First-line single-agent regorafenib in frail patients with metastatic colorectal cancer: a pilot phase II study of the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD).

BACKGROUND: Treatment of frail patients with advanced colorectal cancer (CRC) is controversial. This pilot phase II trial aimed to assess the efficacy and safety of regorafenib when administered in first-line to frail patients with advanced CRC. METHODS: Frail patients without prior advanced colorectal cancer treatment were included in the study. Definition of frailty was defined per protocol based on dependency criteria, presence of chronic comorbid pathologies and/or geriatric features. MAIN OBJECTIVE: to assess progression-free survival (PFS) rate at 6 months. Treatment consisted of 28-day cycles of orally administered regorafenib 160 mg/day (3 weeks followed by 1 week rest). RESULTS: Forty-seven patients were included in the study. Median age was 81 years (range 63-89). Frailty criteria: dependency was observed in 26 patients (55%), comorbidities in 27 (57%) and geriatric features in 18 (38%). PFS rate at 6 months was 45% (95% confidence interval [CI] 30-60]. Median PFS was 5.6 months (95%CI 2.7-8.4). Median overall survival (OS) was 16 months (95%CI 7.8-24). Complete response, partial response and stable disease were observed in one, two and 21 patients respectively (objective response rate 6.4%; disease control rate 51%). Thirty-nine patients (83%) experienced grade 3-4 adverse events (AEs). The most common grade 3-4 AEs were hypertension (15 patients; 32%), asthenia (14; 30%), hypophosphatemia (6; 13%); diarrhea (4; 8%), hand-foot-skin reaction (4; 8%). There were two toxic deaths (4.2%) (grade 5 rectal bleeding and death not further specified). Dose reduction was required in 26 patients (55%) and dose-delays in 13 patients (28%). CONCLUSIONS: The study did not meet the pre-specified boundary of 55% PFS rate at 6 months. Toxicity observed (83% patients experienced grade 3 and 4 AEs) preclude its current use in clinical practice on this setting. Disease control rate and overall survival results are interesting and might warrant further investigation to identify those who benefit from this approach. TRIAL REGISTRATION: This trial was prospectively registered at EudraCT ( 2013-000236-94 ). Date of trial registration: April 9th, 2013.

First Report of Fusarium oxysporum on Sweet Pepper Seedlings in Almería, Spain.

In March of 2013, new symptoms were observed in more than seven million nursery-grown sweet pepper (Capsicum annuum) plants in El Ejido, Almería (southern Spain). Symptoms included wilting without yellowing of leaves and stunting of plants. Plant crowns exhibited necrosis that advanced through the main root along with slight root rot. Xylem was not affected above or below the crown. Symptoms were thought to be caused by the well-known pepper pathogen Phytophthora capsici. However, sporodochia of Fusarium oxysporum were observed on plant crowns. Symptomatic seedlings (n = 200) were sampled and analyzed. Tissue from roots and epidermal crowns were plated on PDA, PARP, and Komada media, as well as stem discs on PDA and Komada. No Phytophthora sp. were observed and F. oxyporum was exclusively isolated from all 200 samples, from roots and crowns, but not from xylem. Pathogenicity of 60 of these F. oxysporum isolates was studied by inoculation onto sweet pepper plants (cv. del Piquillo) at the 2-true-leaf stage. Twelve plants per isolate, grown on autoclaved vermiculite, were inoculated by drenching with 20 ml of a conidial suspension (1 × 105 CFU/ml) of each isolate per plant. Each suspension was obtained by blending one PDA petri dish fully covered with one isolate. Non-inoculated plants served as control. Plants were maintained for 30 days in a growth chamber with a 14-h photoperiod (1.6 ×·104 lux) and temperatures at 23 to 26°C. The assay was conducted twice. Symptoms described above were reproduced on crown and roots of the inoculated plants with no symptoms in stem discs. No symptoms were observed on controls after 48 days. Host specificity was tested for 13 isolates to tomato (Solanum lycopersicum) cv. San Pedro, eggplant (S. melongena) cv. Alegria, cucumber (Cucumis sativus) cv. Marketmore, watermelon (Citrullus lanatus) cv. Sugar Baby, and Chinese cabbage (Brassica campestris subsp. condensa) cv. Kasumi (4). These plants were inoculated as previously described for pathogenicity tests (12 plants per species, repeated twice). None of the plants exhibited the characteristic symptoms after 60 days. Five isolates of F. oxysporum f. sp. radicis-cucumerinum and four isolates of F. o. f. sp radicis-lycopersici were also inoculated without any symptoms in any of the inoculated sweet pepper plants. Morphological identity of all isolates corresponded to F. oxysporum. The fungi were identified following the morphological keys and methodology provided by (1) and (2). Three isolates from the 60 tested were selected for molecular identification. Molecular identification was performed by sequencing partial TEF-1α gene (3). Subsequent database searches by BLASTn indicated that the resulting sequence of 659-bp had 100% identity with the corresponding gene sequence of F. oxysporum. The sequences were identical for the three isolates and were deposited on the EMBL Sequence Database (HG916993, HG916994, and HG916995). Results suggest that the pathogenic ability of the isolates varies from a vascular Fusarium wilt. F. oxysporum f. sp. capsici is a reported pathogen to sweet pepper (5), but the symptoms we have found are closer to those manifested by the formae speciales that causes root and crown rot of other plants. Consistent with the convention stablished for similar diseases we propose the name F. oxysporum f. sp. radicis-capsici f. sp. nov. References: (1) J. F. Leslie and B. A. Summerell. The Fusarium Laboratory Manual. Blackwell, Ames, IA, 2006. (2) P. E. Nelson et al. Fusarium species. An Ilustrated Manual for Identification. The Penn St. University Press, 1983. (3) K. O'Donnell et al. Proc. Nat. Acad. Sci. 95:2044, 1998.(4) L. M. Oelke and P. W. Bosland. Capsicum Eggplant Newsl. 20:86, 2001. (5) V. C. Rivelli. M.S. Thesis. Dep. Plant Pathol. and Crop Phys. Louisiana State Univ., Baton Rouge, 1989.

Long-term outcomes in patients with schizophrenia treated with risperidone long-acting injection or oral antipsychotics in Spain: results from the electronic Schizophrenia Treatment Adherence Registry (e-STAR).

BACKGROUND: The electronic Schizophrenia Treatment Adherence Registry (e-STAR) is a prospective, observational study of patients with schizophrenia designed to evaluate long-term treatment outcomes in routine clinical practice. METHODS: Parameters were assessed at baseline and at 3 month intervals for 2 years in patients initiated on risperidone long-acting injection (RLAI) (n=1345) or a new oral antipsychotic (AP) (n=277; 35.7% and 36.5% on risperidone and olanzapine, respectively) in Spain. Hospitalization prior to therapy was assessed by a retrospective chart review. RESULTS: At 24 months, treatment retention (81.8% for RLAI versus 63.4% for oral APs, p<0.0001) and reduction in Clinical Global Impression Severity scores (-1.14 for RLAI versus -0.94 for APs, p=0.0165) were significantly higher with RLAI. Compared to the pre-switch period, RLAI patients had greater reductions in the number (reduction of 0.37 stays per patient versus 0.2, p<0.05) and days (18.74 versus 13.02, p<0.01) of hospitalizations at 24 months than oral AP patients. CONCLUSIONS: This 2 year, prospective, observational study showed that, compared to oral antipsychotics, RLAI was associated with better treatment retention, greater improvement in clinical symptoms and functioning, and greater reduction in hospital stays and days in hospital in patients with schizophrenia. Improved treatment adherence, increased efficacy and reduced hospitalization with RLAI offer the opportunity of substantial therapeutic improvement in schizophrenia.

Mycophenolate mofetil levels in stable kidney transplant recipients.

The usefulness of mycophenolate mofetil (MMF) levels in stable kidney transplant patients is not well known. We measured MMF trough levels in 137 adult kidney recipients with more than 1 year of stable graft function. The MMF dose was adjusted according to hematological or gastrointestinal toxicity, it was 500 mg in 22 (16%) patients; 750 mg in 22 (16%); 1000 mg in 69 (50.5%); 1500 mg in 15 (11%); and 2000 mg in 9 (6.5%). We analyzed the total dose, virgule dose/kg, and MMF levels in relation to efficacy parameters (creatinine, proteinuria) and hematological toxicity (erythrocytes, leukocytes, and platelets) at the time of MMF level determinations and 3 months thereafter. Statistical analyses were performed with SSPS 12.0, including sensitivity and specificity analyses by ROC. Mean MMF levels were 3.68 mg/L (Pc25, 1.6-Pc75, 4.4 mg/L) with significant differences according to dose (P < .001). Trough MMF levels did not have discriminatory capacity in the area under the ROC for anemia, renal failure, or proteinuria at the time of determination or 3 months later. The percentage of patients without proteinuria was high among patients with MMF levels between 1.6 and 4.4 mg/L. The MMF levels were low in patients who had a major increase in creatinine (1.6 vs 3.8 mg/L, P < .05). In stable renal transplant patients the levels of MMF were related to the administered dose, and they are higher than those previously described in patients with less than a year follow-up with a functioning kidney. They did not have discriminatory value at the time of determination or 3 months later. Nevertheless, low MMF levels could help recognize patients at risk of developing chronic nephropathy.

Variability of mycophenolate mofetil trough levels in stable kidney transplant patients.

Great interindividual variability in the pharmacokinetics of mycophenolate mofetil (MMF) exists among kidney transplanted patients. The within-patient variability in stable transplanted patients is not well established. We performed 258 determinations of trough MMF levels in 86 stable transplant patients without hematological or gastrointestinal toxicity after at least year of a functioning kidney and a fixed dose of MMF. We examined the within-patient variability of levels related with clinical factors (age, gender, underlying cause of kidney failure, time since transplant, associated immunosuppression, and MMF dose) and analytical factors (serum creatinine, proteinuria, hemoglobin). Trough MMF levels were 3.6 mg/L, percentile (Pc) 25 1.6 mg/L, Pc 75 4.4 mg/L with intraindividual variability median of 65% (Pc 25 14%, Pc 75 79%). For the data analysis a variation of 14% was chosen, which corresponded to the 25th percentile. We did not observed differences between patients with variation below or above the Pc 25 in age, gender, underling cause of kidney failure, basal MMF levels, and MMF dose. Patients with greater variations showed significantly higher serum creatinine and proteinuria values than the others (1.84 +/- 0.54 vs 1.46 +/- 0.44 mg/dL and 0.45 +/- 0.42 vs 0.19 +/- 0.14 g/L; P < .05). Therefore, great within-patient variability in trough MMF levels was associated with poor kidney function and proteinuria.

[Assessment of cortical brain blood flood by brain perfusion spect in patients with a diagnosis of eating behavior disorders]. / Valoración del flujo cortical cerebral mediante SPECT de perfusión cerebral en pacientes con diagnóstico de trastornos de la conducta alimentaria.

OBJECTIVE: To evaluate cortical brain blood flow by 99mTc-HMPAO SPECT in patients with Eating Disorders (ED): restrictive anorexia (RA) and purgative bulimia (PB). MATERIAL AND METHOD: The study included 7 women with diagnostic criteria of RA and 12 with PB. The control group was made up of 12 healthy women. All subjects underwent brain 99mTc-HMPAO SPECT. The SPECT studies were quantified, yielding semiquantitative indexes relating to cerebellar activity in different regions. Body dissatisfaction was assessed by means of the BSQ (Body Shape Questionnaire). The results were analyzed with the ANOVA variance and had a statistical significance of p < 0.05. RESULTS: Mean BSQ scores were 98.28 (range 71-159) in the RA group, 145.05 (range 73-191) in the PB group, and 57.4 (range 37-88) in the control group. All patients in the sample (i.e., both RA and PB) showed global cerebral hypoperfusion versus the controls, although the difference only reached statistical significance in the RA group in the left parietal lobe (p = 0.02) and in the right (p = 0.004) and left temporal lobes (p = 0.015). In the PB group, the significantly hypoperfused regions were the right (p < 0.001) and left (p = 0.008) superior frontal lobe, the right inferior frontal lobe (p = 0.042), the right (p = 0.042) and left (p = 0.002) parietal lobes, and the right temporal lobe (p = 0.002). CONCLUSION: The results obtained showed that patients with ED had cerebral hypoperfusion compared with healthy subjects. This pattern is common in parietotemporal regions for both PB and AR although with temporal and parietal predominance in RA and PB, respectively. In addition, patients with PB had frontal region involvement.

Umbilical artery histomorphometry: a link between the intrauterine environment and kidney development.

Prematurity is a risk factor for hypertension, vascular stiffness, nephron deficit and adult onset cardiorenal disease. The vascular tree and kidneys share morphogenic drivers that promote maturation in utero before 36 weeks of gestation. Vascular elastin accrual terminates after birth leaving collagen to promote vascular stiffness. Our objective was to determine if the histomorphometry of the umbilical artery, an extension of the aorta, parallels nephron mass across gestational age groups. From a cohort of 54 newborns, 32 umbilical cord specimens were adequate for evaluation. The umbilical cord was sectioned, stained with trichrome, and digitalized. Muscular and collagenous areas of the umbilical artery were measured in pixels using the Image J 1.48q software. Total kidney volume was measured by ultrasound and factored by body surface area (TKV/BSA). The umbilical artery total area was significantly greater in term v. preterm infants (9.3±1.3 v. 7.0±2.0 mm2; P<0.05) and increased with gestational age; while the percent muscular and collagen areas were independent of gestational age (R 2=0.04; P=ns). Percent muscular area correlated positively with TKV/BSA (r=0.53; P=0.002); while an increase in collagen correlated inversely with kidney mass (r=-0.53; P=0.002). In conclusion, an enhanced % muscular area and presumed vascular elasticity was associated with increased renal mass in all infants. Umbilical artery histomorphometry provides a link between the intrauterine environment, vascular and kidney development.

Patterns of sulfadiazine acute nephrotoxicity.

Sulfadiazine acute nephrotoxicity is reviving specially because of its use in toxoplasmosis in HIV-positive patients. We report 4 cases, one of them in a previously healthy person. Under treatment with sulfadiazine they developed oliguria, abdominal pain, renal failure and showed multiple radiolucent renal calculi in echography. All patients recovered their previous normal renal function after adequate hydration and alcalinization. A nephrostomy tube had to be placed in one of the patients for ureteral lithiasis in a single functional kidney. None of them needed dialysis or a renal biopsy because of a typical benign course. Treatment with sulfadiazine requires exquisite control of renal function, an increase in water ingestion and possibly the alcalinization of the urine. We communicate a case in a previously healthy person, a fact not found in the recent literature. Probably many more cases are not detected. We think that a prospective study would be useful.

Memory retraining with adult male alcoholics.

The purpose of the present study was to evaluate the use of group memory retraining in adult male alcoholics. Subjects were 29 residents of a Salvation Army Adult Rehabilitation Center. Fourteen of the men volunteered to be in a memory retraining group and 15 to be in a control group, and all had memory functioning assessed during a pretest and again during a posttest eight weeks later. Memory retraining occurred in groups of three to six men who met one hour per week for eight weeks. Only one test improved significantly with memory retraining. Despite that fact, subjects appreciated the retraining and were more confident of their ability to learn and remember. Since alcoholics have many subjective complaints about memory dysfunction and previous research has demonstrated memory impairment, both a standardized clinically useful memory test battery and effective memory retraining techniques are needed.

[Disseminated inflammatory pseudotumor of the lymph nodes]. / Seudotumor inflamatorio diseminado de los ganglios linfáticos.

Inflammatory pseudotumour of lymph nodes is a benign type of lymphadenopathy recently described as a peculiar nodal reaction, which displays distinctive clinical and histological features. The origin of the disease is unknown although an inflammatory etiology has been suggested. We study a new case of inflammatory pseudotumour of lymph nodes which had an unusual clinical presentation, with lymphadenopathy on both sides of the diaphragm and enlargement of liver and spleen. In addition, focal fibrinoid vascular necrosis was observed on histological examination, an unusual finding which makes difficult the differential diagnosis with other lesions, particularly vasculitis.

[Influence of motivation and clinical outcome in eating disorders]. / Influencia de la motivación en la evolución clínica de los trastornos del comportamiento alimentario.

INTRODUCTION: Our aim was to assess if the degree of motivation at the beginning of the treatment for eating disorders (ED) might have an influence on the clinical outcome at one year of follow-up. METHODS: 102 patients diagnosed of ED, following ED DSM-IV criteria, who initiated treatment at the hospital eating disorders unit, were included in the study. All the patients were examined with the structured interview SCID-I and numerous clinical and demographic variables were recorded. Before beginning eating disorders treatment, patients completed one questionnaire that assessed attitudes towards change in eating disorders (ACTA) and other questionnaires measuring eating and general psychopathology. RESULTS: At one year of follow-up, initial low scores on the "relapse" subscale predicted a greater weight recovery in patients with anorexia nervosa and a lower number of weekly binges in bulimic patients. CONCLUSIONS: Attitude towards treatment at the beginning of a therapeutic program, mainly feeling of relapse, is a significant prognostic factor for the therapeutic response.

[Antipsychotics in treatment of eating disorders patient: a study with risperidone]. / Uso de antipsicóticos en el tratamiento de pacientes con trastorno de la conducta alimentaria: estudio con risperidona.

INTRODUCTION: The use of antipsychotic drugs in the treatment of eating disorders (ED) patients is a controversial issue. Although a few studies support the systematic use of antipsychotics, they are frequently used, mainly in severe disorders with other associated psychopathological symptoms. METHODS: 27 ED patients were included in the study, 7 dropped-out prematurely or did not complete the pharmacological treatment. All the patients were interviewed and diagnosed according to the Structured Clinical Interview for the DSM-IV (SCID-I) and the personality diagnosis was carried out with the Spanish version of the International Personality Disorders Examination (IPDE). The clinical assessment was performed with the Clinical Global Impression (CGI) scale and the Change Severity Assessment (CSA) at baseline and three months after the beginning of the treatment with risperidone. RESULTS: A significant proportion of patients showed clear clinical and general state improvement in areas like physical state, eating behavior, family and social relationships and work ability. CONCLUSIONS: Risperidone associated to the previous therapeutic treatment in patient with a severe ED, with comorbid disorders and where other pharmacological treatments have not been effective, could be a useful option.

Attitudes towards change and treatment outcome in eating disorders.

OBJECTIVE: To investigate the influence of the stage of change on treatment outcome among patients suffering from eating disorders. METHOD: Sixty-seven women receiving free outpatient treatment for eating disorders initially participated in this study. Their demographic, lifetime and clinical characteristics, eating disorder symptoms and general distress were assesssed at baseline and after one year, together with the results of self-report questionnaire on Attitudes towards Change in Eating Disorders (ACTA). RESULTS: High scores on the Maintenance subscale were protective for eating psychopathology as measured by the Eating Attitudes Test (EAT-40), Eating Disorders Inventory (EDI-2) and the frequency of purging. Action was predictive of weight changes. Precontemplation and Relapse respectively predicted little change in EAT and the Bulimic Inventory Test Edinburgh (BITE). High Preparation scores were predictive of the level of EDI-2 Interoceptive Awareness, Maturity Fears, and Ascetism. DISCUSSION: Our results suggest considering the stage of change as a useful outcome predictor.

Risk and protective factors for drug abuse in adolescents. A longitudinal research.

INTRODUCTION: The aim of the present study was to identify possible risk and protective factors for the development of problems with the use of drugs in adolescents. METHODS: A two years follow-up was carried out (from the 2nd to the 4th year of the Compulsory Secondary Education). Sociodemographic variables, general and eating psychopathology, family functioning and patterns of drugs use were assessed in 1,076 students. RESULTS: After controlling the effect of having problems with the use of drugs at the beginning, cigarettes smoking at the age of 13 years predicted the consumption of alcohol 2 years later and vice versa. Independently of the effect of this association, general psychopathology, body image dissatisfaction and self-harm at the beginning were risk factors for alcohol consumption 2 years later. Moreover, besides female gender and high academic achievements, normal family functioning was a protective factor against the fact of suffering problems with drugs later on. CONCLUSIONS: These present findings might have relevance in the development of preventive strategies for the use of drugs in adolescent population.

[Attitudes towards change in eating disorders (ACTA). Development and psychometric properties]. / El cuestionario de actitudes frente al cambio en los trastornos de la conducta alimentaria (ACTA). Desarrollo y propiedades psicométricas.

INTRODUCTION: The aim of the present study was the development of a self-reported instrument in Spanish to assess attitudes towa rds change in eating disord e rs (AC TA ) and to analyze its reliability and validity. METHODS: The questionnaire was elaborated following the transtheoretical approach of stages of changes, proposed by Prochaska and DiClemente and using the clinical records systematically registered regarding patients cognitions, behaviors and emotions related to the disorder. It was administered to 186 patients who where diagnosed an eating disorder according DSM-IV criteria. Subsequently, the process of refinement and validation of the scale was initiated. Moreover, a set of self-reported instruments was used to assess the eating disorder psychopathology: the Eating Attitudes Test (EAT), the Bulimic Investigatory Test Edinburgh (BITE), the Eating Disorders Inventory (EDI-2) and the Body Shape Questionnaire (BSQ). RESULTS: The final version consisted of 59 items divided into six subscales: precontemplation, contemplation, determination, action, maintenance and relapse. All of them s h owed an internal consistency over 0.70 which corresponded to the six factor obtained after the factorial analysis. Furthermore, the subscales were logically correlated to each other and to the questionnaires measuring eating psychopathology. CONCLUSIONS: The present results suggest that the ACTA be an easily administered, reliable and valid questionnaire, which could be used withinthe motivational approach. This could provide interesting information regarding the knowledge of the therapeutical process.

Cholinergic control of stanniocalcin release in the rainbow trout, Oncorhynchus mykiss, and the American eel, Anguilla rostrata.

An in vivo whole animal 45Ca influx bioassay was used to study the cholinergic control of the release of stanniocalcin (STC) in the rainbow trout (Oncorhynchus mykiss) and the American eel (Anguilla rostrata). In both species calcium influx (JinCa2+) was lowered in response to hypercalcemia induced by intravascular (trout) or intraperitoneal (eel) injections of CaCl2. In trout, this response was blocked by the cholinergic antagonist atropine (0.25 mumol kg-1) and mimicked by the cholinoceptor agonist carbachol (0.25 mumol kg-1). These observations are consistent with a cholinergic stimulation of STC release in response to hypercalcemia in trout. In eels, pretreatment with atropine did not block the lowering of JinCa2+ in response to hypercalcemia. This suggests that cholinergic stimulation is not obligatory for stanniocalcin release in eels. However, carbachol treatment did elicit STC release as revealed by the lowering of JinCa2+. This response to carbachol was not observed in stanniectomized eels. Thus, in the American eel it appears that there is a potential for cholinergic control of STC release but that other factors such as the local plasma calcium concentration may also be involved, at least in response to severe acute hypercalcemia.

[Spanish version of the Gardner body image validation scale in patients with eating behavior disorders]. / Adaptación española de la escala de evaluación de la imagen corporal de Gardner en pacientes con trastornos de la conducta alimentaria.

This study reports the Spanish version of a new scale for the assessment of body image, developed by Gardner, Stark, Jackson and Friedman (1999). A silhouette method was used as a self-evaluation measure of schematic ideal body size within three groups of women: anorexia nervosa (n= 57), bulimia nervosa (n=57) and normal control (n=168). The results showed that, considering the body mass index as covariant of the results, the clinical groups formed by anorexic and bulimic patients judged their current body size as significantly greater than the control group. In the same way, the clinical groups judged their ideal body size significantly thinner than that considered by the control group. We can conclude that this scale for assessment is a sensitive psychometrical measure of the body image.