Monitorización farmacocinética de terapias biológicas en enfermedad inflamatoria intestinal / Pharmacokinetic monitoring of biological therapies in inflammatory bowel disease

Objective: To analyze the activity developed by a multidisciplinary team of pharmacists, digestive specialists and clinical analysts for the therapeutic drug monitoring (TDM) of anti-TNFa therapies in inflammatory bowel disease (IBD).Methods: A prospective observational study (January-December 2019) was conducted of referrals from digestive specialists to the Clinical Pharmacokinetics Unit (CPU) of our general hospital for the TDM of anti-TNFa drugs (infliximab/adalimumab) in adults with IBD. Serum anti-TNFa concentrations were quantified in our Clinical Analysis Laboratory using lateral flow chromatography. When concentrations were undetectable, the presence of anti-drug antibodies (ADAs) was analyzed.CPU recommendations were based on the correct interpretation of anti-TNFa concentrations, therapeutic algorithms, and populational pharmacokinetic models implemented using MW-Pharm++® software. Results: Referrals were received for 84 patients (81.0% with Crohn’s disease, 8.3% with ADAs) treated with infliximab (46.4%) or adalimumab (53.6%); 64.3% were also treated with concomitant immunomodulators (IMMs). Sixty-three referrals (75.0%) were for proactive monitoring (treatment optimization) and the remainder for reactive monitoring after therapeutic failure. Anti-TNFa concentrations were subtherapeutic in 36.9% of patients, therapeutic in 39.3%, and supratherapeutic in 23.8%. Subtherapeutic/undetectable concentrations were significantly more frequent (p≤0.004) in patients treated with infliximab versus adalimumab (64.1% vs.. 13.3%) and in concomitant IMM non-adherents versus adherents (85.7% vs. 25.5%). Conclusions: Anti-TNFa TDM is frequently proactive in patients with IBD. The wide variability in anti-TNFa concentrations is in part explained by the type of anti-TNFa drug and adherence to IMM. (AU)

Objetivo: Analizar la actividad desarrollada por un equipo multidisciplinar formado por farmacéuticos, digestólogos y analistas clínicos para la monitorización farmacocinética (TDM) de terapias anti-TNFa en la enfermedad inflamatoria intestinal (EII).Métodos: Estudio observacional prospectivo (enero–diciembre 2019) de las interconsultas de TDM de anti-TNFa (infliximab/adalimumab) en pacientes adultos con EII, solicitadas por digestólogos a la Unidad de Farmacocinética Clínica (UFC) del Servicio de Farmacia de un hospital general. Las concentraciones séricas (Cs) de anti-TNFa fueron cuantificadas en el Laboratorio de Análisis Clínicos mediante cromatografía de flujo lateral. Cuando las Cs fueron indetectables, se analizó la presencia de anticuerpos anti-fármaco (AAF).La UFC realizó recomendaciones en base a la correcta interpretación de las Cs de anti-TNFa, algoritmos terapéuticos y modelos farmacocinéticos poblacionales implementados en el programa informático de ajuste bayesiano MW-Pharm++®. Resultados: Se solicitaron interconsultas para 84 pacientes (81,0% enfermedad de Crohn, 8,3% AAF positivos) con infliximab (46,4%) ó adalimumab (53,6%). 64,3% recibía otros inmunomoduladores (IMM) concomitantes. 63 interconsultas (75,0%) se relacionaron con monitorización ‘pro-activa’ (optimizar tratamiento); el resto fueron ‘re-activas’ a fallo terapéutico. Se observaron Cs de anti-TNFa subterapéuticas en 36,9% de pacientes, terapéuticas en 39,3% y supraterapéuticas en 23,8%. Las Cs subterapéuticas/indetectables fueron significativamente (p≤0,004) más frecuentes en pacientes tratados con infliximab versus adalimumab (64,1% vs. 13,3%); y en ‘no-adherentes’ versus ‘sí-adherentes’ al IMM concomitante (85,7% vs. 25,5%). Conclusiones: En estos pacientes, la TDM de anti-TNFa es frecuentemente ‘pro-activa’. Existe gran variabilidad en las Cs de anti-TNFa, explicada en parte por el fármaco anti-TNFa y la adherencia al IMM. (AU)

Relationship between prenatal and postnatal conditions and accelerated postnatal growth. Impact on the rigidity of the arterial wall and obesity in childhood.

Restricted growth in utero and accelerated postnatal growth (APG) in the postnatal period have been associated with the development of overweight, obesity and an increased cardiovascular risk in childhood. The objectives of this study were to evaluate the influence of prenatal and perinatal conditions on APG and to evaluate the influence of this APG on different cardiovascular risk factors such as body mass index (BMI), body fat mass index (FMI), blood pressure (BP) and arterial wall stiffness [carotid to femoral pulse wave velocity (cf-PWV)]. All measurements were performed in 355 children (185 boys and 170 girls; 8-11 years). Data on mother weight before and during pregnancy, gestational age (weeks), birth weight (g) and breastfeeding of children were obtained through interviews with families. Children who presented APG were born of mothers with lower BMIs before pregnancy and who gained less weight during the second trimester of pregnancy. They also have a lower gestational age and birth weight, a shorter duration of breastfeeding and a longer duration of artificial feeding (AF). Later in childhood, they had higher values of cf-PWV, BMI, FMI and higher prevalence of hypertension. Low maternal gestational weight gain, inadequate fetal development (low birth weight, shorter gestational age) and reduced breastfeeding duration favor APG. Infants with such APG had higher values of cf-PWV, BP, BMI and FMI later in childhood, along with a higher risk of hypertension and obesity. The interaction between APG and a longer duration of AF had a negative effect on cf-PWV (arterial stiffness) and FMI.

Anorectal malformations: definitive surgery during adulthood.

BACKGROUND: Anorectal malformations (ARMs) are rarely seen in adults, since majority of cases are corrected in infancy or childhood. The aim of this study was to describe the profile of patients who underwent definitive surgery to correct their ARM in adulthood, and to discuss the outcomes of surgery (morbidity, mortality, and function). METHODS: This retrospective study included patients 18 years old and above, managed surgically by the Division of Colorectal Surgery at the Philippine General Hospital, University of the Philippines, Manila, from January 1, 2004, to December 31, 2012. Data from the Integrated Surgical Information System and the patients' hospital records were used to fill out a Data Collection Form. Frequencies and percentages were then computed. RESULTS: Eight patients were included in the study. The most common reason for consult was recurrent urinary tract infection (UTI, 25%). One patient had an imperforate anus (IA) without a fistula, and 1 patient had IA with rectal atresia, and the 6 had an IA with a fistula. All but one (87.5%) of the patients had undergone a prior diversion in infancy or childhood. Definitive surgical procedures included posterior sagittal anorectoplasty (PSARP) in 3 patients, anal transposition in 2 patients, laparotomy with colocutaneous anastomosis in two patients, and laparotomy and PSARP in 1 patient. There were 3 cases (37.5%) of postoperative complications. These complications included ureteral injury, enterocutaneous fistula, anal stricture, rectal stricture, rectovesical fistula, and recurrent rectourethral fistula. There was no reported mortality. Five patients already had their stomas reversed at the time of this writing. CONCLUSION: Our results showed that the rarity of the disease, limited surgical experience, and a technically challenging anatomy make the management of ARMs that persist into adulthood a formidable undertaking.

The erosion of the beaches on the coast of Alicante: Study of the mechanisms of weathering by accelerated laboratory tests.

One of the main problems that coasts around the world present, is the regression and erosion of beaches. However, the factors involved in these processes are unclear. In this study, the influence of sediment erosion on beach regression has been analysed. In order to do that, a three-step investigation has been carried out. Firstly, coastline variations of four Spanish beaches have been analysed. Secondly, a study on sediment position along the beach profile has been developed. Finally, the process that beach sediments undergo along the surf zone when they are hit by the incident waves has been simulated by an accelerated particle weathering test. Samples of sand and shells were subjected to this accelerated particle weathering test. Results were supplemented with those from carbonate content test, XRD, SEM and granulometric analysis. Results shows a cross-shore classification of sediments along the beach profile in which finer particles move beyond offshore limit. Besides, it was observed that sediment erosion process is divided into three sages: i) particles wear due to crashes ii) dissolution of the carbonate fraction, and iii) breakage and separation of mineral and carbonate parts of particles. All these processes lead to a reduction of particle size. The mechanism responsible of beach erosion would consist of multiples and continuous particle location exchanges along the beach profile as a consequence of grain-size decrease due to erosion.

The impacts of Segura River (Spain) channelization on the coastal seabed.

Human actions over rivers and coasts have generated great changes along seaboard. In order to know future development of those changes, it is necessary to understand the development of the coast during the past. When there is a complex morphologic system as a result of the combination of natural elements with human construction elements, the study of the abovementioned changes requires a wider perspective than the one provided by traditional two-dimensional methods. Thus, the Geographic Information Systems (GIS) become a suitable tool for that kind of studies. In this work, GIS are used to understand changes in bathymetry, sediments properties and transport, as well as surface variations of plant species occurred in the Segura River mouth (Spain) within a period of 17 years due to the channelization of the river low course. The methodology followed here implies the integration of data coming from different sources and with different formats in a GIS, what allows for a spatial analysis. Results obtained show the grain-size spatial distribution for every period of time studied, as well as bathymetry changes and seabed morphology. It can be concluded that the construction works carried out in the riverbed have affected sediment grain-size in the area. Clays have nearly disappeared and consequently there is a descent of seabed level that affects plant species, such as Posidonia oceanica.

A randomized controlled clinical trial comparing the outcomes of circumferential subcuticular wound approximation (CSWA) with conventional wound closure after stoma reversal.

BACKGROUND: The creation of a stoma is commonplace in colorectal surgery. Circumferential subcuticular wound approximation (CSWA) is a method of wound closure following stoma reversal that has been reported to result in decreased wound infection rates and more desirable aesthetic outcomes. The aim of the present study was to determine the effectiveness of the CSWA method, in terms of wound infection and cosmesis by comparing the technique to the conventional method of wound closure. METHODS: All adult patients who presented for stoma reversal at the outpatient clinic of the Division of Colorectal Surgery at the Philippine General Hospital were randomized into two groups, CSWA and conventional. Patients were followed up for up to 30 days postoperatively, photographic documentation of wound appearance was obtained, and wound infections and complications were documented. Patients were asked to complete a satisfaction survey at the end of the follow-up period. RESULTS: A total of 121 patients were included in the study. One (1.6%) patient in the CSWA group developed wound infection, while six (10%) patients in the conventional group had a wound infection (p = 0.061). The CSWA group had a higher total satisfaction score than the conventional group (25 and 24, respectively, p = 0.012). CONCLUSIONS: With regard to wound infection rates, the CSWA method was better than the conventional method, although this was found to be borderline significant. With regard to patient satisfaction, the CSWA method proved to be superior to the conventional method, and this was found to be statistically significant. In addition, the technique is applicable to all forms of stoma regardless of the bowel segment involved, trephine size, and indication for diversion.

Evolution of fungal populations in corn silage conserved under polyethylene or biodegradable films.

AIMS: To identify cultivable filamentous fungi before ensiling, after silage conservation, in farm-silos covered with two different plastic films (polyethylene (PE) vs biodegradable (MB)), as well as after aerobic exposure of whole-crop corn silage. METHODS AND RESULTS: Molecular techniques coupled with traditional microbial counting were utilized to identify the predominant fungal species. The cultivable fungal population changed remarkably from harvesting to silo opening. Anaerobiosis and low pH reduced mould count and the presence of Fusarium species both under PE and MB film. However, in the peripheral areas of the silo, where air penetration could not be completely prevented, the fungal population did not decrease. The predominant fungal species after aerobic exposure of silage was Aspergillus fumigatus, without differences between the two plastic films. CONCLUSIONS: Maintenance of anaerobiosis and a low pH also in the upper layer of the silo reduce the risk of mould growth during corn silage feed-out. SIGNIFICANCE AND IMPACT OF THE STUDY: Even if the new MB plastic film did not completely maintain the anaerobiosis in the upper layer of silage, the overall silage quality was not compromised and was similar to that observed under PE, indicating that the development and use of MB film to cover silage is promising, but needs some improvement.

Synthesis and characterization of graphene: influence of synthesis variables.

The optimization of graphene growth on copper foils using an atmospheric pressure chemical vapor deposition setup is reported. CH4 and H2 were used as precursor gases and Raman spectroscopy as the main graphene characterization technique. Different growth parameters, including temperature and reaction time, the molar ratio of CH4/H2 in the feed and total flow of gases during the reaction step, were studied in detail. It was shown that graphene growth was not homogeneous in the entire sample, multilayer graphene was present in most of the sample, however as the synthesis parameters were optimized, graphene gained better quality, obtaining bilayer graphene over most of the sheet in the final optimized sample. Homemade software was used to analyze the quality of the synthesised graphene, obtaining a more quality graphene according to the synthesis parameters optimized. An optimal bilayer graphene sample was prepared at the lowest growth time (10 min) and the highest synthesis temperature (1050 °C), using a CH4/H2 flow ratio and a total flow rate ratio of precursors of 7% and 60 Nml (CH4 + H4) per min respectively.

[Limits of therapeutic effort. Professional opinions]. / Limitación del esfuerzo terapéutico. Opinión de los profesionales.

INTRODUCTION: In our clinical practice we find the need to care for patients with irreversible conditions, due to advanced age or underlying chronic disease, and a change in the types of disease currently facing the health workforce.The objective of this research was to study the ethical assessment of health professionals in our Hospital on extraordinary life support measures. MATERIAL AND METHODS: Prospective descriptive study conducted at the Hospital General Universitario de Ciudad Real during the months of April to August 2010. The convenience sample consisted of 189 professionals from different categories working in our hospital during the study period.It included a questionnaire adapted for use in hospitals, comprising 18 items with dichotomous responses.Informed consent was requested and the confidentiality of information ensured. RESULTS: A sample of 189 professionals, of whom 21.7% were male and 78.3% were female. The mean age was 40.39 years SD + 10, with a mode of 31 years.The professionals involved were doctors, nurses and nursing assistants, with an average experience of 15.8% ± 10.4 SD years.A total of 79.9% were in favour of euthanasia, 93.6% against dysthanasia, 92.6% for antidysthanasia, and 99.5% for orthotonasia. The medical group was the one most against the use of euthanasia P=.0001. Differences were found between religious practice and the ethical situations at the end of life. CONCLUSIONS: Most participants took into account the patient's decision to limit extraordinary measures in terminal disease situations.The study reveals that the effectiveness and usefulness of our clinical practice should include an ethical evaluation by professionals with the patient. It became clear that the majority of the sample of professionals is against over-aggressive treatment, and for a dignified death.

Evolución médico-quirúrgica de neonatos con gastrosquisis acorde al tiempo, método de cierre abdominal ycompromiso intestinal: Seis años de experiencia / Medical-surgical course of neonates with gastroschisis according to time, abdominal closure method and intestinal involvement: Six years of experience

Introducción. La gastrosquisis es una malformación congénita abdominal frecuente. Su tratamiento requiere cierre quirúrgico. Los dos métodos más utilizados son el cierre primario o el cierre diferido. Los resultados de ambas técnicas varían ampliamente en cada serie publicada. En México, la experiencia es limitada. Objetivos. Comparar la evolución clínico-quirúrgica de neonatos con gastrosquisis y evaluar los riesgos asociados y las complicaciones. Material y Métodos. Se realiza un estudio (2003-2008) en neonatos con gastrosquisis tratados mediante cierre primario y diferido. Se comparó el tiempo de ventilación mecánica, ayuno, nutrición parenteral, alimentación enteral, complicaciones médico-quirúrgicas, estancia hospitalaria y tipo de evolución. El análisis estadístico se realizó mediante las pruebas de t de student (..) (AU)

Introduction. Gastroschisis is a common congenital abdominal malformation. The management of this disease is by surgical repair. The two most common modes of repair are staged silo repair and primary closure. The outcomes of both modalities of surgical repairvary extensively from each published study. Experience in Mexicois limited. Objective. Compare clinical and surgical evolutions between neonates with (..) (AU)

[Medical-surgical course of neonates with gastroschisis according to time, abdominal closure method and intestinal involvement: six years of experience]. / Evolución médico-quirúrgica de neonatos con gastrosquisis acorde al tiempo, método de cierre abdominal y compromiso intestinal: seis años de experiencia.

INTRODUCTION: Gastroschisis is a common congenital abdominal malformation. The management of this disease is by surgical repair. The two most common modes of repair are staged silo repair and primary closure. The outcomes of both modalities of surgical repair vary extensively from each published study. Experience in Mexico is limited. OBJECTIVE: Compare clinical and surgical evolutions between neonates with gastroschisis and evaluate associated risks and complications. METHODS: In a cohort study of six years (2003-2008) we evaluated patients with diagnosis of gastroschisis treated by staged silo repair and primary closure. We compared time of ventilation, fasting, total parenteral nutrition, full feeds, length of hospital stay, medical and surgical complications, and mortality. Statistical analysis was performed using Student t-test, chi2 and Mann-Whitney U test. Relative risk factor (95% confidence interval) was calculated and logistic regression analysis was performed. RESULTS: Thirty four neonates with gastroschisis were included, 24 (70.5%) were treated by primary closure, 10 (29.5%) by staged silo repair, 14 (41.2%) underwent primary closure before 24 hours of life, 20 (58.8%) after 24 hours, 5 (14.7%) showed mild intestinal compromise, 22 (64.7%) moderate and 7 (20.6%) severe intestinal compromise. A significant difference was observed (p < 0.001) for each study variable with an exception in hospital discharge (dead or live) regarding the degree of intestinal compromise. Severe intestinal compromise was associated with an increase in medical (RR 1.46; IC 95%: 1.10-1.95) and surgical complications (RR 1.83; IC 95%: 0.97-3.44). CONCLUSIONS: There is no difference regarding hospital stay between neonates treated before or after 24 hours of life and also between patients treated by primary closure or staged silo repair. Nonetheless, newborns that presented severe intestinal compromise had a worse evolution and more medical and surgical complications.

Panhypopituitarism as first manifestation of a lung cancer

Pituitary metastases of solid tumours are infrequent, specially as a first manifestation. When they happen, they are usually due to breast or lung cancer and are asymptomatic or produce diabetes insipidus. It is very strange that they produce hormonal deficiency. We present a case report of a bronchogenic adenocarcinoma in a 65-year-old man which began with panhypopituitarism, diabetes insipidus and visual alterations. Magnetic resonance imaging revealed a large sellar mass, with clivus infiltration and invading the right cavernous sinus. The biopsy result was adenocarcinoma metastases from lung cancer (AU)

Composite scales of morningness and preferences: preliminary validity data in Peruvian undergraduates.

The aim of this study is to offer preliminary results about the validity of the composite morningness scale (CS) and the early/late preferences scale (PS) in a Peruvian sample. The relationship of both scales with the preferred rising and retiring times was analysed, along with the level of self-reported alertness. In Bohle et al.'s (2001) work, the relationship between morningness and preferred rising and retiring times was higher over the weekend than on weekdays. This difference explained the dispositional nature of morningness, due to the possible lesser influence of time schedules over the weekend in individuals' preferences. This result is replicated in a group of 139 Peruvian undergraduates, aged between 18 and 29 years (M = 21.73), of whom 78.4% were women. The relationship between morningness and (actual) normal rising and retiring times on weekdays and over the weekend is considered. The results partially confirm Bohle et al.'s (2001) hypothesis about preferred rising and retiring times and their relationship with the PS, and actual rising time and its relationship with the CS and PS. The differences in the level of self-reported alertness between morning, intermediate and evening-oriented groups provide support for the validity of both scales. Finally, the scores of CS and PS in Peruvian undergraduates are similar to those found by Smith et al. (2002) in university students from six countries.

[Multiple sclerosis and depression]. / Esclerosis multiple y depresion.

INTRODUCTION: Depression has frequently been reported in multiple sclerosis. However, prevalence rates must be interpreted in the light of the conceptual and methodological limitations of these studies. Depression has traditionally been associated with response to the diagnosis of this disease, the presence of physical and cognitive limitations, the damage of specific neural systems and inmunomodulatory therapy. AIMS: To assess the evolution of emotional state and its relationship with motor and cognitive slowness, in relapsing remitting patients with minimal levels of neurological disability. PATIENTS AND METHODS: Data are reported for 35 patients with relapsing remitting multiple sclerosis, 27 treated with interferons and 8 without interferon treatment. Mood disturbance (Beck Depression Inventory, BDI), physical disability (Kurtzke Expanded Disability Status Scale, EDSS) and speed of information processing (reaction times) were assessed. The first testing was carried out before the start of treatment and the second testing one year later. RESULTS AND CONCLUSIONS: The group of patients showed a total BDI score indicative of minimal depression associated with items expressing performance difficulties and somatic complaints. Emotional state was not related to physical disability but was related to processing speed measures. A significant improvement of depression was observed after one year of treatment with inmunomodulatory therapy.

[Prolonged muscle weakness associated with the administration of non-depolarizing neuromuscular blocking agents in critically ill patients]. / Debilidad muscular prolongada asociada a la administración de bloqueadores neuromusculares no despolarizantes en el paciente crítico.

Generalized muscle weakness is a common disorder in patients undergoing mechanical ventilation. The cause is unknown but is attributed to the administration of non-depolarizing neuromuscular blocking and other drugs, mainly steroids, or to the presence of sepsis or multiorgan failure. Specific clinical pictures (polyneuropathy, myopathy and prolonged muscle weakness) develop in function of the underlying cause, although etiological factors may sometimes interact. Differential diagnosis is carried out with the aid of electromyography and pathology of the peripheral muscle. Costs are high and prognosis is uncertain. Completeness of neuromuscular blockade must be monitored in these patients to guide the administration of drugs, to avoid overdoses, to maintain muscle activity and to detect a chain of reactions among concomitant medications or pathophysiologic changes.

GABA immunoreactivity in the olfactory bulbs of the adult sea lamprey Petromyzon marinus L.

The distribution of gamma-aminobutyric acid (GABA) immunoreactivity in the olfactory bulbs of the adult sea lamprey was studied using an antibody against this transmitter. Five types of GABA-immunoreactive (GABAir) cells were observed. Medium-sized GABAir cells (periglomerular cells) were located around the olfactory glomeruli and occasionally within them. In the inner cellular layer of the bulbs and around the olfactory ventricles, two types of GABAir perikarya were present: some medium-sized GABAir cells and numerous small GABAir cells (granules). In the walls of the olfactory ventricle, some medium-sized GABAir cells of cerebrospinal fluid-contacting type were observed. At the entrance of the olfactory nerves, medium-sized GABAir bipolar cells were present, mostly located between the olfactory nerve and the glomerular layer or close to the meninges, but some in the intracranial portion of the olfactory nerve. GABAir processes were present in all layers of the olfactory bulb. In addition there were also GABAir cells in the dorsal interbulbar commissure. The distribution of GABA observed in the olfactory system of lampreys indicates that this transmitter plays a major role in the modulation of bulbar circuits. The presence of granular and periglomerular cells in lampreys indicates that these two intrinsic GABAergic neurons of the olfactory bulbs are shared by most vertebrates, although lampreys have additional GABAir cell types.

[Malignant mesothelioma: clinical and radiological description of 45 cases with and without asbestos exposure]. / Mesotelioma maligno: descripción clínica y radiológica de 45 casos con y sin exposición a asbestos.

OBJECTIVE: Our aim was to identify and describe the main symptoms, clinical presentation, and radiographic changes in malignant mesothelioma (MM) patients. MATERIAL AND METHODS: We reviewed the medical and X-ray records of all patients diagnosed with MM, admitted between 1991 and 1998 to the National Institute of Respiratory Diseases (INER), which is a governmental institution specialized in chest disease in Mexico City. The following data were collected: Age, occupation, asbestos exposure, latency, family history of cancer, clinical symptoms, and X-ray changes. Data are presented as percentages by sex and age group. RESULTS: We found 45 cases of MM; in 80% of them a history of asbestos exposure could not be documented. The 51-60 years age group had the highest frequency of MM. Dispnea and chest pain were the presenting symptoms in most patients. Pleural effusion and pleural thickening were the X-ray abnormalities observed in 75% of the patients. CONCLUSIONS: The clinical and radiographic findings among patients with MM without asbestos exposure were similar to those with a history of asbestos exposure.

Helping the family carers of Alzheimer's patients: from theory...to practice. A preliminary study.

Alzheimer's disease (AD) represents one of the most important health issues in the western world. The ongoing care that the AD patient requires typically causes high stress levels, fatigue, irritation and depression in the caregiver, as well as socio-economical problems. The current study aimed to introduce a support program for carers of AD patients, in order to improve their quality of life. A Questionnaire for Carers and an Anxiety State Feature Questionnaire (STAI) was used to assess the carers. Results showed an overall improvement in the carers' health. Their subjective wellbeing increased, and though their situation had not changed, they nevertheless described feeling less trapped. It can be concluded that possibly the mere fact that the carers feel that they have help available is enough to endorse the value of the program.

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.