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Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective in prolonging progression-free survival time of patients with non-small cell lung carcinoma, typically adenocarcinoma, bearing some active EGFR mutations in their tumors. However, the close relationship between the EGFR mutations and pleomorphic carcinoma of the lung, which is a very rare type of primary lung cancer, has never been elucidated. We present a 60-year-old Japanese woman with pleomorphic carcinoma of the lung that became resistant to cytotoxic chemotherapies including platinum-based chemotherapy, and her general condition seriously deteriorated. Thereafter, treatment with gefitinib was started and resulted in significant tumor shrinkage and a dramatic improvement in her general condition for up to 8.5 months. Analyses of the EGFR mutation in separately microdissected specimens from adenocarcinoma and spindle cell components revealed that both components possessed the L858R point mutation. These findings gave us some insight into the carcinogenesis of pleomorphic carcinoma of the lung in relation to EGFR gene alteration. Testing for EGFR mutation may be important in patients with advanced pleomorphic carcinoma including adenocarcinoma component that is usually chemoresistant. more...

The effect of sleep stage change on pulmonary circulation has not been well documented in patients with obstructive sleep apnea syndrome (OSAS). We investigated whether or not stage-specific change can affect pulmonary artery pressure (Ppa) in patients with OSAS. Thirty-one patients with OSAS underwent right cardiac catheterization in the daytime and the following night, including 19 patients in whom Ppa could be measured throughout non‐rapid eye movement (NREM) and rapid eye movement (REM) sleep. Ten of the 19 patients had daytime pulmonary hypertension (PH) defined by a mean Ppa ( ) > 20 mm Hg. Then we analyzed Ppa response to hypoxia spontaneously occurring during the period of sleep apnea. The slopes of the regression lines between arterial oxygen saturation measured by pulse oximeter (Sp O2 ) and curves were almost the same in both NREM and REM patient groups with or without daytime PH, whereas the response curve was significantly shifted upward in REM compared with NREM patients with daytime PH. Furthermore, Ppa was elevated more markedly in association with REM burst, phasic REM, compared with tonic REM. We conclude that vascular tone of pulmonary artery could be elevated in association with REM sleep which is independent of the degree of hypoxia, and that this state-specific change is manifested in patients with daytime PH. Niijima M, Kimura H, Edo H, Shinozaki T, Kang J, Masuyama S, Tatsumi K, Kuriyama T. Manifestation of pulmonary hypertension during REM sleep in obstructive sleep apnea syndrome. AM J RESPIR CRIT CARE MED 1999;159:1766‐1772. Ppa more...

Vibratory stimulation applied to the chest wall during inspiration reduces the intensity of breathlessness, whereas the same stimulation during expiration has no effect or may increase breathlessness. The purpose of the present study was to determine whether vibration reduced the intensity of breathlessness during progressive hypercapnia with and without the addition of an external resistive load. A second objective was to see whether the mouth occlusion pressure at 0.2 s (P0.2) was reduced by the vibratory stimulation. Hypercapnic ventilatory response was conducted in 10 healthy male volunteers with simultaneous measurement of visual analog scale, P0.2, and minute ventilation. Hypercapnic ventilatory response was performed and randomly combined with or without vibratory stimulation (100 Hz) as well as with or without inspiratory load. With inspiratory load, in-phase vibration did not cause any significant changes in the slopes of P0.2 and minute ventilation to CO2, whereas the slope of visual analog scale to CO2 significantly decreased from 0.47 ± 0.15 to 0.34 ± 0.11 (SE) cm/Torr ( P < 0.05). We conclude that in-phase vibration could decrease the slope of breathlessness elicited by inspiratory load combined with hypercapnia without changing motor output. more...

To clarify the characteristics of upper airway muscles under hypoxic condition in obstructive sleep apnea syndrome (OSAS), we performed the isocapnic progressive hypoxia test during wakefulness in 8 controls and 7 OSAS patients. Electromyographic activities were recorded from the genioglossal muscle (EMG(GG)) and diaphragm (EMG(DIA)) with ventilatory variables. Minute EMG (peak integrated EMG x respiratory rate) activity against P(ET)O2 was calculated by exponential equation, and its response slope represented the hypoxic sensitivity of each muscle, slope(GG) and slope(DIA). There was no significant difference between the slopes of OSAS and control. In contrast, the ratio of the two responses, slope(GG)/slope(DIA), was significantly higher in OSAS (1.61 +/- 0.49 SD) than in control (0.98 +/- 0.43). Moreover, the slope(GG)/slope(DIA) ratio was negatively correlated with the ratio of sleep time with SpO2 lower than 90% to total sleep time. We conclude that the neuromuscular compensatory mechanism of upper airway muscles is effectively developed and plays an important role in preventing nocturnal hypoxemia in OSAS. more...

Since obstructive sleep apnea syndrome (OSAS) is often linked with systemic hypertension, we sought to clarify the characteristics of prostanoid metabolism in OSAS. In 7 OSAS patients (apnea-hypopnea index, 51.0 +/- 23.4) and 7 non-snorers as control, nocturnal urine was sampled and analyzed for stable metabolites of prostacyclin (PGI2) and thromboxane A2 (TxA2), [6-keto-PGF1alpha and thromboxane B2 (TxB2)]. The ratio of 6-keto-PGF1alpha to TxB2 was significantly higher in OSAS (2.97 +/- 1.52) than in control (1.38 +/- 0.38). Successful treatment with nasal continuous positive airway pressure (8.3 +/- 1.5 cmH2O) for 3 days caused a significant decrease in mean blood pressure in OSAS. Moreover, the 6-keto-PGF1alpha to TxB2 ratio also significantly decreased to 1.74 +/- 0.58, a level which may not significantly different from control. These results suggest that the production ratio of PGI2 to TxA2 is shifted toward vasodilatation in untreated OSAS. We conclude that the production of prostanoids plays a role in compensating for the systemic hypertension in OSAS. more...

The patient was a 74-year-old woman who had been obese since age 18. Her obesity was refractory to dietary manipulation. She had been suffering from increasing dyspnea for several months and eventually could not even move. She was admitted to a hospital and diagnosed as having heart failure. Although her cardiac function recovered with medical treatment, her symptoms did not improve. The patient was then sent to our hospital. On admission, her height and weight were 149 cm and 81.9 kg, respectively, yielding a body mass index (BMI) of 36.6 kg/m2. Arterial blood gas analysis in room air revealed hypoxemia and an apnea index of 27 per hour. She was given a daily 500-1000 kcal diet. After four months of treatment, her weight decreased to 65 kg with a BMI of 29.3 kg/m2. Weight reduction together with the usage of progesterone-derivatives resulted in marked improvement of sleep apnea. The apnea index decreased to 3/h and arterial blood gas values normalized. This patient seemed to have suffered from both obesity hypoventilation syndrome and sleep apnea syndrome. Improvement of respiratory function was achieved through relief of airway obstruction and weight reduction, with activation of the respiratory center due to progesterone treatment. more...

Recent studies on lung cancer screening with CT disclosed a discrepancy between its efficiency in detecting early lung cancer and a lack of proof for decreasing mortality from lung cancer. The present study, in a city in Japan where an X-ray screening program is provided, bi-annual CT screening was performed for X-ray screening negative subjects for 4 years. Ten patients with lung cancer were detected among 22,720 person-year subjects (0.044%) through the X-ray screening. Among the X-ray screening-negative subjects, 3305 subjects participated in a CT screening program resulting in the detection of 15 patients with lung cancer (0.454%). All 15 cases detected by CT screening and 5 of the 10 cases detected by X-ray screening were at stage IA. In respect of gender, histological type and CT findings, patients detected by CT screening had a better prognostic profile than those detected by X-ray screening. Survival was significantly better in the former than the latter, both in its entirety comparison and in a comparison limited to patients who underwent surgery. In conclusion, CT screening might have the potential to detect lung cancer with good prognostic factors not limited to early detection. Sufficiently long follow-up time, therefore, would be required to evaluate the efficacy for decreasing lung cancer mortality with CT screening. more...

Ventilatory response to eucapnic sustained mild hypoxia was measured in one patient with unilateral and three patients with bilateral carotid body (CB) resection (defined UR and BR, respectively). The profile of ventilatory response in UR patient was initially augmented then gradually declined (biphasic pattern) as generally seen in normal subjects although the absolute magnitude was substantially low. On the other hand, biphasic pattern was disappeared in all three BRs. Lack of hypoxic ventilatory decline (HVD) in the late period of sustained hypoxia was in marked contrast to that reported in the anaesthetized and CB-denervated animals whose ventilation was severely depressed lower than the pre-hypoxic control level. In view of recent knowledge that the analogous mild hypoxia in normal animals and humans elicits an useful adaptation to economize energy expenditure with maintaining reversible excitability in control of respiration, BR patients were considered to have lost this ability. We conclude that in awake humans the CB not only stimulates ventilation but also controls the degree of subsequent HVD during sustained hypoxia. more...

The carotid body (CB) is the most important chemoreceptor for eliciting hyperpnea in response to hypoxic exposure.1 However, the level of hypoxic hyperventilation is not maintained at a constant level: ventilation (VI) during sustained mild hypoxia initially increases rapidly, and then gradually declines with time.2-4 The initial rapid rise is generally considered to be induced by CB excitation, whereas the mechanism for the subsequent gradual decline (hypoxic ventilatory decline, HVD) is a matter of controversy.5-9 It has also been confirmed in humans as well as in other animal species that the magnitude of the initial ventilatory increment is closely correlated with secondary HVD.10-13 Fig. 1 illustrates an example of such a finding previously obtained by us.13 This fact led us to assume that this specific profile of hypoxic hyperpnea is possibly entirely related to the CB activity. Therefore, we intended to study CB-resected patients who underwent a therapeutic surgery for bronchial asthma some 40 yrs ago. We found that these patients revealed no HVD. more...

The depression of EMG activity in upper airway muscles during sleep is known to be a predisposing factor causing upper airway obstruction in patients with obstructive sleep apnea syndrome (OSAS). To clarify whether or not the selective depression of upper airway muscles could be associated with the hypoxic ventilatory depression, we performed sustained hypercapnic hypoxia tests during wakefulness in 11 control subjects and 10 patients with OSAS. Isocapnic sustained hypoxia around SaO2 80% with mild hypercapnia [PETO2: 45.8 +/- 1.6 (SD) and 46.7 +/- 2.8 mm Hg and PETCO2: 44.2 +/- 4.7 and 43.1 +/- 5.0 mm Hg in control and OSAS groups, respectively] was applied for 20 min. Electromyogram activities were recorded from the genioglossal muscle (EMGGG) and diaphragm (EMGDIA) with ventilatory variables. The magnitudes of hypoxic depression in terms of minute ventilation (VI) and minute EMGDIA (EMGDIA/min) were compared in percentage between peak value and the value at the late period. These values were not significantly different between two groups (VI: 79.2 +/- 10.7 and 66.9 +/- 12.8% and EMGDIA/min: 63.2 +/- 17.1 and 60.4 +/- 24.0% in control and OSAS, respectively). On the contrary, the depression in EMGGG was not consistently observed in control (86.1 +/- 38.6% of the peak value) whereas EMGGG was markedly depressed in OSAS (38.6 +/- 15.7% of the peak value; p0.01). It is concluded that sustained hypoxia attenuates the activity in genioglossal muscle in patients with OSAS, but not in control subjects.(ABSTRACT TRUNCATED AT 250 WORDS) more...