Epidermal Growth Factor Receptor Intron-1 Polymorphism Predicts Gefitinib Outcome in Advanced Non-small Cell Lung Cancer

IntroductionEpidermal growth factor receptor (EGFR) gene intron 1 contains a polymorphic single sequence dinucleotide repeat (CA)n whose length has been found to inversely correlate with transcriptional activity. This study was designed to assess the role of (CA)n polymorphism in predicting the outcome of gefitinib treatment in advanced non-small cell lung cancer (NSCLC).MethodsBlood and tumor tissue from 58 patients with advanced NSCLC submitted to gefitinib were collected. EGFR intron 1 gene polymorphism, along with EGFR gene mutation, gene copy number and immunohistochemistry expression were determined. Moreover, a panel of lung cancer cell lines characterized for EGFR intron 1 polymorphism was also studied.ResultsEGFR intron 1 polymorphism showed a statistically significant correlation with the gefitinib response (response rate 25 versus 0%, for patients with a (CA)16 and with a (CA)else genotype, respectively; p = 0.044). Patients with a (CA)16 genotype had a longer survival compared with those with a (CA)else genotype (11.4 versus 4.8 months, respectively; p = 0.037). In addition, cell lines lacking the (CA)16 allele showed a statistically significant higher IC50 compared with cell lines bearing at least one (CA)16 allele (p = 0.003).ConclusionsThis study supports a potential role of EGFR intron 1 polymorphism in predicting the outcome of gefitinib treatment in advanced NSCLC

Association of the Genomic Profile of Medullary Thyroid Carcinoma with Tumor Characteristics and Clinical Outcomes in an International Multicenter Study

Purpose: The prognostic importance of RET and RAS mutations and their relationship to clinicopathologic parameters and outcomes in medullary thyroid carcinoma (MTC) need to be clarified. Experimental Design: A multicenter retrospective cohort study was performed utilizing data from 290 patients with MTC. The molecular profile was determined and associations were examined with clinicopathologic data and outcomes. Results: RET germ line mutations were detected in 40 patients (16.3%). Somatic RET and RAS mutations occurred in 135 (46.9%) and 57 (19.8%) patients, respectively. RETM918T was the most common somatic RET mutation (n = 75). RET somatic mutations were associated with male sex, larger tumor size, advanced American Joint Committee Cancer (AJCC) stage, vascular invasion, and high International Medullary Thyroid Carcinoma Grading System (IMTCGS) grade. When compared with other RET somatic mutations, RETM918T was associated with younger age, AJCC (eighth edition) IV, vascular invasion, extrathyroidal extension, and positive margins. RET somatic or germ line mutations were significantly associated with reduced distant metastasis-free survival on univariate analysis, but there were no significant independent associations on multivariable analysis, after adjusting for tumor grade and stage. There were no significant differences in outcomes between RET somatic and RET germ line mutations, or between RETM918T and other RET mutations. Other recurrent molecular alterations included TP53 (4.2%), ARID2 (2.9%), SETD2 (2.9%), KMT2A (2.9%), and KMT2C (2.9%). Among them, TP53 mutations were associated with decreased overall survival (OS) and disease-specific survival (DSS), independently of tumor grade and AJCC stage. Conclusions: RET somatic mutations were associated with high-grade, aggressive primary tumor characteristics, and decreased distant metastatic-free survival but this relationship was not significant after accounting for tumor grade and disease stage. RETM918T was associated with aggressive primary tumors but was not independently associated with clinical outcomes. TP53 mutation may represent an adverse molecular event associated with decreased OS and DSS in MTC, but its prognostic value needs to be confirmed in future studies

Investigations of Defect Centres in Alkali Halides Doped with Trivalent Cations. Part 1: Bismuth in NaCl, KCl and RbCl Crystals

A correlated set of experiments was performed with a view to study the effect of trivalent bismuth upon some properties of NaCl, KCI and RbCI crystals. For NaCI the effect of BiO$\text{}^{+}$ ions was also investigated. It was stated that: 1. The hydrolytic properties of bismuth are responsible for the formation of BiO$\text{}^{+}$ centres also in crystals doped with BP$\text{}^{3+}$ ions. 2. During all experiments performed, the dopant remains in the form of trivalent cations. 3. Optical absorption spectra of bismuth are similar to those characteristic of other heavy metal ions with the s$\text{}^{2}$ electronic configuration. 4. The charge excess of BP$\text{}^{3+}$ ions is compensated by cation vacancies whereas for BiO$\text{}^{+}$ ions the preferential bonding between Bi$\text{}^{3+}$ and O$\text{}^{2-}$ serves for the charge compensation

Thermally-Induced Depolarization Current Spectra of NaCl:Ni2\text{}^{2}+ Crystals

The technique of thermally stimulated depolarization currents was exploited to search dipolar defects in NaCl crystals doped with divalent nickel in a wide concentration range. The results were critically compared with those typical of other impurities. It has been shown that the main features of the detected polarizations are qualitatively similar to those characteristic of alkali halides doped with divalent cations. The differences observed in some instances can be understood in terms of different mobility and/or stability of the elementary defects related with the impurities

IONIC THERMOCONDUCTIVITY AS A METHOD TO STUDY NUCLEATION OF THE SUZUKI PHASE IN KCl : Pb AND IMPURITY CLUSTERS IN LiF : Be

La versatilité de la technique ITC a été exploitée pour analyser : 1) les cinétiques de nucléation et de croissance d'occlusions d'une phase séparée aux dépends des dipôles lacune-impureté (L. I.) dans KCl : Pb, entre 420-500 K ; 2) la relaxation relative, du type Maxwell-Wagner, qui donne naissance à la grosse bande ITC-B ; 3) la structure des occlusions qui vient tentativement identifiée par la phase de Suzuki ; 4) la taille des occlusions qui paraît être celle d'une baguette ; 5) la grosse bande ITC qu'on observe du côté des hautes températures (T > 273 K) dans la courbe ITC après trempe du LiF : Be dans l'intervalle de température 100 ⩽ Ta ⩽ 700 °C et qui peut être liée à des amas d'impuretés autour des dislocations.The ITC technique versatility has been exploited to analyze : 1) the kinetics of the nucleation and growth of segregated phase occlusions at the expense ofimpurity-vacancy (I. V.) dipoles in KCl : Pb in the annealing température range 420-500 K ; 2) the related Maxwell-Wagner-like relaxation which originates the huge ITC-B band ; 3) the structure of the occlusions, which is tentatively identified as the Suzuki phase ; 4) the shape of the occlusions which turned out to be rod like. 5) the huge ITC band which appears in the high temperature (T > 273 K) side of the ITC plot upon annealing LiF : Be in the température range 100 ⩽ Ta ⩽ 700 °C and which can berelated to impurity clouds surrounding dislocations

Investigations of Defect Centres in Alkali Halides Doped with Trivalent Cations. Part 2: The NaCl:Cr3+\text{}^{3+} Crystals

On the basis of ITC studies, complemented by some spectroscopic and ionic conductivity measurements, it was stated that dielectric relaxations of the NaCl:Cr$\text{}^{3+}$ crystals are more complicated than those typical of AH:Me$\text{}^{2+}$ systems. The complexity of these phenomena concerns the number, shape and positions of the bands appearing in the ITC spectrum. The origin of the main peaks was discussed in terms of relaxations related with the chromium centres; substitutionally and off-center located Cr3$\text{}^{+}$ ions, accompanied by two cation vacancies at geometrically different positions, and Cr clusters distributed around dislocations were considered