Phase II study of S-1 monotherapy in patients with previously treated, advanced non-small-cell lung cancer.

BACKGROUND: In this phase II clinical trial, we evaluated the efficacy and safety of S-1 monotherapy in patients with previously treated advanced non-small-cell lung cancer (NSCLC). We also measured plasma concentrations of 5-fluorouracil (5-FU) and 5-chloro-2,4-dihydroxypyridine components of S-1 and examined correlation with effectiveness and toxicity. METHODS: S-1 was given orally at a dose of 80 mg/m(2)/day for 14 consecutive days, followed by a 7-day rest period. This treatment course was repeated until disease progression or intolerable toxicity. RESULTS: We enrolled 30 patients. The response rate was 26.7% (8/30), and the disease control rate was 70% (21/30). Median progression-free survival (PFS) was 3.1 months, and median overall survival (OS) was 11.2 months. Mutations in the epidermal growth factor receptor (EGFR) gene were analyzed in 27 patients. The response rate was higher in patients with mutant EGFR (50.0%) than in those with wild-type EGFR (11.8%, P = 0.0288). Median PFS was 4.8 and 2.5 months (P = 0.038), and median OS was 22.4 and 8.4 months (P = 0.071). There was no grade 4 toxicity in this study. Five patients had grade 3 non-hematologic toxicity, and there was a trend toward higher plasma concentrations of 5-FU in those patients than in another patients. CONCLUSIONS: S-1 monotherapy is effective and well-tolerated treatment for previously treated advanced NSCLC.

Aminophylline increases parasternal intercostal muscle activity during hypoxia in humans.

To clarify the mechanism of action of aminophylline on the hypoxic ventilatory response in humans, we analyzed the effects of aminophylline on respiratory neural output. To evaluate the respiratory neural output, we analyzed the electromyogram (EMG) of the parasternal intercostal muscle, one of the major inspiratory muscles, in eight healthy subjects. Both before and during aminophylline administration, measurements of ventilatory parameters with EMG recordings were conducted in room air, mild hypoxia (F(I)(o)(2) 0.15), and severe hypoxia (F(I)(o)(2) 0.11). Before administering aminophylline, hypoxic stimulation elicited ventilatory augmentation in a hypoxia-intensity dependent manner. Administration of aminophylline caused significant increases in ventilation (V (I)), tidal volume (V(T)), respiratory frequency (f(R)), and the respiration-related phasic moving averaged EMG amplitude (tidal EMG), at corresponding levels of hypoxia compared to before aminophylline. Augmentation patterns of hypoxia-induced increases in V(T) and tidal EMG showed close similarity. These results indicate that augmentation of hypoxic ventilatory response by aminophylline is mainly mediated by an increase in the respiratory neural drive in healthy humans.

Neck and abdominal muscle activity during a sniff.

Measurement of sniff nasal inspiratory pressure (SNIP) is now used widely as a simple, non-invasive assessment of global respiratory muscle strength, even though the technique evolved originally from measurements of trans-diaphragmatic pressure (Pdi) that reflect the status of the diaphragm. The relative participation of major respiratory muscles, apart from the diaphragm, in the generation of SNIP is not known. Therefore, we examined the activity during a sniff of both neck and abdominal "accessory" muscles. In seven young adults we implanted fine wire EMG electrodes under direct vision with high-resolution ultrasound into scalene, sternocleidomastoid, trapezius, and transversus abdominis. SNIP was measured during sniffs that were short and sharp, from low to maximal intensity, in both standing and supine postures. Mean maximum SNIP was -105.6cmH2O (SD 32.9) in supine and -94.5cmH2O (26.6) in the standing posture, (difference NS). In every subject, scalene activity appeared even at the lowest SNIP, and increased linearly with increasing SNIP. Sternomastoid activity appeared at higher SNIP levels in three of seven subjects. By contrast, trapezius activity was never present at low SNIP, and appeared in only 2 subjects at maximum SNIP. Sniff abdominal expiratory activity was inconsistent with no activity of transversus in four of seven subjects even at greatest SNIP. Thus, we observed differential activation among these non-diaphragm respiratory muscles during SNIP; while some accessory muscles were very active, others were unlikely to contribute to generation of SNIP. Clinically, this indicates SNIP will be impacted unequally by loss of function of specific respiratory muscles.

Geniohyoid muscle function in awake canines.

The geniohyoid (Genio) upper airway muscle shows phasic, inspiratory electrical activity in awake humans but no activity and lengthening in anesthetized cats. There is no information about the mechanical action of the Genio, including length and shortening, in any awake, nonanesthetized mammal during respiration (or swallowing). Therefore, we studied four canines, mean weight 28.8 kg, 1.5 days after Genio implantation with sonomicrometry transducers and bipolar electromyogram (EMG) electrodes. Awake recordings of breathing pattern, muscle length and shortening, and EMG activity were made with the animal in the right lateral decubitus position during quiet resting, CO2-stimulated breathing, inspiratory-resisted breathing (80 cmH2O. l-1. s), and airway occlusion. Genio length and activity were also measured during swallowing, when it shortened, showing a 9.31% change from resting length, and its EMG activity increased 6.44 V. During resting breathing, there was no phasic Genio EMG activity at all, and Genio showed virtually no movement during inspiration. During CO2-stimulated breathing, Genio showed minimal lengthening of only 0.07% change from resting length, whereas phasic EMG activity was still absent. During inspiratory-resisted breathing and airway occlusion, Genio showed phasic EMG activity but still lengthened. We conclude that the Genio in awake, nonanesthetized canines shows active contraction and EMG activity only during swallowing. During quiet or stimulated breathing, Genio is electrically inactive with passive lengthening. Even against resistance, Genio is electrically active but still lengthens during inspiration.

[Relation between neck accessory inspiratory muscle electromyographic activity and lung volume].

Years ago it was reported that, as lung volume increased, there was a corresponding increase in scalene EMG activity (Raper et al. J Appl Physiol 21: 497-502, 1966). Otherwise, the relationship between changing lung volume and the EMG of the respiratory muscles has not been defined. We therefore inserted fine wire electrodes into the scalene (SCLN), sternocleidomastoid (STERNO), and trapezius (TRAPEZ) muscles in 6 healthy subjects under direct vision using high-resolution ultrasound. Maximum EMG activity (EMGmax) was obtained for each muscle by a variety of respiratory and postural maneuvers. Then, in the standing posture, air flow, raw and moving average EMG signals were sampled and input to a computer during quasi-static inspiration from functional residual capacity (FRC) to total lung capacity (TLC). We found that the relationship between EMG and lung volume for SCLN, but not for STERNO or TRAPEZ, was expressed by exponential curves. The onset of SCLN, STERNO and TRAPEZ EMG occurred at 13.3 +/- 7.4 (mean +/- SE), 67.8 +/- 14.6, and 89.2 +/- 3.9% of inspiratory capacity. The EMG of SCLN, STERNO, TRAPEZ, reached 85.7 +/- 2.6, 60.7 +/- 8.6, and 11.8 +/- 5.2% of EMGmax, respectively, at TLC. We conclude that: 1) SCLN is the most, and TRAPEZ the least, active neck accessory inspiratory muscle, while STERNO is intermediate, and 2) there is a lung volume dependency of the neck accessory muscle EMG activity.

[Postural effects on electromyographic activity of the transversus abdominis muscle].

During breathing at rest in humans, electromyographic activity of the expiratory muscles (EMGem), tidal volume (VT), and minute ventilation (V(I)) are higher when standing than when supine. EMGem is known to correlate with VT and V(I). It is not known whether increased EMGem when standing results directly from the change in posture or indirectly from postural changes in ventilatory pattern. Moving average electromyographic activity of the transversus abdominis (EMGta) was recorded using a pair of fine wire electrodes during carbon dioxide (CO2) rebreathing both while standing and while supine. At matched end-tidal CO2 (ETCO2), VT, or V(I) values, EMGta was significantly higher when standing than when supine. Postural differences in EMGta had no correlation with increasing ETCO2, VT, or V(I) during CO2 rebreathing. These results suggested that both the direct effect of the postural change and an indirect effect through changes in ventilatory pattern contribute to the increased EMGem observed when standing compared to that when supine.

[Electromyographic activity of neck muscles during the production of inspiratory pressure].

The differential inspiratory EMG activities of the scalene (SCLN), sternocleidomastoid (STERNO), and trapezius (TRAPEZ) muscles were studied in 6 awake and healthy men (mean age, 22 years; and mean weight, 62.4 kg). Pairs of fine wire EMG electrodes were inserted into each of these muscles using a guide needle and high-resolution ultrasonography. With subjects on a mouthpiece, inspiratory effort against an occluded airway was recorded at end expiratory position in the standing position. Mouth pressure and integrated EMG signals were sampled to a computer during the gradual production of maximal static inspiratory pressure (PImax) over 10 s. Maximum EMG activity (EMGmax) was obtained for each muscle during specific respiratory and postural maneuvers. Mouth pressures and integrated EMG activities were expressed as percentages of PImax and EMGmax, respectively. As mouth pressure increased, SCLN, then STERNO, and finally TRAPEZ EMGs were sequentially activated in 5 subjects. In one subject, STERNO preceded SCLN EMG activation. Group mean (+/- SE) mouth pressures at the onset of SCLN, STERNO, and TRAPEZ EMG were 10.3 +/- 5.8% PImax. 30.8 +/- 8.2% PImax, and 79.3 +/- 9.6% PImax, respectively. TRAPEZ mouth pressures differed from SCLN and STERNO values (p < 0.05). At 90% PImax, group mean (+/- SE) SCLN, STERNO, and TRAPEZ EMG activity reached 69.7 +/- 9.0% EMGmax, 51.5 +/- 11.1% EMGmax, and 5.1 +/- 2.4% EMGmax, respectively. TRAPEZ EMG at 90% PImax differed from both SCLN and STERNO values (p < 0.05). These results suggest that SCLN has strong, STERNO intermediate, and TRAPEZ weak, inspiratory activities.

[Effects of uvulopalatopharyngoplasty on patients with obstructive sleep apnea--the severity of preoperative tonsillar hypertrophy].

Predicting outcome following uvulopalatopharyngoplasty (UPPP) in obstructive sleep apnea is difficult. We hypothesized that UPPP is effective in obstructive sleep apnea patients with severe tonsillar hypertrophy. We examined the relationship between the severity of pre-operative tonsillar hypertrophy and the effect of UPPP in 38 patients with obstructive sleep apnea (oxygen desaturation index (ODI) > or = 20). The patients were classified into three groups according to the Mackenzie Classification of tonsillar hypertrophy. Ten patients were classified as grade 1 (M1) hypertrophy, i.e. tonsils just visible beyond the palatal arch. Five patients had grade 3 (M3) hypertrophy, i.e. tonsils appearing to contact each other at the midline. The remaining 23 patients had grade 2 (M2) hypertrophy, i.e. intermediate enlargement. We measured the apnea index, ODI, DST 90, and DST 85 (%time with SaO2 < or = 90% and < or = 85%, respectively) using a screening device for sleep apnea (Apnomonitor II, CHEST M. I. Co. Tokyo, Japan) before and after UPPP. Following UPPP, the mean ODI decreased significantly in all groups: 59 to 9/hr (p < 0.005) in the M3 group, 53 to 27/hr (p < 0.001) in the M2 group, and 48 to 33/hr (p < 0.05) in the M1 group. Post-UPPP ODI decreased by 83% in M3, 45% in M2, and 28% in M1 patients. Successful UPPP, defined by a post-UPPP ODI of less than 20/hr and a greater than 50% decrease in post-UPPP ODI, occurred in 80% of M3, 43% of M2, and 10% of M1 patients. We conclude that tonsillar hypertrophy can predict a successful response to UPPP in obstructive sleep apnea patients.

[A case of severe acute hepatorenal failure due to Aeromoas hydrophila septicemia].

A case of septicemia due to Aeromonas hydrophila (A. hydrophila) in a 54-year-old male suffering from progressive severe jaundice and fatigue is reported. The patient developed multiple organ failure despite aggressive therapy including plasma exchange and glucose-insulin therapy. Upon admission to our hospital, therapy was started with ampicillin (ABPC) 4 g/day, gentamicin (GM) 120 mg/day, hemodialysis, continuous hemofiltration, catecholamines and a respirator, but he expired on the 2nd hospital day. Blood culture and histology revealed A. hydrophila. Postmortem examination showed alcoholic liver fibrosis which was most likely liver cirrhosis. In the literature, patients with septicemia due to Aeromonas had underlying hepatic cirrhosis more often than did those with septicemia due to other gram-negative bacilli. Therefore, it is important-to consider the possibility of liver cirrhosis in patients with A. hydrophila septicemia.

[Pulmonary tuberculosis manifesting predominantly as ileus secondary to peritoneal tuberculosis in a young man].

A 27-year-old man was admitted to our hospital because of abdominal pain and vomiting. A radiograph of the chest revealed widening of the right superior part of the mediastinum, and an abdominal radiograph showed many air-fluid levels. A computed tomographic scan of the chest revealed a solitary nodule in the right anterior lobe of the lung, and right paratracheal lymphadenopathy. Ileus was diagnosed and a nasogastric tube was inserted. The patient's condition gradually worsened, and on hospital day 17 a laparotomy was performed. Operative findings were significant for numerous, white nodules all over the peritoneum, omentum, and mesentery, which ranged from miliary to rice grain-sized. Examination of an omental specimen revealed noncaseating granulomas with Lang hans' giant cells. The polymerase chain reaction was used to examine fluid from the nasogastric tube used before surgery, and on hospital day 40 that fluid was found to be positive for Mycobacterium tuberculosis. M. tuberculosis was also cultured from the fluid. From these findings, we concluded that this was a case of pulmonary tuberculosis manifesting predominantly as ileus secondary to tuberculous peritonitis. Anti-tuberculosis therapy consisting of isoniazid, rifampin, and ethambutol was started postoperatively. On repeat laparoscopy 224 days later, no white nodules were seen. A computed tomographic scan of the chest revealed that the right paratracheal lymphadenopathy was markedly reduced, and the solitary nodule in the right anterior lobe of the lung was almost gone. Few cases of young people with pulmonary tuberculosis manifesting primarily as ileus have been reported. Tuberculosis should be included in the differential diagnosis in patients presenting with ileus.