morphology. The outer hair cells were normal in number except for a 30% reduction in just the apical turn. Examination of the sural nerve and the auditory nerve adjacent to the brainstem showed marked loss of fibres with evidence of incomplete remyelination of some of the remaining fibres. Studies of auditory function in surviving family members using electrophysiological and psychoacoustic methods provided evidence that the hearing deficits in this form of auditory neuropathy were probably related to a decrease of auditory nerve input accompanying axonal disease. Altered synchrony of discharge of the remaining fibres was a possible additional contributing factor.