Effect of smoking status on progression-free and overall survival in non-small cell lung cancer patients receiving erlotinib or gefitinib: a meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as erlotinib or gefitinib are indicated for the treatment of non-small cell lung cancer (NSCLC). EGFR tyrosine kinase domain mutations have been reported to be associated with EGFR-TKI response in patients with NSCLC. Certain patient subgroups in which EGFR somatic mutations are more frequently observed are thought to derive more clinical benefit from EGFR-TKI therapy. We performed a systematic review and meta-analysis to summarize the evidence regarding the association of smoking status with overall survival (OS) and progression-free survival (PFS) in patients with NSCLC receiving EGFR-TKI therapy with erlotinib or gefitinib. METHODS: Eligible studies were selected by two independent reviewers using the inclusion and exclusion criteria predefined in the protocol. Eligible studies included those evaluating the association of smoking status with OS and PFS in patients with NSCLC receiving erlotinib or gefitinib. Non-clinical studies, case reports, non-peer-reviewed abstracts and non-relevant studies were excluded. RESULTS AND DISCUSSION: Data on OS and PFS in patients with NSCLC treated with EGFR-TKIs were available in nine and ten trials, respectively. The OS and PFS from both the treatment and control groups were not significantly different between never smokers and former or current smokers (OS: odds ratio [OR], 0·80; 95% confidence interval [CI], 0·63-1·09; PFS: OR, 0·75; 95% CI, 0·49-1·14), respectively. However, in comparison within each smoking group, EGFR-TKI treatment led to more favourable OS and PFS in never smokers (OS: OR, 0·55; 95% CI, 0·42-0·73; PFS: OR, 0·43; 95% CI, 0·33-0·54), compared with former or current smokers (OS: OR, 0·89; 95% CI, 0·80-0·97; PFS: OR, 0·73; 95% CI, 0·62-0·85). WHAT IS NEW AND CONCLUSION: Among patients with NSCLC receiving EGFR-TKI therapy with erlotinib or gefitinib, never smokers appear to show longer OS and PFS as compared to former or current smokers. However, this is based on indirect comparisons and more robust larger head-to-head trials are required for more robust inferences.

A Large National Cohort Study of the Association between Bisphosphonates and Osteonecrosis of the Jaw in Patients with Osteoporosis: A Nested Case-control Study.

The purpose of this study was to examine the association between bisphosphonate exposure and osteonecrosis of the jaw (ONJ) in Korean patients with osteoporosis. A nested case-control study was performed using the claims database during 2002 to 2010 provided by the National Health Insurance Service. We identified a cohort of individuals with diagnosis of osteoporosis during 2002 to 2010. Cases and controls were identified during 2004 to 2010, and the date of potential cases of ONJ was defined as the index date. Bisphosphonate exposure was evaluated during 2 y prior to the index date. The association between bisphosphonate exposure and ONJ was tested by performing a conditional logistic regression analysis for matched data, and odds ratios (ORs) with 95% confidence intervals (CIs) were presented. Subjects were classified as nonuser, recent user, past user, or continuous user, depending on the prescription of bisphosphonates in 2 periods (1 to 2 y and 0 to 1 y prior to the index date). Continuous users were defined as patients who were exposed to bisphosphonate in both periods. We also examined the impact of bisphosphonate medication compliance by measuring the cumulative duration of exposure (CDE) on the risk of ONJ. A total of 212 cases with ONJ and 2,120 controls matched by sex, age, income level, and insurance type were identified among 109,787 patients with osteoporosis out of 1,025,340 enrollees in the sample cohort. The odds of having ONJ after adjusting for patient comorbidities significantly increased in continuous users of bisphosphonates (OR, 3.9; 95% CI, 2.4 to 6.2) compared to nonusers. Increased odds of ONJ were observed as CDE increased. The adjusted OR in patients with 1.5 y < CDE ≤ 2 y prior to the index date was 7.8 (95% CI, 4.0 to 15.5) versus nonusers. Our study results support significantly increased occurrences of potential ONJ in patients with osteoporosis who were exposed to bisphosphonates compared to those without exposure.

Intracellular lipid accumulation inhibitory effect of Weissella koreensis OK1-6 isolated from Kimchi on differentiating adipocyte.

AIMS: To investigate the intracellular lipid accumulation inhibitory effect of spent culture medium extract and the cytoplasmic fraction of Weissella koreensis OK1-6 cells isolated from kimchi in differentiating 3T3-L1 cells. METHODS AND RESULTS: Differentiating 3T3-L1 cells were treated with either cytoplasmic fraction of W. koreensis OK1-6 cells or its spent media for 4 days. Both the spent culture medium extract and cytoplasmic fraction of W. koreensis OK1-6 cells significantly decreased the triglyceride concentration and intracellular lipid accumulation in the treated groups compared with the control group. The mRNA expression levels of C/EBP-α, one of the major transcriptional factors involved in adipocyte differentiation, were significantly less expressed in 3T3-L1 cells treated with the spent medium and cytoplasmic fraction. The expressions of aP2, fatty acid synthase (FAS) and SREBP1 genes were also decreased significantly. CONCLUSIONS: These results suggested that W. koreensis OK1-6 could play a crucial role in preventing intracellular lipid accumulation by down-regulating the expression of adipocyte-specific genes C/EBPα, aP2, SREBP1 and FAS. SIGNIFICANCE AND IMPACT OF THE STUDY: These results may contribute to nutraceutical and food industries in developing probiotic-based therapies for the treatment and prevention of obesity.

Association of MCP-1 and CCR2 polymorphisms with the risk of late acute rejection after renal transplantation in Korean patients.

Among the factors modulating transplant rejection, chemokines and their respective receptors deserve special attention. Increased expression of monocyte chemoattractant protein-1 (MCP-1) and its corresponding receptor (chemokine receptor-2, CCR2) has been implicated in renal transplant rejection. To determine the impact of the MCP-1-2518G and CCR2-64I genotypes on renal allograft function, 167 Korean patients who underwent transplantation over a 25-year period were evaluated. Genomic DNA was genotyped using polymerase chain reaction followed by restriction fragment length polymorphism analysis. Fifty-five (32.9%) patients were homozygous for the MCP-1-2518G polymorphism. Nine (5.4%) patients were homozygous for the CCR2-64I polymorphism. None of the investigated polymorphism showed a significant shift in long-term allograft survival. However, a significant increase was noted for the risk of late acute rejection in recipients who were homozygous for the MCP-1-2518G polymorphism (OR, 2.600; 95% CI, 1.125-6.012; P = 0.022). There was also an association between the MCP-1-2518G/G genotype and the number of late acute rejection episodes (P = 0.024). Although there was no difference in the incidence of rejection among recipients stratified by the CCR2-V64I genotype, recipients with the CCR2-V64I GG genotype in combination with the MCP-1-2518G/G genotype had a significantly higher risk of acute or late acute rejection among the receptor-ligand combinations (P = 0.006, P = 0.008, respectively). The MCP-1 variant may be a marker for risk of late acute rejection in Korean patients.

Age-related change of somatostatin-immunoreactive neurones in the main olfactory bulb of the rat.

Somatostatin is found in the olfactory system, including the main olfactory bulb (MOB), and is thought to be one of the neuroactive substances for olfaction. However, somatostatin immunoreactivity in the olfactory system has not been determined during ageing. Hence, we examined the age-related changes of somatostatin-immunoreactive (IR) neurones in the rat MOB over a period of 2 years, at the following various ageing stages: post-natal month 1 (PM 1), PM 3, PM 6, PM 12 and PM 24. In PM 1 group, a few somatostatin-IR neurones were detected in the granule cell layer (GCL), and had slender or oval somata and short processes. At PM 3, somatostatin-IR neurones were observed in the glomerular, external plexiform and GCL. The size of somatostatin-IR somata was larger than that at PM 1. In PM 6 group, the number and size of somatostatin-IR neurones increased, and their processes became longer while running in various directions. At PM 12, somatostatin-IR neurones increased in number, and their processes became markedly longer than those at PM 6. At this stage, somatostatin-IR neurones had multipolar somata, and were the largest in size. In PM 24 group, somatostatin-IR neurones were most numerous. However, the processes of somatostatin-IR neurones were shorter than those at PM 12. This study suggests that the increased number of somatostatin-IR neurones in the MOB of aged rats may play a role to compensate for any decrease of olfactory function.

Muscular sarcoidosis: Ga-67 scintigraphy and magnetic resonance imaging.

Ga-67 scintigraphy is helpful in the assessment of active extrapulmonary sarcoidosis. Muscular involvement of sarcoidosis is often asymptomatic or nonspecific, and laboratory examinations do not provide convincing evidence of muscular involvement. The authors report a case of muscular sarcoidosis detected by Ga-67 scintigraphy. In a patient who had fever and arthralgia of both knee joints, Ga-67 scintigraphy showed mediastinal and hilar involvement of sarcoidosis with unexpected extensive muscular uptake. Magnetic resonance imaging revealed in detail intramuscular infiltration of sarcoid granuloma. Ga-67 scintigraphy is useful in detecting inflammatory muscular involvement of sarcoidosis and other multiorgan involvement.

Chronological changes of N-methyl-D-aspartate receptors and excitatory amino acid carrier 1 immunoreactivities in CA1 area and subiculum after transient forebrain ischemia.

We investigated changes of immunoreactivities of N-methyl-D-aspartate receptor (NR) and of excitatory amino acid carrier 1 (EAAC-1), the neuronal glutamate transporter, in the vulnerable CA1 area and the less vulnerable subiculum of the gerbil hippocampus at various times following transient forebrain ischemia. At 30 min after ischemia-reperfusion, the intensity of NR immunoreactivity increased markedly in neurons of CA1 and subiculum, particularly NR2A/B, while EAAC-1 immunoreactivity was reduced in CA1. At 3 hr after reperfusion, the density of NR1 immunoreactivity markedly decreased in CA1. In contrast EAAC-1 immunoreactivity increased in CA1 and in the subiculum. At 12 hr after reperfusion, the decrease of NR1 immunoreactivity was not detected whereas EAAC-1 immunoreactivities in the CA1 area were intensified. In the subiculum, both NR subunits immunoreactivities decreased significantly, in contrast to the maintenance of EAAC-1 immunoreactivity. At 24 hr after reperfusion, both NR2A/B and EAAC-1 immunoreactivities decreased markedly in CA1 and subiculum. We tentatively suggest that the increase of NR immunoreactivity in CA1 at early times after ischemia-reperfusion may increase the delayed neuronal death, and that the increase or maintenance of EAAC-1 immunoreactivity at early times after ischemia-reperfusion may be an important factor in survival of neurons.

Effect of dietary linoleate/alpha-linolenate balance on the brain lipid composition, reproductive outcome and behavior of rats during their prenatal and postnatal development.

The effect of the dietary linoleate (LA)/alpha-linolenate (LNA) balance during development on the brain lipid composition, reproductive outcome and behavior of rats was studied. Female rats were fed on experimental diets during pregnancy and the resulting pups for 16 weeks. The dietary LA/LNA ratios were 1.07 (LA1), 2.64 (LA2), 4.45 (LA3), 7.68 (LA4) and 10.35 (LA5). The relative content of docosahexaenoate (DHA) in the brain of pups tended to increase with decreasing LA/LNA ratio at 0 and 3 weeks, while the level of DHA was maintained constant at 16 weeks regardless of the dietary LA/LNA ratio. The learning ability was measured at 12 weeks of age, and there was no difference among the groups. In an open field test, the exploratory index was significantly lower in the LA1 group than in the LA2 group. The LA1 group had a smaller litter size and lower survival rate than the other groups. We conclude that if the diet contained appropriate amounts and balance of LA and LNA, it was possible for rats to synthesize an appropriate amount of DHA and have normal behavioral activity without DHA supplementation.

Whole-body and pinhole bone scintigraphic manifestations of Reiter's syndrome: distribution patterns and early and characteristic signs.

The characteristic whole-body and pinhole scintigraphic manifestations of osteo-enthesopathy and arthropathy in Reiter's syndrome (RS) are described, with an emphasis on early diagnosis. We analysed 59 sets of whole-body and pinhole bone scintigrams of 59 patients with RS. The population comprised 47 men and 12 women with an age range from 15 to 53 years (mean=29.4). Bone scintigraphy was carried out 2-2.5 h after intravenous injection of technetium-99m hydroxydiphosphonate using a single-head gamma camera (Siemens Orbiter Model 6601) with a low-energy high-resolution and a 4-mm pinhole collimator for whole-body and pinhole scintigraphy, respectively. In total 262 lesions of osteo-enthesopathy and arthritis were detected on 59 whole-body scintigrams, an incidence of 4.4 lesions per patient. As anticipated, the lesional distribution was asymmetrical: 68% were in the lower limb skeleton and 32% in the axial and upper limb skeleton. Pinhole bone scintigraphy, applied selectively to one region of interest in each case, enabled us to accurately diagnose arthritis and osteo-enthesopathy. It was noteworthy that osteo-enthesopathy, alone or in combination with arthritis, occurred in 78.9%, and had a strong predilection for the foot bones, especially the calcaneus (25. 6%). Pinhole scintigraphy detected enthesopathy in the absence of radiographic alteration in 14.1% of cases and portrayed characteristic signs of RS in 6.9%. Whole-body bone scintigraphy augmented with pinhole scintigraphy was found to be useful in order to panoramically display the systemic involvement pattern, to assess the characteristic bone and articular alterations and to detect early signs of RS.

Low dietary protein impairs blood coagulation in BHE/cdb rats.

The influence of dietary protein on blood coagulation tests was evaluated in BHE/cdb rats. Three experiments were conducted in order to compare effects of diets with low (8 g/100 g diet) or high (38 g/100 g diet) protein, to establish values for coagulation tests at intermediate (12-30 g/100 g diet) concentrations of dietary protein, and to compare feeding identical quantities of diets with 8 g protein/100 g diet vs. 18 g protein/100 g diet. After 4 wk of feeding the semipurified diets, bleeding time exceeded 15 min in the groups fed low protein diets, compared to a range of 3-6 min for the groups fed high protein diets. Several in vitro tests of coagulation were abnormal in the rats fed low protein diets. For example, prothrombin time averaged 27 +/- 8 s in rats fed 8 g protein/100 g diet plus beef tallow, but 17 +/- 1 s in rats fed 38 g protein/100 g diet plus tallow. The coagulation deficit in rats fed low protein was not affected by fat source (tallow vs. menhaden oil), but fibrinogen was elevated in rats fed diets with menhaden oil. Conversely, no differences in coagulation tests were observed among rats fed 12-30 g protein/100 g diet. Bleeding times ranged from 7 to 9 min, and prothrombin time was 17-18 s. Significant differences in plasma fibrinogen concentration and prothrombin time were observed in rats fed 8 vs. 18 g protein/100 g diet at a fixed rate of 6 g/100 g body weight. Platelet and blood cell numbers were unaffected by dietary protein. The evidence for multiple deficits in the coagulation system suggests that hepatic function in BHE/cdb rats may become impaired when the rats are fed low protein diets of the composition used here.

Impact of a primary reader's opinion on the detection of rib fractures.

RATIONALE AND OBJECTIVES: The authors assessed the influence of a prior reader's opinion on the detectability of rib fractures. METHODS: Six pairs of observers read the chest PA radiographs of 92 subjects with rib fracture(s) and 28 normal subjects to detect rib fracture(s) according to a five-point rating of confidence with three methods. In method A, each reader read films as a primary reader. In method B, each reader read films after knowing his or her partner's opinion. In method C, each reader initially observed films and then made the final decision after knowing his or her partner's opinion. RESULTS: Methods B and C were superior to method A in sensitivity. There was no difference in performance between methods B and C. Method C required a significantly longer time than the other methods. CONCLUSION: Detection of rib fractures is improved by seeking the opinion of other observers.