International consensus for a dissection room quality system (DRQS): A Delphi panel study.

Dissection Rooms (DRs) are key facilities that allow teaching and research on human anatomy, where students and researchers work with human bodies to acquire, increase, or create new knowledge. Usually, DRs work with a Body Donation Program (BDP), where living donors bequeath their bodies for use in teaching and research after they expire. Despite DRs being part of universities worldwide, no common guidelines, regulations, or quality management systems (QMS) exist that could be applied to different countries. With that purpose in mind, we aimed to develop a QMS that could be applied to DRs globally, using a Delphi panel to achieve consensus about the items that should constitute the QMS. The panel was constituted by 20 anatomy professors from 20 different countries, and the 167 standards to create the rules or guidelines that constitute the QMS were divided in five categories: direction, body donation, students, instructors, and research. After two rounds of revisions, 150 standards were considered "essential" or "important" by more than 70% of the participants, thus being incorporated to the Dissection Room Quality System (DRQS). The results of this panel represent a minimum list of items of the DRQS for improving the functioning of DRs globally.

Embodiment and repeated exposure do not suffice for abstract concepts acquisition: evidence from tonal music cognition.

Research on abstract concepts (AC) suggests that while some AC are enacted indirectly and occasionally, others are largely grounded in our sensory-motor and affective experience, and the opportunities to enact them are countless, which would allow us to acquire them without supervision. From this, the following question arises: do embodiment and repeated exposure suffice to dispense with supervision in abstract concepts acquisition (ACA)? In the present study, this question was addressed in the context of tonal music cognition, which demands a high level of abstraction, and via musical materials that participants had frequently heard and sung. Specifically, highly trained, moderately trained, and untrained participants (24 each) were given 12 well-known melodic fragments ending on tones instantiating 6 different scale degrees (2 times each) and asked to group (round 1) or pair (round 2) those fragments whose last tone conveyed the same (or a similar enough) level of stability or rest. If embodiment and repeated exposure suffice for ACA, then one would expect a scale degree-based grouping strategy regardless of participants' training level. Results showed that only highly trained participants systematically grouped stimuli ending on the same scale degree, particularly in round 2; moderately trained participants' performance was mixed, and tonality's influence on untrained participants was negligible. Further, moderately trained and untrained participants performed inconsistently, discarding in round 2 almost all of the pairs formed in round 1. These findings are integrated with previous findings on the effect of language, affect, and category type on conceptualization to account for why and when ACA requires supervision.

Cirugía endoscópica vs. cirugía abierta en pacientes con neoplasias nasosinusales malignas con invasión cerebral. Estudio de serie de casos / Endoscopic versus open surgery in patients with malignant sinonasal tumors and brain invasion. A case series study

Objetivos: Evaluar la efectividad, la seguridad y los costos perioperatorios del abordaje endonasal endoscópico en pacientes con tumores nasosinusales malignos con invasión cerebral. Pacientes y método: Se realizó un estudio observacional de serie de casos. Se compararon 30 pacientes con tumores nasosinusales malignos e invasión cerebral operados (2015-2017) mediante abordaje endoscópico con una serie histórica de 53 casos operados (2010-2015) mediante cirugía abierta. Se utilizó el método de emparejamiento por puntaje de propensión para controlar el efecto de factores pronósticos. Las variables de respuesta primaria fueron el control local y la supervivencia global a los tres años. Se analizaron variables de costo perioperatorio. Resultados: Después del emparejamiento se identificaron 50 pacientes (25 en cada grupo terapéutico) con edad promedio de 55 años, 62% de sexo masculino. Predominó el carcinoma de células escamosas y la invasión cerebral grado II. El control local de la enfermedad a los tres años, la supervivencia global y libre de progresión fueron superiores en el abordaje endoscópico. El abordaje endoscópico redujo el tiempo quirúrgico en 1 hora y 20 minutos y la estadía hospitalaria en 19 días en comparación con la cirugía abierta. El abordaje endoscópico mejoró la independencia funcional y redujo las complicaciones. El ahorro promedio estimado con el abordaje endoscópico fue de aproximadamente $7.355,18 por paciente. Conclusiones: El abordaje endonasal endoscópico constituye un procedimiento seguro, efectivo y más económico en los pacientes con neoplasias nasosinusales malignas e invasión cerebral (AU)

Objectives: To determine the safety, effectiveness and perioperative costs of endonasal endoscopic approach in brain invasive malignant sinonsal tumors patients. Materials and methods: This was a case series bidirectional study; that included 30 brain invasive malignant sinonsal tumors patients treated by endonasal endoscopic approach (2015-2017) and 53 by open surgery (2010-2015). Propensity score matching was used to compensate the prognostic factors; in a sample of 50 patients (25 per group). Primary response variables was local control and 3-years overall survival. Perioperative cost variables were analyzed. Results: A number of 50 patients were included after matching (25 in each therapeutic group). The age average was 55 years and male proportion was 62%. Squamous cell carcinoma and grade II lesions were the most represented in the sample. Endonasal endoscopic approach reduced surgical time in 1 hour 20 minutes, transfusion needs in 5.5 fold and hospitalization in 19 days; in comparison with open technique. Oncologic control based on surgical free margins, local control, overall survival and progression free survival after three years was higher when the resection was performed endoscopically. Functional status was enhanced and complications diminished by using endoscopic approach. Saving was estimated in $7 355.18 per patient. Conclusions: Endonasal endoscopic approach represents a safe, effective and economic procedure in selected patients with malignant sinonasal tumors and brain invasion (AU)

Global and local sensitivity analysis to improve the understanding of physically-based urban wash-off models from high-resolution laboratory experiments.

Physically-based urban wash-off models are a promising means of studying the transport of finer suspended solids and their associated pollutants during rain events, considering spatial and temporal heterogeneities. This study contributes to the understanding of these models through an in-depth sensitivity analysis to provide the necessary information to simplify the model and deal with parameter identifiability. First, based on twelve tailored high-resolution experiments, the accurate measurement of input variables was used to study the parameters of the Hairsine-Rose sediment transport model through a global sensitivity analysis. Using Standardized Regression Coefficients (SRC) and Extended Fourier Amplitude Sensitivity Test (EFAST) methods, the analysis showed that both the total washed-off mass and the TSS peaks concentration are highly sensitive to the critical mass, which considers the reduction in the detachment of particles when the sediment available decreases and is scattered over the surface. In addition, the rain- and flow-driven detachment parameters were presented as key for smaller and larger sediment particles, respectively. Then, those uncertainties that are associated in field studies with the determination of the model input variables were also considered by conducting a local sensitivity analysis. The initial load of sediment and the mean grain size were seen to be the most important variables, thus underlining the need for very accurate measurements here. Moreover, a precise definition of Harsine-Rose parameters is also necessary to achieve reliable results in order to work on treatment and management techniques to minimize the impact of urban surface contaminants on urban environments.

Prediction of the presence of esophageal varices using spleen stiffness measurement by transient elastography in cirrhotic patients.

BACKGROUND AND STUDY AIMS: Upper gastrointestinal endoscopy (UGE) is currently recommended in cirrhotic patients to detect the presence of esophageal varices (EV). Spleen stiffness measurement (SSM) with FibroScan has been used for this purpose, showing variable sensitivity (S) and specificity (Sp). The aim of this study was to evaluate the capability of SSM to detect the presence and size of EV in cirrhotic patients in comparison to other noninvasive modalities. PATIENTS AND METHODS: Sixty-six patients with cirrhosis who had undergone UGE in the previous 6 months underwent SSM and liver stiffness measurement (LSM) using FibroScan. Biochemical parameters and ultrasonography data were also collected to calculate other noninvasive indexes. RESULTS: Valid spleen stiffness measurements were obtained for 60 of the 66 patients initially included in the study (90.1%). In the multivariate analysis only splenomegaly and SSM were predictive of esophageal varices. SSM was the most accurate diagnostic tool, obtaining an area under the ROC curve of 0.8 for values below 48 KPascals, with S = 87%, Sp = 69%, and 76.7% of successfully diagnosed patients. CONCLUSIONS: SSM with FibroScan was significantly higher for cirrhotic patients with EV. Our study suggests that spleen stiffness may be useful to identify cirrhotic patients at risk of having EV, although further studies are needed.

Micelle Formation in Aqueous Solutions of Room Temperature Ionic Liquids: A Molecular Dynamics Study.

1-Alkyl-3-methylimidazolium cations in the presence of water are used as a test system to study by molecular dynamics the formation of micelles in aqueous mixtures of highly anisotropic room temperature ionic liquids (IL). Structural properties, i.e., radial distribution functions (RDF) and transport parameters, such as diffusion coefficients and conductivities, are computed as a function of the IL/water mole fraction. The concentration plots reveal a sharp change of the slope of both the cation self-diffusion coefficient and the first peak of the head-head RDF at approximately the same value of the concentration. This transition, considered as a measure of a critical micellar concentration, appears only for the most anisotropic systems, composed of longer alkyl chains. The formation of the micelles is confirmed from the analysis of the tail-tail and cation-water RDFs. As a general result, we found that the larger the anisotropy of the ionic liquid the lower the critical concentration and the larger the proportion of monomers forming part of the micelles. The molecular dynamics predictions are in line with the experimental evidence reported for these systems.

Evaluation of the efficacy of therapeutic endoscopy in gastrointestinal bleeding secondary to angiodysplasias. / Evaluación de la eficacia terapéutica endoscópica en hemorragia digestiva secundaria a angiodisplasias.

INTRODUCTION: Gastrointestinal angiodysplasias are defined as vascular dilations that communicate capillaries and veins in the walls of the digestive tract. The clinical presentation of these lesions varies from chronic occult bleeding to severe gastrointestinal hemorrhage. AIM: The primary aim of our study was to analyze lesion location, the efficacy of therapeutic endoscopy with argon plasma coagulation, and the factors associated with rebleeding in patients with gastrointestinal angiodysplasias. MATERIAL AND METHODS: A retrospective study of 32,042 endoscopies was carried out within the time frame of January 2012 and December 2013 at our hospital center. Gastrointestinal angiodysplasia was the diagnosis in 331 of the endoscopies. The procedures included upper gastrointestinal endoscopy, colonoscopy, sigmoidoscopy, and enteroscopy. RESULTS: The most frequent location of the angiodysplasias was the cecum (49%), followed by the ascending colon (17%) and the sigmoid colon (16%). They were most frequently found in the duodenum (60%) and gastric body (49%) at upper gastrointestinal endoscopy. Therapeutic endoscopy was performed in 163 cases (49.8%) and the most predominant methods were fulguration with argon (90%) and combination treatment (argon plasma coagulation and injection sclerotherapy) (6.7%). The macroscopic rebleeding rate after therapeutic endoscopy was 7.4%. Patients that had rebleeding presented with a lower hemoglobin concentration, higher mean age, and the presence of multiple angiodysplasias at endoscopy (P<.05). CONCLUSIONS: Therapeutic endoscopy was performed in 49.8% of the patients with angiodysplasias. The macroscopic rebleeding rate after treatment was 7.4%. There were statistically significant differences in the patients with rebleeding in relation to mean age, hemoglobin values, and the presence of multiple angiodysplasias.

The interaction between hybrid organic-inorganic halide perovskite and selective contacts in perovskite solar cells: an infrared spectroscopy study.

The interaction of hybrid organic-inorganic halide perovskite and selective contacts is crucial to get efficient, stable and hysteresis-free perovskite-based solar cells. In this report, we analyze the vibrational properties of methylammonium lead halide perovskites deposited on different substrates by infrared absorption (IR) measurements (4000-500 cm(-1)). The materials employed as substrates are not only characterized by different chemical natures (TiO2, ZnO and Al2O3), but also by different morphologies. For all of them, we have investigated the influence of these substrate properties on perovskite formation and its degradation by humidity. The effect of selective-hole contact (Spiro-OmeTad and P3HT) layers on the degradation rate by moisture has also been studied. Our IR results reveal the existence of a strong interaction between perovskite and all ZnO materials considered, evidenced by a shift of the peaks related to the N-H vibrational modes. The interaction even induces a morphological change in ZnO nanoparticles after perovskite deposition, pointing to an acid-base reaction that takes place through the NH3(+) groups of the methylammonium cation. Our IR and X-ray diffraction results also indicate that this specific interaction favors perovskite decomposition and PbI2 formation for ZnO/perovskite films subjected to humid conditions. Although no interaction is observed for TiO2, Al2O3, and the hole selective contact, the morphology and chemical nature of both contacts appear to play an important role in the rate of degradation upon exposure to moisture.

Correction: The effect of recombination under short-circuit conditions on the determination of charge transport properties in nanostructured photoelectrodes.

Correction for 'The effect of recombination under short-circuit conditions on the determination of charge transport properties in nanostructured photoelectrodes' by J. Villanueva-Cab et al., Phys. Chem. Chem. Phys., 2016, 18, 2303-2308.

The effect of recombination under short-circuit conditions on the determination of charge transport properties in nanostructured photoelectrodes.

We report on the commonly unaccounted for process of recombination under short-circuit conditions in nanostructured photoelectrodes with special attention to the charge collection efficiency. It is observed that when recombination under short circuit conditions is significant, small perturbation methods overestimate the charge-collection efficiency, which is related to the inaccurate determination of the electron diffusion coefficient and diffusion length.

Effective electrostatic interactions arising in core-shell charged microgel suspensions with added salt.

The mixture formed by charged (ionic) microgels in the presence of 1:1 added salt, with explicit consideration of a core-shell structure of the microgel particles, is studied. By solving numerically the three-component Ornstein-Zernike integral equations, the counter- and coion penetration inside the microgel network and the resulting effective microgel-microgel electrostatic interaction are calculated. This is done in the limit of very low microgel concentration, so that the resulting pair-wise effective potential is not affected by many-body particle-particle interactions. The ion-ion, microgel-ion, and microgel-microgel correlations are all treated within the Hypernetted-Chain approximation. The results obtained clearly show that the addition of salt to the microgel suspension has a deep impact on the screening of the bare charge of the particles, confirming an already well-known result: the strong reduction of the effective charge of the microgel occurring even for diluted electrolyte concentrations. We show that this effect becomes more important as we increase the shell size of the particle and derive a semi-empirical model for the effective charge as a function of the electrolyte concentration and the shell extension. The resulting microgel-microgel effective pair potential is analysed as a function of the shell extension and salt concentration. In all cases the interaction is a soft potential when particles overlap. For non-overlapping distances, our theoretical results indicate that microgel particles can be regarded as hard spherical colloids bearing an effective charge given by the net charge inside the particle and the microgel-microgel interaction shows a Yukawa-like behaviour as a function of the interparticle distance. It is also observed that increasing the bare-charge of the microgel induces a strong microgel-counterion coupling in the limit of very low electrolyte concentrations, which cannot be justified using linearized theories. This leads to an even more important adsorption of counterions inside the microgel network and to a reduction of the microgel-microgel effective repulsion.

ZnO-based dye solar cell with pure ionic-liquid electrolyte and organic sensitizer: the relevance of the dye­oxide interaction in an ionic-liquid medium.

The use of non-volatile electrolytes and fully organic dyes are key issues in the development of stable dye-sensitized solar cells (DSCs). In this work we explore the performance of ZnO-based DSCs sensitized with an indoline derivative coded D149 in the presence of a pure ionic-liquid electrolyte. Commercial nanostructured zinc oxide and an electrolyte composed of iodine plus (1) pure 1-propyl-3-methyl imidazolium iodide (PMII) and (2) a blend of PMII with low-viscosity ionic liquids were employed to construct the devices. Without further additives, the fabricated devices exhibit remarkable short-circuit photocurrents and efficiencies under AM1.5 simulated sunlight (up to 10.6 mA cm−2, 2.9% efficiency, 1 sun, active area = 0.64 cm2) due to the high surface area of the ZnO film and the high absorptivity of the D149 dye. Impedance spectroscopy is used to characterize the devices. It is found that the addition of the low-viscosity ionic-liquid improves the transport features (leading to a better photocurrent) but it does not alter the recombination rate. The robustness of the dye­oxide interaction is tested by applying continuous illumination with a Xenon-lamp. It is observed that the photocurrent is reduced at a slow rate due to desorption of the D149 sensitizer in the presence of the ionic liquid. Exploration of alternative ionic-liquid compositions or modification of the ZnO surface is therefore required to make stable devices based on ZnO and fully organic dyes.

Management of chylous fistula as a complication of neck dissection: a 10-year retrospective review.

Chylous fistula is a serious complication of neck surgery. The aim of this study was to analyse the incidence, treatment and evolution of chylous fistula in neck dissection. We conducted a retrospective study of 304 patients, 295 (97.03%) men and nine (2.97%) women. Ages ranged from 24 to 80 years (mean = 59.28 years, SD = 6.02) and they had all undergone neck dissection. Chylous fistula occurred in four cases (1.31%). Incidence was 1.83% in laryngeal cancer and 2.7% in oral cavity and oropharyngeal cancer. No statistically significant correlation was found between tumoral stage and fistula occurrence. Radiotherapy prior to surgery was a risk factor although the association was not statistically significant. The incidence rates for radical and functional neck dissection were 3.3% and 0.46%, respectively, statistically significant (P = 0.042). The fistulas were located on the left side in all cases. One of the four patients required surgical intervention and another one died. The occurrence of chylous fistula increased significantly the length of hospital stay (P = 0.01). Chylous fistulas appear on the left side, radiotherapy prior to surgery is a risk factor and there is not correlation with tumoral stage. Chylous fistulas are significantly more common in radical than in functional dissections and increase significantly the length of hospital stay.

Visual inspection in oral cancer screening in Cuba: a case-control study.

A case-control study was conducted to evaluate the efficacy of an on-going oral cancer screening programme in Cuba in preventing advanced oral cancer in Cuba. The cases for the study consisted of 200 oral cancer patients with stage III and IV disease. Three apparently healthy subjects per case, matched for sex, age (plus or minus 5 years) and residing within a perimeter of 200 m of the house with the case, and willing to be interviewed, were recruited as the controls. Information on socio-economic indicators, smoking, drinking, diet and screening history in the form of visits to the dentist were collected by personal interview with the subjects. Odds ratio (OR), with 95% confidence intervals (CI), of being diagnosed with an advanced oral cancer, in relation to the screening experience at the date of diagnosis of case, 1, 2, 3, 6, and 12 months prior to the date of diagnosis of case were estimated by conditional logistic regression for matched data. The odds ratio of advanced oral cancer associated with screening in relation to screening experience 3 months prior to the diagnosis of the case was 0.67 (95% CI: 0.46-0.95). The odds ratio was 0.91 (95% CI: 0.60-1.37) for a single screening test and 0.41 (95% CI: 0.24-0.68) for two or more tests. The protection offered by screening persisted up to 3 years since the last test. The results of a descriptive evaluation of the programme also revealed limited evidence towards a shift from advanced to early stages after the introduction of the programme. Nonetheless, the results should be interpreted with caution in view of the several limitations in the study, particularly the fact that screening history was established indirectly by interviews and advanced oral cancers constituted the cases, rather than those who died from the disease.

Risk factors for cancer of the oral cavity and oro-pharynx in Cuba.

In terms of worldwide levels, Cuba has an intermediate incidence of cancer of the oral cavity and oro-pharynx. We studied 200 cases of cancer of the oral cavity and pharynx, of whom 57 women (median age = 64) and 200 hospital controls, frequency matched with cases by age and sex, in relation to smoking and drinking history, intake of 25 foods or food groups, indicators of oral hygiene and sexual activity, and history of sexually transmitted diseases. Odds ratios (OR) and 95% confidence intervals (CI) were obtained from unconditional multiple logistic regressions and adjusted for age, sex, area of residence, education, and smoking and drinking habits. In the multivariate model, high educational level and white-collar occupation, but not white race, were associated with halving of oral cancer risk. Smoking > or =30 cigarettes per day showed an OR of 20.8 (95% CI: 8.9-48.3), similar to smoking > or =4 cigars daily (OR = 20.5). Drinking > or = 70 alcoholic drinks per week showed an OR of 5.7 (95% CI: 1.8-18.5). Hard liquors were by far the largest source of alcohol. Increased risk was associated with the highest tertile of intake for maize (OR = 1.9), meat (OR = 2.2) and ham and salami (OR = 2.0), whereas high fruit intake was associated with significantly decreased risk (OR = 0.4). Among indicators of dental care, number of missing teeth and poor general oral condition at oral inspection showed ORs of 2.7 and 2.6, respectively. Number of sexual partners, marriages or contacts with prostitutes, practice of oral sex and history of various sexually transmitted diseases, including genital warts, were not associated with oral cancer risk. 82% of oral cancer cases in Cuba were attributable to tobacco smoking, 19% to smoking cigars or pipe only. The fractions attributable to alcohol drinking (7%) and low fruit intake (11%) were more modest. Thus, decreases in cigarette and cigar smoking are at present the key to oral cancer prevention in Cuba.

k-FGF protoncogene expression is associated with murine testicular teratogenesis, but is not involved during mouse testicular development.

The k-FGF gene, which belongs to the family of the fibroblast growth factor genes, is implicated in tumoral and developmental processes. It is expressed in embryonal carcinoma cells, in embryonic stem cells, during limb and tooth formation and in some germ cell tumors. However, the expression of this protooncogene during testicular development as well its relationship to spontaneous teratogenesis have not been determined. Here we investigate k-FGF expression during testicular development in mice, as well as in a spontaneous testicular teratoma (STT) and in the OTT6050 teratocarcinoma (TC) by Northern blotting, RT-PCR and it situ hybridization. Several data indicate that k-FGF gene contains downstream regulatory sequences which bind octamer factors. One of these transcription factors which binds to k-FGF enhancer is Oct-4. Although the k-FGF gene is activated by Oct-4 in embryonal carcinoma and embryonic stem cells and Oct-4 is expressed in the germ cells of the embryo, our results indicate that there is no detectable k-FGF expression in mouse testicular germ cells at any stage of development. This indicates that Oct-4 does not activate transcription of the k-FGF gene in mouse germ cells, and that k-FGF is not implicated during testicular development. We also show that there is a high k-FGF expression in the experimental OTT6050 TC, but only very low levels in a murine differentiated STT, suggesting that k-FGF activation may be responsible for the genesis and development of STT, behaving as a marker of malignancy in these neoplasms.

Prognostic value of replication errors on chromosomes 2p and 3p in non-small-cell lung cancer.

As chromosomes 2p and 3p are frequent targets for genomic instability in lung cancer, we have addressed whether alterations of simple (CA)n DNA repeats occur in non-small-cell lung cancer (NSCLC) at early stages. We have analysed by polymerase chain reaction (PCR) assay replication errors (RER) and loss of heterozygosity (LOH) at microsatellites mapped on chromosomes 2p and 3p in 64 paired tumour-normal DNA samples from consecutively resected stage I, II or IIIA NSCLC. DNA samples were also examined for K-ras and p53 gene mutations by PCR-single-stranded conformational polymorphism (PCR-SSCP) analysis and cyclic sequencing, as well as their relationship with clinical outcome. Forty-two of the 64 (66%) NSCLC patients showed RER at single or multiple loci. LOH was detected in 23 tumours (36%). Among patients with stage I disease, the 5-year survival rate was 80% in those whose tumours had no evidence of RER and 26% in those with RER (P = 0.005). No correlation was established between RER phenotype and LOH, K-ras or p53 mutations. RER remained a strong predictive factor (hazard ratio for death, 2.89; 95% confidence interval, 2.23-3.79; P = 0.002) after adjustment for all other evaluated factors, including p53, K-ras, LOH, histological type, tumour differentiation and TNM stage, suggesting that microsatellite instability on chromosomes 2p and 3p may play a role in NSCLC progression through a different pathway from the traditional tumour mechanisms of oncogene activation and/or tumour-suppressor gene inactivation.

TP53 mutational pattern in Spanish and Polish non-small cell lung cancer patients: null mutations are associated with poor prognosis.

Inactivation of TP53 tumor suppressor gene is the most frequent molecular alteration in NSCLC, involving up to 60% of cases. Furthermore, TP53 mutational spectrum is related to the type of mutagen exposure, as well as racial and/or diet differences. Nearly 95% of TP53 perturbations affect codons included within exons 5-8 which encode for almost the entire DNA-binding domain. In this study we addressed the possible prognostic value of the molecular alterations identified in exons 5-8 of the TP53 gene in DNAs from 151 paraffin-embedded NSCLC sections corresponding to 59 Spanish and 92 Polish stage I-IIIA resected patients. PCR/single-strand conformation polymorphism (SSCP) analysis revealed that the occurrence of TP53 exon 5-8 mutations was 17/59 (29%) in the Spanish cohort and 17/92 (18%) in the Polish group. However, when DNA sequencing analysis was performed, these frequencies were reduced because of the presence of SSCP-false positive, intronic and silent mutations and polymorphisms. Fifteen of the 59 Spanish NSCLC tumors (25%) harbored TP53 mutations affecting exons 5-8 coding sequences, whereas only 12 of 92 Polish neoplasms (13%) contained alterations in the central hydrophobic region of p53. Our results indicate that the occurrence of TP53 mutations affecting exon 5-8 coding sequences in some European NSCLC populations may be lower than previously reported, and that the TP53 mutational patterns of these cohorts differ somewhat. The Spanish NSCLC patients contained missense mutations (9/59, 15%) and a relatively high percentage of null mutations (5/59, 8%) while the Polish patients mostly harbored missense mutations (9/92, 10%) and only one tumor contained a null type (1/92, 1%). Moreover, most TP53 missense mutations in the Spanish group were located outside the conserved regions, whereas the same mutations in the Polish group affected conserved amino acids. Furthermore, the Polish patients harbored a high percentage of G-->A transitions (most of them at non-CpG sites), while G-->T transversions were predominant in the Spanish group. Our findings suggest that there may be different racial or exogenous factors in these two populations which may help to explain both the distinct TP53 mutational pattern and the lower frequency obtained in the Polish group. The presence of missense mutations did not confer a worse clinical outcome in these subsets of NSCLC patients. However, patients whose tumors contained null TP53 gene mutations had a 5 month median disease-free survival time in contrast with 42 months in those patients without mutations (P=0.008). These findings suggest that loss of p53 function may enhance tumor progression in NSCLC patients independently of whether dominant negative TP53 missense mutations are present.

Molecular staging of non-small cell lung cancer according to K-ras genotypes.

We have previously demonstrated a strong association between K-ras gene mutations, as determined by PCR followed by allele-specific oligonucleotide hybridization (ASO-h), and survival in non-small cell lung cancer patients. The purpose of this study was to determine the relationship between tumor aggressiveness and specific-type K-ras point mutations in non-small cell lung cancer. We developed procedures to examine the status of the K-ras gene by ASO-h and by single-strand conformation polymorphism assay of DNA obtained from formalin-fixed paraffin-embedded tumors. K-ras point mutations at codons 12 and 61 were assessed in 275 consecutively treated stage I-IV non-small cell lung cancers. Among patients with stage I disease, median survival time was 41.5 months in those whose tumors had no evidence of K-ras mutations and 27 months in those with K-ras 12 mutations; among patients with stage IIIA disease, median survival time was 7 months in those with K-ras codon 12 aspartic and serine mutations and 15 months for those with other K-ras mutations (P = 0.01). In a multivariate analysis, specific-type K-ras codon 12 point mutation remained a strong predictive factor (hazard ratio for death, 2.06; 95% confidence interval, 1.11-3.81; P = 0.02) after adjustment for other evaluated factors, including TNM stage and histology. Thus, we concluded that in patients with non-small cell lung cancer, specific K-ras 12 point mutations detected by DNA amplification and either ASO-h or single-strand conformation polymorphism methods predicted a significantly increased risk of recurrence and death, independently of stage and histology.