Different efficacy of EGFR tyrosine kinase inhibitors and prognosis in patients with subtypes of EGFR-mutated advanced non-small cell lung cancer: a meta-analysis

Background

Nearly 85 % of lung-cancer-specific epidermal growth factor receptor (EGFR) sensitive mutations comprise a substitution at position 858 (21L858R) and deletion mutants in exon 19 (19del). The aim of this study was to assess the role of EGFR mutation subtypes in predicting the efficacy of EGFR tyrosine kinase inhibitors (EGFR TKIs) and the prognosis of patients with advanced non-small cell lung cancer (NSCLC).

Method

We systematically searched for eligible articles investigating the association between EGFR mutation subtypes and the efficacy of EGFR TKIs and the prognosis of patients with NSCLC. The summary risk ratio (RR) and mean difference (MD) were calculated using meta-analysis. In addition, we used variance analysis for the progression-free survival data (PFS) and used the rank sum test for the overall survival data.

Results

We identified 22 eligible trials involving 1,082 patients. The objective response rate of the 19del mutation group was significantly higher than the 21L858R mutation group (RR 1.23; 95 % CI 1.12–1.36; P < 0.0001). The PFS (MD 3.55; 95 % CI 0.90–6.20; P = 0.009; MD 2.57; 95 % CI 0.51–4.62; P = 0.01) and overall survival (OS) (MD 10.52; 95 % CI 5.10–15.93; P = 0.0001) of the 19del mutation group were significantly longer than the 21L858R mutation group; the same results were observed in the variance analysis and rank sum test.

Conclusion

The 19del mutation may be a more efficient clinical marker for predicting the response of patients with NSCLC to EGFR TKIs. Furthermore, patients with the 19del mutation have both a longer PFS and OS. The 19del mutation is also the prognostic factor for patients with NSCLC.     

Sociodemographic and disease-related factors are associated with patient-reported anxiety and depression in spondyloarthritis patients in the Swedish SpAScania cohort

Anxiety and depression are common among patients with rheumatic diseases. This study aims to explore which factors are associated with self-reported anxiety and depression in a well-defined cohort of spondyloarthritis (SpA) patients. In 2009, 3,711 patients from the SpAScania cohort were sent a postal questionnaire to assess health-related quality of life (HRQoL) and physical and mental functioning. The Hospital Anxiety and Depression Scale measured anxiety (HADS-A) and depression (HADS-D), subscales 0–21, best–worst. HADS ≥8 indicates possible cases of anxiety or depression. One-way ANOVA (p?HADS scores. Linear regression analysis adjusted for age, gender, and disease duration was used to test for associations between HADS and independent variables. In total, 2,167 (58 %) patients (52 % females, mean age 55.4 years) returned the questionnaire. In total, 683 (32 %) cases were classified as “possible anxiety” and 305 (14 %) as “possible depression” cases with mean (SD) HADS-A 5.9 (4.3) and HADS-D 4.4 (3.6). There were no differences among the SpA subtypes in HADS-A and HADS-D. HADS-A and HADS-D were associated with lower education, lower physical activity (HADS-D only), chronic pain problems, more fatigue, lower general health, lower HRQoL, lower level of functioning, higher disease activity, and lower self-efficacy. Associations with anxiety and/or depression appear multifactorial in patients with SpA including both personal and disease-related factors. Since these comorbidities are increased in SpA and treatable, they should be screened for in clinical practice, possibly with instruments like the HADS.     

Heterogeneous models for an early discrimination between sepsis and non-infective SIRS in medical ward patients: a pilot study

The objective of the study was to determine the accuracy of phospholipase A2 group II (PLA2-II), interferon-gamma-inducible protein 10 (IP-10), angiopoietin-2 (Ang-2), and procalcitonin (PCT) plasma levels in early ruling in/out of sepsis among systemic inflammatory response syndrome (SIRS) patients. Biomarker levels were determined in 80 SIRS patients during the first 4 h of admission to the medical ward. The final diagnosis of sepsis or non-infective SIRS was issued according to good clinical practice. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for sepsis diagnosis were assessed. The optimal biomarker combinations with clinical variables were investigated by logistic regression and decision tree (CART). PLA2-II, IP-10 and PCT, but not Ang-2, were significantly higher in septic (n = 60) than in non-infective SIRS (n = 20) patients (P ≤ 0.001, 0.027, and 0.002, respectively). PLA2-II PPV and NPV were 88 and 86 %, respectively. The corresponding figures were 100 and 31 % for IP-10, and 93 and 35 % for PCT. Binary logistic regression model had 100 % PPV and NPV, while manual and software-generated CART reached an overall accuracy of 95 and 98 %, respectively, both with 100 % NPV. PLA2-II and IP-10 associated with clinical variables in regression or decision tree heterogeneous models may be valuable biomarkers for sepsis diagnosis in SIRS patients admitted to medical ward (MW). Further studies are needed to introduce them into clinical practice.     

Suppression of Placental Metallothionein 1 and Zinc Transporter 1 mRNA Expressions Contributes to Fetal Heart Malformations Caused by Maternal Zinc Deficiency

Zinc has been implicated to have a protective role against heart malformations during fetal development. Metallothionein 1 (MT-1) and zinc transporter 1 (ZnT-1) are two major metabolic factors that are associated with zinc metabolism. The present work aimed to investigate the association of placental MT-1 and ZnT-1 expressions with fetal heart malformations resulting from maternal zinc deficiency. Sprague–Dawley female rats were randomly divided into five groups of extremely low-zinc, low-zinc, moderately low-zinc, marginally low-zinc and normal zinc (n = 9–12), and were fed diets with controlled zinc content at 1.0 ± 0.3, 8.4 ± 1.8, 15.4 ± 2.8, 22.4 ± 4.1 and 29.4 ± 5.3 [mean ± standard deviation (SD)] mg of zinc/kg, respectively, from day 25 of preconception until day 19 of gestation. The female rats were bred, their fetuses were harvested at day 19 of gestation after killing the dams, and fetal hearts were morphologically examined. Zinc concentration and alkaline phosphatase (ALP) activity in maternal venous blood sera were tested, and MT-1 and ZnT-1 mRNA expressions in the placenta were assayed. Zinc concentrations and ALP activities in the blood were low in all zinc-deficient diet groups in a dose-dependent fashion. The incidences of heart malformations were increased, and the levels of placental MT-1 and ZnT-1 mRNA expressions were decreased in the extremely low-zinc, low-zinc and moderately low-zinc groups compared with the normal zinc group. Specifically, mRNA levels of placental MT-1 or ZnT-1 were significantly decreased and were lower than the specific threshold values in the fetuses with heart malformations but not in the fetuses without heart malformations in all the groups. These data indicate that maternal zinc deficiency resulted in an elevated incidence of fetal heart malformations, which was associated with significant decreases in placental MT-1 and ZnT-1 mRNA expressions to the levels below the threshold values that may be a crucial factor to determine the presence of fetal heart malformations.     

Correlations Between Small Airway Function,Ventilation Distribution,and Functional Exercise Capacity in COPD Patients

Background

Interest in using the nitrogen single-breath washout (N₂SBW) test to measure ventilation inhomogeneity and small airway function in COPD patients has grown in recent years. Our aim was to assess the correlation of the measures obtained by the N₂SBW test and other pulmonary function parameters with the six-minute walk distance (6MWD), the degree of dyspnea score, and health status in COPD patients.

Methods

In this cross-sectional study, 31 patients with COPD were subjected to the N₂SBW test, spirometry, whole-body plethysmography, carbon monoxide diffusing capacity measurement, the six-minute walk test, the modified Medical Research Council (mMRC) scale, and the COPD Assessment Test (CAT).

Results

We found a strong correlation between the 6MWD and the phase III slope of the nitrogen single-breath washout (Phase III slope_N2SBW) (r = ?0.796; p = 0.0001). We found moderate correlations between the 6MWD and the residual volume (RV) (r = ?0.651; p = 0.0001) and RV/total lung capacity (RV/TLC) (r = ?0.600; p = 0.0004). We also found moderate correlations between the CAT score and Phase III slope_N2SBW (r = 0.728; p = 0.0001), RV (r = 0.646; p = 0.0001) and RV/TLC (r = 0.603; p = 0.0003). There was a significant difference between the mMRC grades for the following variables: Phase III slope_N2SBW (p = 0.0001), RV (p = 0.0001), and smoking history (p = 0.008). Multivariate analysis showed that Phase III slope_N2SBW was the only independent predictor of the 6MWD (R ²  = 0.703; p = 0.0001), CAT score (R ²  = 0.586; p = 0.0001), and mMRC scale (relative risk = 1.14; p = 0.0001).

Conclusions

In patients with COPD, our findings suggest that the ventilation inhomogeneity impacts the functional exercise capacity, the degree of dyspnea, and health status.     

Is early postpartum HbA1c an appropriate risk predictor after pregnancy with gestational diabetes mellitus?

Compared to the 2-h oral glucose tolerance test (OGTT), the assessment of HbA1c was proposed as a less time-consuming alternative to detect pathologies in carbohydrate metabolism. This report aims to assess the predictive accuracy of HbA1c to detect alterations in glucose disposition early after gestational diabetes mellitus (GDM) pregnancy. A detailed metabolic characterization was performed in 77 women with previous GDM (pGDM) and 41 controls 3–6 month after delivery: 3-h OGTT, frequently sampled intravenous glucose tolerance test. Follow-up examinations of pGDMs were performed up to 10 years. HbA1c (venous samples, HPLC) was assessed at baseline as well as during the follow-up period (475 patient contacts). Moderate associations were observed between HbA1c and measurements of plasma glucose during the OGTT at the baseline examination: The strongest correlation was found for FPG (r = 0.40, p < 0.001), decreasing after ingestion. No associations were detected between HbA1c and OGTT dynamics of insulin or C-peptide. Moreover, baseline HbA1c showed only modest correlation with insulin sensitivity (r = ?0.25, p = 0.010) and disposition index (r = ?0.26, p = 0.007). A linear model including fasting as well as post-load glucose levels was not improved by HbA1c. However, pGDM females with overt diabetes manifestation during the follow-up period showed more pronounced increasing HbA1c in contrast to females remaining normal glucose tolerant or developing prediabetes. It is suggested that the performance of HbA1c assessed early after delivery is inferior to the OGTT for the detection of early alterations in glucose metabolism. However, an increase in HbA1c levels could be used as an indicator of risk for diabetes manifestation.     

The BRAF mutation is associated with the prognosis in colorectal cancer

Background

Two members of the Ras/Raf signaling pathway, KRAS and B-raf, are suspected to be involved in the stepwise progression of colorectal cancer (CRC) tumorigenesis.

Objective

We compared the KRAS and BRAF mutation status of CRC patients with their clinicopathological characteristics and examined the effect of mutation status on survival rates.

Methods

DNA was extracted from 164 samples, and the mutation statuses of KRAS and BRAF were assessed using peptide PNA clamp real-time PCR method. The presences of mutation were compared with clinicopathological factors and 5-year survival rate.

Results

Among the 164 CRC cases, KRAS mutation as detected in 71 cases (43.3 %), respectively, with no relationship with clinicopathological factors of the patients. On Kaplan–Meier survival analysis, KRAS mutation was not significantly associated with survival (p = 0.971). BRAF mutation was detected in 26 cases (15.9 %) and not associated with clinicopathological factors of the patients. However, the 5-year survival rate of BRAF mutations was significantly decreased (p = 0.02).

Conclusions

The presence of KRAS mutation did not correlate with the various clinicopathological factors of CRC patients or the survival rate. However, the survival rate was reduced in BRAF-mutated CRC patients. Therefore, BRAF mutation could be an important prognostic factor in CRC patients.     

The DJ-1 protein as a candidate biomarker in obstructive sleep apnea syndrome

Background

Oxidative stress has a central role in the pathophysiology of obstructive sleep apnea syndrome (OSAS). The DJ-1 protein functions as a sensor of oxidative stress, acting both as a reactive oxygen species scavenger (ROS) and an antioxidative response regulator. The aim of our study is to determine the serum levels of DJ-1 in OSAS patients and assess possible correlations with their clinical, demographical, and biochemical characteristics.

Methods

The study included 120 subjects from the Sleep Disorder Laboratory of the University Hospital of Thessaly (100 males vs 20 females, mean age 48?±?10, Apnea–Hypopnea Index (AHI) >5 episodes per hour of sleep). Subjects underwent full-night polysomnography (PSG) followed by morning blood sampling. Serum DJ-1 levels were determined via ELISA kits. Statistical analysis was performed using SPSS 19.

Results

The median DJ-1 levels were 56.7 ng/mL (IQR, 34.9–99.3 ng/mL). Statistically significant correlations were detected between DJ-1’s levels and AHI (Spearman’s rho?=?0.189, P?=?0.04), Desaturation Index (DI; Spearman’s rho?=?0.239, P?=?0.012), and serum low-density lipoprotein (LDL) (Spearman’s rho?=??0.205, P?=?0.042).

Conclusions

DJ-1 may be a useful biomarker in OSAS due to its correlations with AHI and DI. The correlation with serum LDL warrants further investigation regarding possible implications in OSAS patients’ cardiovascular comorbidities.     

Internal tandem duplication of the FLT3 gene confers poor overall survival in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based chemotherapy: an International Consortium on Acute Promyelocytic Leukemia study

Activating internal tandem duplication (ITD) mutations in the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD) are associated with poor outcome in acute myeloid leukemia, but their prognostic impact in acute promyelocytic leukemia (APL) remains controversial. Here, we screened for FLT3-ITD mutations in 171 APL patients, treated with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. We identified FLT3-ITD mutations in 35 patients (20 %). FLT3-ITD mutations were associated with higher white blood cell counts (P?P?=?0.0007), higher hemoglobin levels (P?=?0.0004), higher frequency of the microgranular morphology (M3v) subtype (P?=?0.03), and the short PML/RARA (BCR3) isoform (P?FLT3-ITD^positive patients had a lower 3-year overall survival rate (62 %) compared with FLT3-ITD^negative patients (82 %) (P?=?0.006). The prognostic impact of FLT3-ITD on survival was retained in multivariable analysis (hazard ratio: 2.39, 95 % confidence interval [CI] 1.17–4.89; P?=?0.017). Nevertheless, complete remission (P?=?0.07), disease-free survival (P?=?0.24), and the cumulative incidence of relapse (P?=?0.94) rates were not significantly different between groups. We can conclude that FLT3-ITD mutations are associated with several hematologic features in APL, in particular with high white blood cell counts. In addition, FLT3-ITD may independently predict a shorter survival in patients with APL treated with ATRA and anthracycline-based chemotherapy.     

Associations between functional TNFR2 196 M/R polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis

Several studies have examined the effects of tumor necrosis factor receptor (TNFR) 1 +38 A/G and TNFR2 196 M/R polymorphisms on susceptibility to RA and have reported conflicting results. The purpose of this study was to examine whether the TNFR1 +38 A/G and TNFR2 196 M/R polymorphisms are associated with RA susceptibility. We performed a literature search using the Medical Literature Analysis and Retrieval System Online and Embase citation indices, and conducted a meta-analysis to examine the association between the TNFR1 +38 A/G and TNFR2 196 M/R polymorphisms and RA. Our meta-analysis included a total of 13 studies from 11 articles, consisting of 11 studies of the TNFR2 polymorphism (2,092 cases and 1,483 controls), and two studies of the TNFR1 polymorphism (672 cases and 288 controls). The meta-analysis revealed a significant association between the TNFR2 196 RR genotype and RA risk (OR 1.737, 95 % CI 1.275–2.367, P = 4.6 × 10^?5). Stratification by ethnicity indicated an association between the TNFR2 196 RR genotype and RA in Europeans (OR 2.054, 95 % CI 1.305–3.232, P = 0.002), but not in East Asians (OR 1.596, 95 % CI 0.642–3.971, P = 0.314). Analysis using a homozygote contrast model showed the same pattern for the TNFR2 196 RR genotype in a European and East Asian population. However, no association was found between the TNFR1 +36 A/G polymorphism and RA in a European population. Our meta-analysis demonstrated that the functional TNFR2 196 M/R polymorphism is associated with susceptibility to RA in the European population.     

EGFR Mutation Testing Practice in Advanced Non-Small Cell Lung Cancer

Purpose

Testing tumor samples for the presence of a mutation in the epithelial growth factor receptor (EGFR) gene is recommended for advanced non-squamous non-small cell lung cancer (NSCLC) patients. We aimed to collect data about common practice among Medical Oncologists treating lung cancer patients, regarding EGFR mutation testing in advanced NSCLC patients.

Methods

An internet-based survey was conducted among members of the Israeli Society for Clinical Oncology and Radiotherapy involved in the treatment of lung cancer patients.

Results

24 Oncologists participated in the survey. The participants encompass the Oncologists treating most of the lung cancer patients in Israel. 79 % of them use EGFR testing routinely for all advanced NSCLC patients. Opinions were split regarding the preferable biopsy site for EGFR testing material. 60 % of participants recommend waiting for EGFR test results prior to initiation of first-line therapy.

Conclusions

EGFR testing is requested in Israel routinely by most treating Oncologists for all advanced NSCLC patients, regardless of histology. In most cases, systemic treatment is deferred until the results of this test are received.     

Prevalence of obstructive sleep apnea in patients with mucopolysaccharidosis types I,II, and VI in a reference center

Purpose

Mucopolysaccharidosis (MPS) encompasses a group of rare lysosomal storage disorders that are associated with the accumulation of glycosaminoglycans in organs and tissues. Respiratory disorders occur in all MPS types. In these patients, the prevalence of obstructive sleep apnea syndrome (OSAS), which may confer additional morbidity, remains overlooked, and the results of the few existing studies are controversial. The present study aimed to characterize the prevalence of OSAS in patients with MPS types I, II, and VI in a reference center.

Methods

Forty-five patients with MPS (I, n?=?17; II, n?=?16; and VI; n?=?12) in the Centro de Referência em Erros Inatos do Metabolismo, who underwent full-night polysomnography, were enrolled in a retrospective study. Demographic data and clinical history were collected from medical records of the first medical consultation.

Results

The prevalence of OSAS in patients with MPS was 69.8 %. MPS type I patients seemed to be more susceptible to OSA-induced hypoxemia, as indicated by reduced mean SpO₂ levels during both NREM and rapid eye movement sleep as well as during SpO₂ nadir.

Conclusions

Patients with MPS displayed a high prevalence of OSAS, often with moderate to high severity. Together, our results reinforce the need for OSAS screening in all patients with MPS.     

BRCA1 promoter methylation is a marker of better response to platinum–taxane-based therapy in sporadic epithelial ovarian cancer

Background

The aim of the current study was to investigate the role of BRCA1 promoter methylation as predictive factor of response to platinum–taxane-based therapy in sporadic ovarian cancer.

Patients and methods

BRCA1 promoter methylation was analyzed in 42 sporadic epithelial ovarian cancers. The results were validated in a second cohort of 137 ovarian cancer patients.

Results

BRCA1 promoter methylation was observed in 35.7 % of patients in the first group and in 33.6 % in the second group. BRCA1 promoter methylation was associated with significant increase in median progression-free survival (PFS) of ovarian cancer patients receiving adjuvant platinum–taxane-based chemotherapy (P = 0.008). Multivariate analysis revealed that BRCA1 promoter methylation remains a favorable factor in regard to PFS (HR 0.52; 95 % CI 0.32–0.85, P = 0.009) after adjustment for other prognostic factors. Under the patients with recurrent disease, BRCA1 promoter methylation was associated with significant longer median PFS of 18.5 months in comparison with 12.8 months PFS for patients without BRCA1 promoter methylation.

Conclusions

BRCA1 promoter methylation is predictive for better response to platinum–taxane-based therapy in EOC.     

VEGF neutralization can prevent and normalize arteriovenous malformations in an animal model for hereditary hemorrhagic telangiectasia 2

Arteriovenous malformation (AVM) refers to a vascular anomaly where arteries and veins are directly connected through a complex, tangled web of abnormal AV fistulae without a normal capillary network. Hereditary hemorrhagic telangiectasia (HHT) types 1 and 2 arise from heterozygous mutations in endoglin (ENG) and activin receptor-like kinase 1 (ALK1), respectively. HHT patients possess AVMs in various organs, and telangiectases (small AVMs) along the mucocutaneous surface. Understanding why and how AVMs develop is crucial for developing therapies to inhibit the formation, growth, or maintenance of AVMs in HHT patients. Previously, we have shown that secondary factors such as wounding are required for Alk1-deficient vessels to develop skin AVMs. Here, we present evidences that AVMs establish from nascent arteries and veins rather than from remodeling of a preexistent capillary network in the wound-induced skin AVM model. We also show that VEGF can mimic the wound effect on skin AVM formation, and VEGF-neutralizing antibody can prevent skin AVM formation and ameliorate internal bleeding in Alk1-deficient adult mice. With topical applications at different stages of AVM development, we demonstrate that the VEGF blockade can prevent the formation of AVM and cease the progression of AVM development. Taken together, the presented experimental model is an invaluable system for precise molecular mechanism of action of VEGF blockades as well as for preclinical screening of drug candidates for epistaxis and gastrointestinal bleedings.     

Screening with HbA1c identifies only one in two individuals with diagnosis of prediabetes at oral glucose tolerance test: findings in a real-world Caucasian population

Objective

Discordance between HbA1c and OGTT in screening pre-diabetes may occur because of lack of laboratory standardization, distinct underlying pathophysiological processes or different ethnicity. We evaluated HbA1c efficacy for screening OGTT-defined IFG and IGT conditions in a large Caucasian population using the newly revised IFCC protocol.

Research design and methods

A total of 501 consecutive subjects were screened for pre-diabetic conditions with OGTT with 75 g of glucose. Testing for HbA1c, lipid profile and fasting insulin levels was also performed. For detecting differences between continuous variables, ANOVA followed by Tukey’s honestly significant difference (HSD) post hoc test was used. Logistic regression and ROC curve analysis were also performed for assessing HbA1c screening efficacy.

Results

ROC curve analysis showed that optimal HbA1c cut-off for detecting IFG was 5.6 % (sensitivity of 78 % and specificity of 63 %), while for IGT, the optimal cut-off was 5.9 % (sensitivity of 46 % and specificity of 84 %), with AUCs < 0.8. Screening with HbA1c identified 53.4 % of the 193 patients with IFG and/or IGT diagnosed at OGTT. As regards surrogate markers of insulin resistance, we observed a trend towards higher values of HOMA-IR and lower QUICKI values in subjects with IFG than in those with IGT. Patients with pre-diabetes at both tests had similar values of HOMA and QUICKI, compared with those with altered OGTT only.

Conclusions

IFCC-aligned HbA1c assay proved scarcely effective in detecting IFG and/or IGT in a large Caucasian population, identifying only half of the patients with abnormal OGTT. Moreover, adding HbA1c screening to OGTT may be of little benefit in identifying subjects with a worse metabolic profile.     

Endovascular Versus Medical Therapy for Atherosclerotic Renovascular Disease

The diagnosis of renal artery stenosis (RAS) has become increasingly common in part due to greater awareness of ischemic renal disease and increased use of diagnostic techniques. Over 90 % of RAS cases are caused by atherosclerotic renovascular disease (ARVD). Patients with ARVD are at high risk for fatal and nonfatal cardiovascular and renal events. The mortality rate in patients with ARVD is high, especially with other cardiovascular or renal comorbidities. Recent clinical studies have provided substantial evidence concerning medical therapy and endovascular interventional therapeutic approaches for ARVD. Despite previous randomized clinical trials, the optimal therapy for ARVD remained uncertain until the results of the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial were released recently. CORAL demonstrated that optimal medical therapy was equally effective to endovascular therapy in the treatment of ARVD. Clinicians can now practice with more evidence-based medicine to treat ARVD and potentially decrease mortality in patients with ARVD using optimal medical therapy.     

Serum and intestinal fluid immunoglobulins in patients with giardiasis

To test the possibility that a factor predisposing to symptomatic giardiasis in the general population is immunoglobulin deficiency, we measured immunoglobulins in serum and intestinal fluids of 9 giardiasis patients (8 after eradication ofGiardia lamblia) and 12 healthy individuals. The concentrations of IgG, IgA, IgM, and IgE in serum and of IgA and IgM in intestinal fluids from the 2 groups were similar. Intestinal fluid IgG levels were significantly higher (P<0.1), however, in the patients (5.8±6.3 mg/100 ml) than in the control subjects (1.1±1.9 mg/100 ml). This difference was unexplained and is of uncertain biological significance. We conclude that giardiasis in generally healthy individuals is not etiologically related to unsuspected immunoglobulin deficiencies, even thoughG. lamblia infection is known to be very common in grossly immunoglobulin-deficient patients.     

MYC amplification is associated with poor survival in small cell lung cancer: a chromogenic in situ hybridization study

Purpose

Small cell lung cancer (SCLC) is a highly aggressive tumor, and few studies have examined the amplification status of the MYC gene in tumor samples using chromogenic in situ hybridization (CISH). Emerging target treatments associated with MYC status in SCLC necessitates the evaluation of MYC using current methodologies, such as CISH. In this study, we evaluated tissue samples from untreated patients to determine the relation between MYC amplification and clinical and pathological factors, including survival.

Methods

Formalin-fixed paraffin-embedded tumor samples were obtained from 77 patients with SCLC who underwent a diagnostic biopsy for SCLC. The samples were analyzed by CISH using a MYC probe (ZytoDot^® CISH probe). The relationship between cytogenetic analysis, pathologic characteristics and survival time was evaluated using the Chi-square test, Fisher’s test and Mann–Whitney method. A regression model was constructed to exclude any confounding factors.

Results

Of 77 samples, 64.9 % were from bronchi biopsy and the remainder was from the mediastinal, cervical and supraclavicular lymph nodes. The MYC oncogene was amplified in 20 % of the tumors. After the multivariate regression analysis, patients with MYC amplification had a significantly shorter survival time (4.67 weeks) versus patients without MYC amplification (26.15 weeks) (p = 0.02, CI 1.355–10.261).

Conclusion

MYC amplification is a frequent event in SCLC and is related to a short survival time. MYC amplification may be an independent prognostic factor for SCLC. Further studies are required to support this finding and clarify the role of MYC in SCLC tumorigenesis.     

Mutations of EGFR or KRAS and expression of chemotherapy-related genes based on small biopsy samples in stage IIIB and IV inoperable non-small cell lung cancer

Purposes

Epidermal growth factor receptor (EGFR) and KRAS mutations may predict the outcome of targeted drug therapy and also may be associated with the efficacy of chemotherapy in patients with non-small cell lung cancer (NSCLC). This report investigated the relation of EGFR or KRAS mutation and expression of chemotherapy-related genes, including excision repair cross-complementing 1 (ERCC1), thymidylate synthetase (TYMS), ribonucleotide reductase subunit M1 (RRM1) and class III β-tubulin (TUBB3), as a potential explanation for these observations.

Methods

A total of 143 patients with stage IIIB and IV NSCLC from bronchoscopy or percutaneous lung biopsy obtained tumor samples were analyzed concurrently for EGFR or KRAS mutations, and mRNA expression of ERCC1, TYMS, RRM1 and TUBB3. EGFR or KRAS mutations were detected with xTAG liquidchip technology (xTAG-LCT), and mRNA expression levels of four genes were detected by branched DNA-liquidchip technology (bDNA-LCT).

Results

Of 143 patients, 63 tumors were positive for EGFR-activating mutations, and 16 tumors were positive for KRAS mutations. EGFR-activating mutations are more frequent in females, adenocarcinoma and non-smokers patients, and KRAS mutations are more frequent in smoking patients. ERCC1 mRNA levels were significantly associated with histological type and tumor differentiation, whereas TYMS levels were significantly associated with age. NSCLC specimens that harboring EGFR-activating mutations are more likely to express low ERCC1 and high TUBB3 mRNA levels, whereas tumors from patients with NSCLC harboring KRAS mutation are more likely to express high ERCC1 mRNA levels.

Conclusions

Mutations and expression of chemotherapy-related genes may provide a basis for the selection of suitable molecular markers for individual treatment in a population with stage IIIB and IV NSCLC.