Prognostic markers in node-negative breast cancer: a prospective study.

BACKGROUND: Despite years of research, it is still unclear which women with node-negative (N-) breast cancer will need adjuvant chemotherapy and which women are being treated unnecessarily. Our goal was to determine which factors best predicted disease free survival (DFS) or cancer-specific overall survival (OS) and, therefore, select the correct patients for treatment. A total of 11 parameters were measured: estrogen receptor (ER), progesterone receptor (PR), age, race, ploidy status, %G0/G1 (% non-DNA synthesis), %S (% S-phase), cathepsin D status, size, stage, and histologic grade. RESULTS: In this prospective study, we followed 556 N- patients diagnosed between 1991 and 1996. The tumors were 56% ER+, 51% PR+, 30% diploid, with a mean %S of 8.9%. The level of cathepsin D ranged from 0.50 to 155 pmol/mg of protein with a mean of 42.9 pmol/mg of protein. There were 87 recurrences (16%) and 72 cancer deaths (13%), with a median follow-up of 7.8 years. Ploidy status (p = 0.01), S-phase activity (p = 0.003), G1 phase activity (p = 0.02) and age (p = 0.01) were able to significantly predict DFS in a univariate manner. All of the measurable factors were significant or borderline significant in predicting OS in a univariate manner except for age, race, and ER status. In multivariate analysis with S-phase included, it was the only remaining factor in DFS and OS; with S-phase excluded, age and ploidy status remained as factors for DFS in stepwise regression, while PR, size, and cathepsin D were the remaining factors that predicted cancer-specific OS. The effect of adjuvant treatment on prognosis was also analyzed. CONCLUSIONS: Both biochemical and clinical parameters have the potential to predict prognosis for N- breast cancer. In this large prospective clinical trial, with a median follow-up of 7.8 years, no individual marker adequately predicted the prognosis for an individual patient. %S activity was the best independent marker, but only 77% of the tumors provided this value. Subset analysis provided improved prognostication, but there were limits to its utility. These data represents a definitive study starting in 1991 and ending in 2002.

Sleep-disordered breathing in Duchenne muscular dystrophy: a preliminary study of the role of portable monitoring.

Although Duchenne muscular dystrophy (DMD) is often associated with sleep disordered breathing (SDB), it is not standard clinical practice to routinely test this population for SDB, and the optimal timing and methodology for such testing has not been established. Our objectives were: 1) to examine the concordance between laboratory polysomnography (PSG) and two portable monitoring systems, and 2) to identify clinical factors associated with the onset of SDB. We performed a cross-sectional pilot study of patients with DMD who were 6 years of age or older, and who were registered at the Alberta Children's and Calgary General Hospitals. Patient symptom and functional rating scores were calculated, and pulmonary function tests, awake oxygen saturation, and capillary blood gases were obtained. PSG was performed according to standard methods, and results were compared with Snoresat(R) (Saga Tech Electronics, Inc.) and EdenTec(R) (Nellcor Puritan Bennett) portable home monitors. Eleven boys were studied. Ten of 11 subjects had normal awake oxygen saturation and capillary blood gases. Median forced vital capacity (FVC) was 70% of predicted values (15-104%). PSG identified 3 boys with severe hypoventilation occurring throughout REM sleep. Reported symptom severity did not predict the patients with significant SDB. All 3 boys with SDB had a severe functional disability and severely reduced FVCs. Portable monitoring in the home identified all patients with abnormal PSG. One additional patient was falsely identified by the EdenTec(R) monitor. We conclude that initial results using Snoresat(R) or EdenTec(R) monitoring equipment for the identification of SDB are promising, but further validation of portable home monitoring is required in this group of patients.

Interaction between postural and respiratory control of human intercostal muscles.

To study the interaction between postural and respiratory control of intercostal muscles, we used electromyography of intercostal muscles of the lateral chest wall in conscious humans. Bipolar fine-wire electrodes were placed in external and internal intercostal muscles in the midaxillary line of four subjects who sat on a bench and breathed through a pneumotachograph. They were instructed to hold their breath at end expiration, rotate their thorax to the right or left, and then hold the rotation while resuming breathing. Holding a rotation induces steady tonic activity in either internal or external intercostal muscles, depending on the direction of the rotation. The degree of rotation was varied from one run to the next, resulting in varied levels of tonic postural activity. When breathing resumes, internal intercostal muscles have their activity almost completely suppressed with each inspiration independently of whether the tonic postural tone is small or large. External intercostal muscles show inspiratory increases in activity superimposed on the postural tone, which apparently amplifies the effect of respiratory input to their motoneurons.

Myotonia of the respiratory muscles in myotonic dystrophy.

Myotonic dystrophy is a muscle disorder in which there is a tendency to rapid shallow breathing and a reduced ventilatory response to chemical stimuli. Respiratory failure may occur when respiratory muscle weakness is not marked. One explanation proposed for these observations is that myotonia of the respiratory muscles reduces the compliance of the chest wall. However, direct electrical evidence of myotonia in the respiratory muscles with breathing is lacking. In 11 patients with myotonic dystrophy the scalene, sternocleidomastoid, a parasternal muscle, and a lateral intercostal muscle were studied using intramuscular bipolar wires. Five of the 11 patients had an elevated PaCO2. All patients had a FVC greater than 70% of predicted. Myotonia was sought with needle insertion, quiet tidal breathing, voluntary large breaths, and involuntary larger breaths with chemical stimulation. Two of the 11 patients demonstrated no myotonia. Myotonia on insertion of the needle was seen in four patients. Myotonia was rare in an isolated respiratory cycle during quiet breathing, and repetitive myotonia with consecutive breathing cycles was never noted. Voluntary big breaths produced myotonia in five patients, whereas chemically stimulated larger breaths produced myotonia in seven patients. In two of these seven patients, myotonic activity with consecutive respiratory cycles was seen at higher levels of ventilation. In conclusion, the rare occurrence of myotonia with tidal breathing would suggest myotonia in the muscles does not account for the respiratory failure and tachypneic breathing pattern found in myotonic dystrophy. Its occurrence at higher levels of ventilation may contribute to the reduced ventilatory response to chemical stimuli.

The respiratory muscles in multicore myopathy.

Multicore myopathy is a rare congenital myopathy that can cause progressive weakness, but it has not been recognized previously to have respiratory consequences. This study describes two patients who developed respiratory failure because of respiratory muscle weakness. Both patients had low vital capacities without evidence of airway obstruction, and CO2 retention. Physical examination found that neck accessory muscles and abdominal muscles were very weak. In inspiration the abdomen expanded, but the rib cage contracted. Detailed studies were done in one patient with magnetometers, esophageal and gastric pressures, flow and volume, and electromyograms of abdominal and neck accessory muscles. Peak static inspiratory and expiratory pressures were 28 and 30 cm H2O, respectively, and maximal transdiaphragmatic pressure was 28 cm H2O. Vital capacity was reduced to 44% of predicted. Lung compliance was normal. In spontaneous breathing while supine, rib-cage diameters decreased while gastric pressure increased in inspiration, suggesting the weak diaphragm was the main muscle of respiration. EMG recordings showed no evidence of recruitment of the wasted neck accessory muscles (sternocleidomastoid and scalene), whereas electromyograph plus mechanics measurements gave evidence of abdominal muscle use in the sitting but not the supine posture. More limited studies in the second patient gave similar results. Multicore disease in these two patients thus caused marked weakness of all respiratory muscles, affected the intercostal-accessory group more than the diaphragm, and led to respiratory failure.

Change in recruitment order of motor units in human parasternal intercostal muscles with sleep state.

Recruitment order of individual motor units in the early part of inspiration in parasternal intercostal muscles was observed in normal human subjects during wakefulness and non-rapid-eye-movement sleep. Electromyograms from bipolar fine wire intramuscular electrodes were recorded while the subjects lay supine in a sleep laboratory, and sleep stage was determined by polysomnography. From wakefulness to sleep there were numerous examples of shifts in order of recruitment among the low threshold units of early inspiration. There were corresponding shifts in the order of derecruitment of these units. Analysis of frequency of firing of units also suggested that the levels of excitatory input to one unit of a pair could be altered relative to the level of input of the other one. The data imply that there are at least minor differences in distribution of excitatory inputs from various sources among motoneurons of this muscle pool.

Intercostal muscles are used during rotation of the thorax in humans.

To test the idea that the lateral intercostal muscles may be more suited to aid in rotational than respiratory movements of the thorax, we inserted bipolar fine-wire electrodes in external and internal intercostal muscles in the right midaxillary line in nine sitting subjects and examined the pattern of contraction of these muscles during voluntary axial rotations of the thorax (30-35 degrees), resting breathing, and CO2-induced hyperpnea. The right external intercostal muscles were strongly recruited in rotations to the left but were not active in rotations to the right. In contrast, the right internal intercostal muscles were active in rotations to the right but not in rotations to the left. Rotations completed in 1 or 2 s were associated with an early burst of electromyographic activity, followed by a low plateau that persisted while the rotation was held. Rotations made very gradually over 5-10 s were associated with gradually rising electromyographic activity. The amplitude of activity recorded during 30-35 degrees rotations was equivalent to that measured when minute ventilation was increased by CO2 to 50 l/min. We conclude that the lateral intercostal muscles have a major role in producing axial rotations of the thorax.

Mechanisms of hypoxemia during panendoscopy.

Hypoxemia during esophagogastroduodenoscopy (EGD), or panendoscopy has been generally attributed to sedation. We studied 49 patients ranging in age from 17 to 71 years with normal or nearly normal lung function undergoing EGD to determine the effects of sedation and the effects of the endoscope on arterial oxygen saturation (SaO2). All patients received intravenous diazepam and 41 also received meperidine. EGD was delayed 10.7 +/- 7.5 min after intravenous diazepam administration in the 42 group 1 patients. Seven patients underwent EGD within 2 min of receiving intravenous diazepam (group 2). Ventilation decreased after diazepam, recovered, then decreased immediately after endoscope insertion in the group 1 patients. Periods of hypopnea, up to 39 s long, were observed during EGD. The average decrease in SaO2 was 4.0% after diazepam (p less than 0.0001). SaO2 returned to the pre-EGD level, then decreased 2.4% during EGD (p less than 0.0005). Maximum SaO2 decrease occurred 27 +/- 6 s after insertion of the endoscope then rapidly recovered. There was a linear correlation between the duration of hypopnea and maximum SaO2 decrease (r = 0.84, p less than 0.001). All group 2 patients experienced a period of hypopnea (13.3 +/- 9.6 s) and SaO2 declined 9.0%. The SaO2 decline was significantly greater in the group 2 subjects (p less than 0.0001). Our results confirm previous findings that intravenous sedation causes hypoventilation and hypoxemia. Moreover, hypoventilation and further arterial oxygen desaturation are caused by either the mechanical effect of the endoscope or a reflex stimulated by it.

Comparison of Bactec NR-660 and Signal systems.

Bactec NR-660, a computerised blood culture system using infrared analysis of microbial generated carbon dioxide, was compared with the Signal system, which detects gaseous pressure (due to bacterial metabolism) by a manometer. Four trials were undertaken: an in vitro evaluation of 99 bacteria in simulated blood cultures, and three prospective comparisons of a total of 2588 paired patient samples. Combined results for bacteria in simulated blood cultures showed a highly significant difference (p less than 0.001) between Bactec NR-660 aerobic medium (6A) and any other phial under test. Detection rates for most bacteria by Signal were on average three times slower than the first Bactec phial (mean delay 58.3 hours). Overall, the systems were not comparable.