Treatment of Patients With Non-small-cell Lung Cancer With Uncommon EGFR Mutations in Clinical Practice.

BACKGROUND/AIM: To describe real clinical outcomes in patients with non-small cell lung cancer who have uncommon epidermal growth factor receptor (EGFR) mutations. MATERIALS AND METHODS: We performed a retrospective chart review from 15 medical institutes that cover a population of three million people from April 2008 to March 2019. RESULTS: There were 102 patients with uncommon EGFR mutation. Progression-free survival (PFS) tended to be longer in patients receiving afatinib compared with first-generation EGFR tyrosine kinase inhibitors. PFS in patients treated with afatinib or osimertinib was significantly longer than in patients treated with gefitinib or erlotinib (p=0.030). Multivariate analysis also revealed the contribution of afatinib or osimertinib to increased survival. In patients with exon 20 insertions, chemotherapy was efficacious. CONCLUSION: In treating patients with uncommon EGFR mutations, our results indicate longer-term survival might be achieved with second-generation or later TKIs and cytotoxic chemotherapeutic drugs.

Clinicopathological Features in Elderly ALK-rearranged Non-small Cell Lung Cancer Patients.

AIM: To clarify the clinicopathological features in elderly anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: A retrospective study was performed in 129 ALK rearranged NSCLC patients diagnosed between April 2008 and March 2019 in fifteen Institutions of the Ibaraki prefecture, Japan. RESULTS: Median age of patients was 63 years. In 59 patients aged 65 and older, the proportions of patients with advanced stage and those treated with ALK-tyrosine kinase inhibitor (TKI) were lower than those younger than 65 years. There was no difference in overall survival (OS) between the two age groups. Among the elderly patients, no difference was observed in OS between the patients aged 65-69 and those aged 70 and older. In 89 patients treated with TKI, no significant differences were observed in the progression-free survival of TKIs and OS between patients aged 65 and older and those younger than 65, respectively. CONCLUSION: Evaluation of ALK gene status and TKI treatment are desirable even for elderly patients.

Serum CEA and CYFRA Levels in ALK-rearranged NSCLC Patients: Correlation With Distant Metastasis.

AIM: To clarify the correlation between serum levels of carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA) and metastasis and survival in anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: CEA and CYFRA levels in 131 ALK-rearranged NSCLC patients were determined using fluorescence in situ hybridization (FISH), real time-reverse transcription polymerase chain reaction, and immunohistochemistry, using biopsy specimens, cytology specimens, and plasma specimens. Cut-off value of each marker was determined as 10 ng/ml. RESULTS: In logistic regression analysis, higher levels of both markers had a positive relationship with bone metastases, and higher levels of CYFRA was relevant to liver metastases, and multiple-organ metastases. However, these markers were not proven to be poor prognostic factors in Cox's proportional model analysis. CONCLUSION: Elevated serum CEA and CYFRA levels seem to provide useful clinical information about presence of bone and liver metastasis and multiple-organ metastases, although they were not a powerful indicator of prognosis. These two markers may suggest the extension of metastasis and would be helpful in considering treatment options.

High-level aminoglycoside resistance in Enterococcus faecalis and Enterococcus faecium causing invasive infection: Twelve-year surveillance in the Minami Ibaraki Area.

We examined prevalence of high-level aminoglycoside resistance (HLAR) in Enterococcus faecalis and Enterococcus faecium causing invasive infection in the Minami Ibaraki Area. Ten strains of both species each, recovered from the blood or the cerebrospinal fluid between 2003 and 2014, were randomly selected every year. High-level resistance to gentamicin (HLR-GM) and streptomycin (HLR-SM) was detected in 34% (41 of 120 strains) and 18% (21) of E. faecalis and 9% (11) and 39% (48) of E. faecium, respectively. In comparisons of the proportions among three four-year periods, HLR-SM among E. faecium was significantly lower in the 2011-2014 period. All strains with HLR-GM were positive for the aac(6')-Ie-aph(2″)-Ia gene. The ant(6')-Ia gene was detected in all with HLR-SM except for one E. faecalis strain. The present study showed that prevalence of HLR-GM among E. faecalis and E. faecium causing invasive infection in this area was nearly equivalent to that described in previous studies in Japan and that proportions of strains with HLAR did not vary during the study period except for that of HLR-SM among E. faecium.

The effects of exercise training under mild hypoxic conditions on body composition and circulating adiponectin in postmenopausal women.

PURPOSE: This study aimed to examine the effects of exercise training under mild hypoxic conditions on body composition and circulating adiponectin levels in postmenopausal women. METHODS: Fourteen postmenopausal women (56 ± 1 years) were assigned to a normoxic (N group) or hypoxic (H group) exercise group. Aquatic exercise training was performed at an intensity of 50% peak oxygen uptake level for 30 min per training session, 4 days per week, for 8 weeks. The H group performed the exercise under hypobaric hypoxic conditions, which corresponds to 2000 m above sea level, and each participant was exposed to these conditions for 2 h per session. RESULTS: After the training, no significant changes were observed in any of the measured values for the N group. Conversely, body mass (57·3 ± 2·5 to 54·5 ± 2·3 kg), body mass index (24·6 ± 0·8 to 23·4 ± 0·7 kg m-2 ), body fat (30·7 ± 1·9 to 28·1 ± 1·6%) and preperitoneal fat thickness as an index of visceral fat accumulation (10·3 ± 1·7 to 6·4 ± 1·0 mm) significantly reduced only in the H group. Circulating adiponectin levels significantly increased (9·5 ± 1·8 to 11·4 ± 2·0 µg ml-1 ), and the changes in adiponectin were significantly correlated with those in body mass (r = -0·81) and body mass index (r = -0·85). CONCLUSIONS: These results suggest that exercise training under mild hypoxic conditions could more effectively reduce body fat and increase adiponectin levels in postmenopausal women in a shorter period, than exercise training in normoxia.

Fatty liver in men is associated with high serum levels of small, dense low-density lipoprotein cholesterol.

AIMS: Our study addressed potential associations between fatty liver and small, dense low-density lipoprotein cholesterol (sd-LDL-C) levels using a cross-sectional analysis. METHODS: We enrolled 476 male subjects. Serum sd-LDL-C concentrations were determined using precipitation assays. RESULTS: Subjects were divided into four groups based on triglyceride (TG) and LDL-C levels: A, TG < 150 mg/dl and LDL-C < 140 mg/dl; B, TG < 150 mg/dl and LDL-C ≥ 140 mg/dl; C, TG ≥ 150 mg/dl and LDL-C < 140 mg/dl; and D, TG ≥ 150 mg/dl and LDL-C ≥ 140 mg/dl. sd-LDL-C levels and the prevalence of fatty liver were significantly higher in groups B, C, and D than in group A. Subjects were also categorized into four groups based on serum sd-LDL-C levels; the prevalence of fatty liver significantly increased with increasing sd-LDL-C levels. Additionally, logistic regression analysis revealed an independent association between sd-LDL-C concentrations and fatty liver using such potential confounders as obesity and hyperglycemia as variables independent of elevated TG or LDL-C levels. CONCLUSIONS: Fatty liver is a significant determinant of serum sd-LDL-C levels independent of the presence of obesity or hyperglycemia. Fatty liver may alter hepatic metabolism of TG and LDL-C, resulting in increased sd-LDL-C levels.

Vascular adaptations to hypobaric hypoxic training in postmenopausal women.

The objective of this study was to examine the effects of exercise training in hypoxia on arterial stiffness and flow-mediated vasodilation (FMD) in postmenopausal women. Sixteen postmenopausal women (56±1 years) were assigned to a normoxic exercise group (Normoxic group, n=8) or a hypoxic exercise group (Hypoxic group, n=8). The Hypoxic group performed exercise under hypobaric hypoxic conditions corresponding to 2000 m above sea level, and was exposed to these conditions for 2 h per session. Aquatic exercise was performed at an intensity of around 50% peak oxygen uptake for 30min, 4days per week, for 8 weeks. Arterial stiffness was assessed by brachial-ankle pulse wave velocity (baPWV), and FMD was evaluated by peak diameter of the popliteal artery during reactive hyperemia. After the 8 weeks of training, the Normoxic group showed no significant changes. In contrast, baPWV (P < 0.05) was significantly reduced and peak diameter (P<0.05) and %FMD (P<0.01) were significantly increased in the Hypoxic group after training. These results suggest that exercise training under mild intermittent hypoxic conditions could more effectively reduce arterial stiffness in postmenopausal women, compared with exercise training performed at the same relative intensity under normoxic conditions. Our data also indicate that hypoxic exercise training may induce vascular functional adaptation, for example an increase in FMD response. These findings therefore could have important implications for the development of a new effective exercise prescription program.

The relationship between physical fitness and ambulatory activity in very elderly women with normal functioning and functional limitations.

The effect of daily ambulatory activity on physical fitness has not yet been identified by quantitatively measuring the time spent on the intensity levels of ambulatory activity in elderly women over 75 with different functional capacity levels. The subjects consisted of 147 elderly women over 75 years old (82.8±4.3 years old) who were all capable of performing basic daily activities by themselves. Physical fitness was measured for 7 items (handgrip strength, knee extensor strength, postural stability, stepping, one-legged standing time with eyes open, 10 m walking, and the Timed Up and Go Test). The subjects wore a triaxial accelerometer for 2 consecutive weeks to measure their daily physical activities. The functional capacity level was assessed by the Tokyo Metropolitan Institute of Gerontology Index of Competence. The subjects were divided into two groups, a group with a score ≥10 points (high functional capacity group, n=59) and a score <10 points (low functional capacity group, n=88), and the relationship between physical fitness and physical activity was examined in both groups. In both the high and low functional capacity groups, 10 m walking, the Timed Up and Go Test, and one-legged standing time with eyes open significantly correlated with either the total steps/day or the ambulatory activity intensity. In the high functional capacity group, the knee extensor strength also significantly correlated with the total steps/day and moderate ambulatory activity. It is suggested that very elderly women with a reduced functional capacity should maintain their mobility by simply increasing their daily ambulatory activity.

Morphological characteristics of cardiac calcium release units in animals with metabolic and circulatory disorders.

Metabolic and circulatory disorders such as diabetes and hypertension are associated with cardiac dysfunction. Research on these types of experimental animals has observed abnormal calcium (Ca(2+)) sparks and waves in cells; a potential mechanism altering excitation-contraction (e-c) coupling in the myocardium. The e-c coupling depends on the intricate spatial relationship between the sarcolemma and sarcoplasmic reticulum calcium release units (CRU's). The objective of this study was to assess for a presence or absence of abnormalities in CRU's from type II diabetic and hypertensive rat models. Myocardial tissue underwent perfusion fixation followed by selective staining of the CRU's and the features observed using a high voltage electron microscope. Results revealed both diabetic groups had significant increases in body weight, a tendency toward an enlarged heart, and a significant disruption of the CRU's and displacement of transverse (t)-tubules in a longitudinal direction. The hypertensive model characteristically showed a dramatic increase in heart size, a significant increase in disrupted CRU's and a tendency towards longitudinal t-tubule orientation. We propose the two disorders of diabetes and hypertension have a similar etiology of cardiomyopathy resulting, in part, from an increase in the number of incomplete CRU's, due to a morphological change in the architecture and orientation of the t-tubules. These architectural changes could potentially explain the impaired calcium signaling previously observed in diabetic and hypertensive cardiomyopathy.