Self- but Not Other-Dimensions of Mentalizing Moderate the Impairment Associated With Social Anxiety in Adolescents From the General Population.

Mentalizing, or social cognition, refers to the brain's higher order capacity that allows humans to be aware of one's own and others' mental states (e.g., emotions, feelings, intentions). While cognition in social anxiety has been broadly analyzed, there is a paucity of research regarding the role of social cognition. Moreover, mentalizing or social cognition research is traditionally focused on the understanding of others' mental states, rather than self-mentalizing. Finally, most studies analyze the role of social cognition in the development or maintenance of social anxiety, yet no study to date has analyzed whether social cognition moderates functional impairment associated with it. This study analyzes whether self- and other-mentalizing moderate the relationship between social anxiety and impairment in social and self-functioning. A sample of 262 adolescents from the non-clinical population was assessed on measures of social anxiety, self- and other- mentalization, indicators of social functioning (social competence and sociometric status), and indicators of self-functioning (depression and self-esteem). Multiple linear regressions were conducted to test possible moderation effects of self-mentalizing and other-mentalizing on the relationships between social anxiety and social and self-functioning. Results revealed that other-mentalizing does not moderate social- nor self-functioning, while self-mentalizing moderates the impairment of all of them. While impairment in social functioning is buffered by one dimension of self-mentalizing (emotional clarity; b = 0.003, p = 0.043 and b = 0.016, p = 0.008 for social competence and sociometric status, respectively), impairment in self-functioning is strengthened by the other dimension (attention to emotions; b = -0.007, p = 0.008 and b = 0.009, p = 0.047 for self-esteem and depression, respectively). Probing the moderation at the 16th, 50th, and 84th percentiles revealed that the negative imbalance between dimensions (i.e., high attention and low clarity) tended to exacerbate impairment most on all indicators, while the positive imbalance (i.e., low attention and high clarity) was usually the most buffering condition. This supports that "low-flying" or implicit mentalizing provides more resilience than explicit mentalizing (i.e., high attention and high clarity). Findings suggest that the work on emotional self-awareness should be stressed in the intervention of the social anxiety spectrum conditions in order to improve prevention, functioning, and ultimately, treatments, of people impaired by symptoms of social anxiety.

Does the placebo effect on hot flashes depend on the placebo dose?

PURPOSE: To investigate the presence of a placebo dose-response effect in four randomized, double-blind, placebo-controlled, multi-dose hot flash clinical trials conducted at Mayo Clinic. METHODS: Hot flash score, frequency, and hot flash-related distress for each placebo dose level were summarized at each time point by mean and standard deviation and changes from baseline were plotted to visualize a possible placebo dose-effect response. Furthermore, a meta-analysis was conducted for each endpoint in the highest and lowest dosage arms across the four trials. RESULTS: Longitudinal plots of mean hot flash scores, frequencies, and hot flash-related distress scores in patients taking placebo in each study showed a decline in hot flash scores over time without any clinically meaningful differences between the lowest and highest dosage arms in each study. The meta-analysis for each endpoint in the highest and lowest dosage arms across the four trials revealed no clinically important differences either. CONCLUSION: While the current study cannot rule out the existence of a placebo dose-response effect in multi-dose placebo-controlled trials in patients with hot flashes or other conditions, it suggests, along with the available data in the placebo literature, that, at least in well-conducted multi-dose clinical trials in which the placebo was used as control, such an effect, if it exists at all, should be very small. Therefore, pooling data from different placebo subgroups is unlikely to compromise the validity of comparisons between the combined placebo arms and each treatment arm.

Inhibition of Mycobacterium abscessus, M. chelonae, and M. fortuitum biofilms by Methylobacterium sp.

Methylobacterium sp. is isolated from water distribution systems and has been linked in the biofilms of the systems with a lower presence of Mycobacterium avium. In this study we aimed to determine the in vitro activity of Methylobacterium sp. in the development of rapidly growing mycobacteria (RGM) biofilms. Methylobacterium sp. CECT 7805 was added as a suspension of living bacteria (LB), an autoclaved suspension (AS), and an extract obtained after sonication (ES) at different times (24, 48, and 72 h), to preformed biofilms of Mycobacterium abscessus DSM 44196, Mycobacterium chelonae ATCC 19235, and Mycobacterium fortuitum ATCC 6841, using a 96 h control of each species. The biofilms were analyzed by confocal laser scanning microscopy and by the Calgary biofilm device using the plates MBECTM Biofilm Inoculator. A statistically significant reduction in the thickness and covered surface was observed in all mycobacterial biofilms with all forms of Methylobacterium sp. A statistically significant increase in the autofluorescence was observed in M. abscessus biofilms but not in other biofilms. The increased percentage of dead mycobacteria was statistically significant in all cases. The reduced log CFU (colony-forming units)/peg recount was statistically significant in M. chelonae biofilms after treatment with AS and ES, but in M. fortuitum biofilms the recount decreased only with AS. M. abscessus biofilms were always significantly reduced with AS at 72 h and with ES. Methylobacterium sp. could inhibit RGM biofilm formation. Living cells of Methylobacterium sp. were not necessary to inhibit the growth of a preformed biofilm. M. chelonae biofilms were the most greatly reduced.

An innovative quick solidifying technique for the forensic investigation of brain circulation using addition silicones.

Post-mortem study of the brain is extremely relevant to medico-legal autopsies. However, it can be difficult to handle due to its fragility. This article presents a study on the development of an arterial solidifying technique that can be applied to analyze arterial circulation, consequently easing the handling and later diagnosis of diseases in this anatomical site. Vinylpolysiloxane silicone is introduced into the internal carotid arteries until it completely fills the arterial tree, creating a detailed model of the arterial's internal anatomy. This technique is fast, easy to apply and requires no previous tissue fixation. In addition, it allows for further toxicological and pathological tests. In conclusion, this technique represents a simple, sensitive and efficient method to employ in conventional autopsies, which can help in the diagnosis of death.

Evaluation of dried blood spot sampling for pharmacokinetic research and therapeutic drug monitoring of anti-tuberculosis drugs in children.

BACKGROUND: Dried blood spot (DBS) sampling for pharmacokinetic (PK) studies and therapeutic drug monitoring have unique advantages over venous sampling. This study aimed to evaluate a DBS method for first-line anti-tuberculosis drugs in children, and DBS sampling to assess PK parameters. METHODS: Paraguayan children were treated according to the revised paediatric dosing scheme of the World Health Organization. A PK curve was performed both with DBS sampling and conventional venous sampling for rifampicin, pyrazinamide and ethambutol. Passing-Bablok regression, Bland-Altman plots and predictive performance evaluation were used to assess agreement between DBS and plasma concentrations. The percentages of patients attaining population PK values for Cmax and AUC0-24h were calculated. RESULTS: After use of a conversion factor, Passing-Bablok regression showed no significant proportional or systematic bias between DBS and plasma concentrations. Bland-Altman plots showed that 95% of the ratios of the DBS predicted:observed plasma concentrations lay between 0.6 and 1.4 for rifampicin, 0.5 and 1.6 for pyrazinamide and -0.4 and 2.8 for ethambutol. DBS measurements showed acceptable predictive performance for rifampicin and pyrazinamide, but not for ethambutol. Assessment of Cmax target attainment was 62.5% for isoniazid, 25% for rifampicin, 100% for pyrazinamide and 75% for ethambutol. CONCLUSION: For rifampicin and pyrazinamide, the DBS method was accurate in predicting plasma concentrations, and was used successfully for PK parameter assessment. However, predicting ethambutol plasma concentrations with DBS measurement was associated with too much imprecision. Despite higher dosing, only 25% of the population reached average target adult rifampicin exposures.

Short-term dentoskeletal changes following Class II treatment using a fixed functional appliance: the Austro Repositioner : A pilot study.

OBJECTIVE: Purpose of this prospective study was to evaluate the skeletal and dentoalveolar effects of a fixed functional appliance, the Austro Repositioner, in dolicho- and brachyfacial skeletal Class II patients. MATERIAL AND METHODS: In all, 20 dolicho- and 25 brachyfacial consecutive patients treated with the Austro Repositioner were compared with untreated controls (20 dolicho- and 20 brachyfacial patients) with the same initial dentoskeletal features. Lateral cephalograms were acquired before and 1.0±0.2 year after therapy. RESULTS: Significant improvements in skeletal Class II relationships were observed in both groups. The ANB angle decreased (3.56° in dolicho- and 3.13° in brachyfacial patients, P < 0.001) due to changes localized exclusively in the mandible, the SNB angle increased to 3.20° in dolicho- and 3.02° in brachyfacial patients, and the total mandibular length (Co-Pg) increased to 6.47 mm in dolicho- and 5.78 mm in brachyfacial patients (P < 0.001). A favorable guidance of vertical pattern was also achieved in both groups, and no significant changes were observed in the upper and lower incisors in both groups. CONCLUSIONS: The Austro Repositioner was effective for short-term treatment of skeletal Class II malocclusion resulting from the retrusion of the mandible in both dolicho- and brachyfacial patients.

Childhood behavioral inhibition is associated with impaired mentalizing in adolescence.

Recent advances suggest that impairment in social cognition (SC) may play a role in the development of social anxiety (SA). However, very few studies have analyzed whether SA fosters poorer social-cognitive development as it leads to social avoidance. This study aimed to analyze whether retrospectively assessed behavioral inhibition (BI) (i.e., an early form of SA) in childhood is associated with a deficit in social cognition operationalized as impairment of mentalizing (MZ) in adolescence. A sample of 256 adolescents (range: 12-18 years; mean age: 14.7 years; SD = 1.7) from general population were assessed for MZ capacities and retrospective BI through self-report and interview measures. Results comparing three groups of adolescents with different levels of childhood BI (low, moderate or high) and controlling for concurrent SA and depression reveal that the higher the level of BI, the lower the level of MZ. These results were consistent for almost all mentalization measures, including when both extreme (i.e., high vs. low BI) and non-extreme (i.e., high vs. moderate BI) were compared in both self-report and interview measures and in both dimensions of MZ (i.e., MZ referred to others' and to own mental states). These findings support that childhood forms of SA are associated to deficit in SC in adolescence. A possible bi-directional relationship between SA and SC, and the role that it may play in the pathway to clinical SA are discussed.

Colectomía mediante puerto único vs colectomía mediante laparoscopia multipuerto. Revisión sistemática y metaanálisis de más de 2.800 procedimientos / Single-port colectomy vs multi-port laparoscopic colectomy. Systematic review and meta-analysis of more than 2800 procedures

OBJETIVOS: La cirugía laparoscópica multipuerto (CLM) ha demostrado su seguridad y efectividad en la cirugía del colon. Con la intención de reducir la agresividad surgen otras técnicas como la cirugía por puerto único (SILS). El objetivo de este metaanálisis es evaluar la seguridad y la viabilidad de la técnica SILS en la cirugía del colon. MATERIAL Y MÉTODOS: Se realiza un metaanálisis de 27 estudios observacionales y uno prospectivo aleatorizado mediante el modelo de efectos aleatorios. RESULTADOS: Se han analizado 2.870 procedimientos: 1.119 SILS y 1.751 CLM. No se han encontrado diferencias estadísticamente significativas en la edad (DMP 0,28 [−1,13, 1,68]; p = 0,70), IMC (DMP −0,63 [−1,34, 0,08]), ASA (DMP −0,02 [−0,08, 0,04]; p = 0,51), longitud de incisión (DMP −1,90 [−3,95, 0,14]; p = 0,07), tiempo operatorio (DMP −2,69 [−18,33, 12,95]; p = 0,74), complicaciones (OR = 0,89 [0,69, 1,15]]; p = 0,37), conversión a laparotomía (OR = 0,59 [0,33, 1,04]; p = 0,07), mortalidad (OR = 0,91 [0,36, 2,34]; p = 0,85) o número de ganglios obtenidos (DMP 0,13 [−2,52, 2,78]; p = 0,92). La pérdida de sangre (DMP −42,68 [−76,79, −8,57]; p = 0,01) y la estancia hospitalaria (DMP −0,73 [−1,18, −0,28]; p = 0,001) son significativamente menores en el grupo SILS. CONCLUSIONES: La cirugía colorrectal mediante SILS es segura y efectiva, con ligeros beneficios respecto a la CLM. Sin embargo, se necesitan más estudios aleatorizados antes de que la SILS se pueda considerar una alternativa a la CLM

OBJECTIVE: Multiport laparoscopic surgery in colon pathology has been demonstrated as a safe and effective technique. Interest in reducing aggressiveness has led to other procedures being described, such as SILS. The aim of this meta-analysis is to evaluate feasibility and security of SILS technique in colonic surgery. MATERIAL AND METHODS: A meta-analysis of twenty 7 observational studies and one prospective randomized trial has been conducted by the use of random-effects models. RESULTS: A total amount of 2870 procedures was analyzed: 1119 SILS and 1751 MLC. We did not find statistically significant differences between SILS and MLC in age (WMD 0.28 [−1.13, 1.68]; P=.70), BMI (WMD −0.63 [−1.34, 0.08]; P=.08), ASA score (WMD −0.02 [−0.08, 0.04]; P=.51), length of incision (WMD −1.90 [−3.95, 0.14]; P=.07), operating time (WMD −2.69 (−18.33, 12.95]; P=.74), complications (OR = 0.89 [0.69, 1.15]; P=.37), conversion to laparotomy (OR = 0.59 [0.33, 1.04]; P=.07), mortality (OR = 0.91 [0.36, 2.34]; P=.85) or number of lymph nodes harvested (WMD 0.13 [−2.52, 2.78]; P=.92). The blood loss was significantly lower in the SILS group (WMD −42.68 [−76.79, −8.57]; P=.01) and the length of hospital stay was also significantly lower in the SILS group (WMD −0.73 [−1.18, −0.28]; P=.001). CONCLUSION: Single-port laparoscopic colectomy is a safe and effective technique with additional subtle benefits compared to multiport laparoscopic colectomy. However, further prospective randomized studies are needed before single-port colectomy can be considered an alternative to multiport laparoscopic surgery of the colon

Single-port Colectomy VS Multi-port Laparoscopic Colectomy. Systematic Review and Meta-analysis of More Than 2800 Procedures.

OBJECTIVE: Multiport laparoscopic surgery in colon pathology has been demonstrated as a safe and effective technique. Interest in reducing aggressiveness has led to other procedures being described, such as SILS. The aim of this meta-analysis is to evaluate feasibility and security of SILS technique in colonic surgery. MATERIAL AND METHODS: A meta-analysis of twenty 7 observational studies and one prospective randomized trial has been conducted by the use of random-effects models. RESULTS: A total amount of 2870 procedures was analyzed: 1119 SILS and 1751 MLC. We did not find statistically significant differences between SILS and MLC in age (WMD 0.28 [-1.13, 1.68]; P=.70), BMI (WMD -0.63 [-1.34, 0.08]; P=.08), ASA score (WMD -0.02 [-0.08, 0.04]; P=.51), length of incision (WMD -1.90 [-3.95, 0.14]; P=.07), operating time (WMD -2.69 (-18.33, 12.95]; P=.74), complications (OR=0.89 [0.69, 1.15]; P=.37), conversion to laparotomy (OR=0.59 [0.33, 1.04]; P=.07), mortality (OR=0.91 [0.36, 2.34]; P=.85) or number of lymph nodes harvested (WMD 0.13 [-2.52, 2.78]; P=.92). The blood loss was significantly lower in the SILS group (WMD -42.68 [-76.79, -8.57]; P=.01) and the length of hospital stay was also significantly lower in the SILS group (WMD -0.73 [-1.18, -0.28]; P=.001). CONCLUSION: Single-port laparoscopic colectomy is a safe and effective technique with additional subtle benefits compared to multiport laparoscopic colectomy. However, further prospective randomized studies are needed before single-port colectomy can be considered an alternative to multiport laparoscopic surgery of the colon.

Lipid-specific immunoglobulin M bands in cerebrospinal fluid are associated with a reduced risk of developing progressive multifocal leukoencephalopathy during treatment with natalizumab.

OBJECTIVE: Progressive multifocal leukoencephalopathy (PML) is a serious side effect associated with natalizumab treatment in multiple sclerosis (MS). PML risk increases in individuals seropositive for anti-John Cunningham virus (JC) antibodies, with prolonged duration of natalizumab treatment, and with prior exposure to immunosuppressants. We explored whether the presence of lipid-specific immunoglobulin M oligoclonal bands in cerebrospinal fluid (CSF; IgM bands), a recognized marker of highly inflammatory MS, may identify individuals better able to counteract the potential immunosuppressive effect of natalizumab and hence be associated with a reduced risk of developing PML. METHODS: We studied 24 MS patients who developed PML and another 343 who did not suffer this opportunistic infection during natalizumab treatment. Patients were recruited at 25 university hospitals. IgM bands were studied by isoelectric focusing and immunodetection. CSF lymphocyte counts were explored in 151 MS patients recruited at Ramon y Cajal Hospital in Madrid, Spain. RESULTS: IgM bands were independently associated with decreased PML risk (odds ratio [OR] = 45.9, 95% confidence interval [CI] = 5.9-339.3, p < 0.0001) in patients treated with natalizumab. They were also associated with significantly higher CSF CD4, CD8, and B-cell numbers. Patients positive for IgM bands and anti-JC antibodies had similar levels of reduced PML risk to those who were anti-JC negative (OR = 1.55, 95% CI = 0.09-25.2, p = 1.0). Higher risk was observed in patients positive for anti-JC antibodies and negative for IgM bands (19% of the total cohort, OR = 59.71, 95% CI = 13.6-262.2). INTERPRETATION: The presence of IgM bands reflects a process that may diminish the risk of PML by counteracting the excess of immunosuppression that may occur during natalizumab therapy.

Paracoccidioidomicosis: características clínicas de 94 casos / Paracoccidioidomycosis: Clinical Characteristics of 94 Cases

Paraguay es considerado una zona afectada por esta micosis endémica en gran parte de Sudamérica. No existe trabajo analítico en nuestro país que evalúe las formas de presentación y los desenlaces de la forma crónica de la paracoccidioidomicosis. Objetivo: Descripción de las características clínicas de casos de paracoccidioidomicosis con compromiso pulmonar. Material y métodos: Estudio observacional descriptivo de fichas clínicas de pacientes con diagnóstico de paracoccidioidomicosis internados en el INERAM durante el período de enero 1980-diciembre 2003. El análisis estadístico consistió en un análisis bivariado (X2 y ANOVA), considerando significativa una p < 0,05. Resultados: Se identificaron 94 casos diagnosticados durante el periodo de estudio. La edad de presentación fue de 49±11 años y un notorio bajo índice de masa corporal promedio (16,6) sumado a la alta prevalencia de tabaquismo (77%) caracterizaron a la serie. A pesar de la preponderancia de síntomas respiratorios, se consignaron además lesiones mucosas en 33% y adenopatías cervicales en 19% de los registros médicos. Se describen hallazgos en la analítica sanguínea y en los análisis radiográficos asentados. El análisis de las variables entre el grupo de los fallecidos y de los sobrevivientes mostró una diferencia significativa en la frecuencia respiratoria y en la distribución radiográfica de las lesiones al momento de la internación. Utilizando imidazólicos en 97% de los casos, la mejoría sintomática fue constatada a las 1.6 semanas en promedio, aunque se ha registrado una mortalidad intrahospitalaria del 11.7%. Los pacientes quedaban internados durante 63±58 días para poder recibir tratamiento, pero una vez en condiciones ambulatoriales, el 88% discontinuaba los fármacos. Conclusión: Pese a los síntomas inespecíficos, se debería considerar el diagnóstico de esta micosis en cuadros respiratorios subagudos o crónicos concomitantes a lesiones mucosas y/o adenopatías. Urgen medidas generales que puedan paliar la alta tasa de abandono terapéutico.

Paraguay is an endemic country for paracoccidiomycosis. There is no analytical work in our country evaluating the clinical presentation and the outcomes of the chronic form of paracoccidioidomycosis. Objective: To describe the clinical characteristics of paracoccidioidomycosis cases with pulmonary involvement. Material and Methods: Observational study of clinical records of patients admitted with a diagnosis of paracoccidioidomycosis during the period of January 1980 - December 2003 in INERAM, a reference medical center. Statistical analysis consisted of a bivariate analysis (X2 and ANOVA), considering significant a p < 0.05. Results: 94 cases diagnosed during the study period were identified. The mean age of presentation was 49 ± 11 years old. The patients had notorious low average body mass index (16.6) and a high prevalence of smoking habit (77%). Respiratory symptoms, mucosal lesions (33%) and cervical lymphadenopathy (19%) were noted. Blood testing and radiographic results are described. The analysis of the variables between the group who died and the survival group showed significant difference in the respiratory rate and the radiographic images at admission. Most patients (97%) were treated with imidazole antifungal drugs; clinical improvement was observed after on average 1.6 weeks of treatment. Lethality among hospitalized patients was 11.7%. Patients were hospitalized for 63 ± 58 days, in order to receive treatment but once at home, 88% discontinued the drugs . Conclusion: Despite the nonspecific symptoms, diagnosis should be suspected in patients with subacute or chronic respiratory symptoms which are concomitant with mucosal lesions and lymphadenopathy. General measures should be taken to decrease the high rate of treatment default at home.

Paracoccidioidomicosis: características clínicas de 94 casos

Paraguay es considerado una zona afectada por esta micosis endémica en gran parte de Sudamérica. No existe trabajo analítico en nuestro país que evalúe las formas de presentación y los desenlaces de la forma crónica de la paracoccidioidomicosis. Objetivo: Descripción de las características clínicas de casos de paracoccidioidomicosis con compromiso pulmonar. Material y métodos: Estudio observacional descriptivo de fichas clínicas de pacientes con diagnóstico de paracoccidioidomicosis internados en el INERAM durante el período de enero 1980-diciembre 2003. El análisis estadístico consistió en un análisis bivariado (X2 y ANOVA), considerando significativa una p < 0,05. Resultados: Se identificaron 94 casos diagnosticados durante el periodo de estudio. La edad de presentación fue de 49±11 años y un notorio bajo índice de masa corporal promedio (16,6) sumado a la alta prevalencia de tabaquismo (77%) caracterizaron a la serie. A pesar de la preponderancia de síntomas respiratorios, se consignaron además lesiones mucosas en 33% y adenopatías cervicales en 19% de los registros médicos. Se describen hallazgos en la analítica sanguínea y en los análisis radiográficos asentados. El análisis de las variables entre el grupo de los fallecidos y de los sobrevivientes mostró una diferencia significativa en la frecuencia respiratoria y en la distribución radiográfica de las lesiones al momento de la internación. Utilizando imidazólicos en 97% de los casos, la mejoría sintomática fue constatada a las 1.6 semanas en promedio, aunque se ha registrado una mortalidad intrahospitalaria del 11.7%. Los pacientes quedaban internados durante 63±58 días para poder recibir tratamiento, pero una vez en condiciones ambulatoriales, el 88% discontinuaba los fármacos. Conclusión: Pese a los síntomas inespecíficos, se debería considerar el diagnóstico de esta micosis en cuadros respiratorios subagudos o crónicos concomitantes a lesiones mucosas y/o adenopatías. Urgen medidas generales que puedan paliar la alta tasa de abandono terapéutico.(AU)

Paraguay is an endemic country for paracoccidiomycosis. There is no analytical work in our country evaluating the clinical presentation and the outcomes of the chronic form of paracoccidioidomycosis. Objective: To describe the clinical characteristics of paracoccidioidomycosis cases with pulmonary involvement. Material and Methods: Observational study of clinical records of patients admitted with a diagnosis of paracoccidioidomycosis during the period of January 1980 - December 2003 in INERAM, a reference medical center. Statistical analysis consisted of a bivariate analysis (X2 and ANOVA), considering significant a p < 0.05. Results: 94 cases diagnosed during the study period were identified. The mean age of presentation was 49 ± 11 years old. The patients had notorious low average body mass index (16.6) and a high prevalence of smoking habit (77%). Respiratory symptoms, mucosal lesions (33%) and cervical lymphadenopathy (19%) were noted. Blood testing and radiographic results are described. The analysis of the variables between the group who died and the survival group showed significant difference in the respiratory rate and the radiographic images at admission. Most patients (97%) were treated with imidazole antifungal drugs; clinical improvement was observed after on average 1.6 weeks of treatment. Lethality among hospitalized patients was 11.7%. Patients were hospitalized for 63 ± 58 days, in order to receive treatment but once at home, 88% discontinued the drugs . Conclusion: Despite the nonspecific symptoms, diagnosis should be suspected in patients with subacute or chronic respiratory symptoms which are concomitant with mucosal lesions and lymphadenopathy. General measures should be taken to decrease the high rate of treatment default at home.(AU)

Phase II study of temozolomide (TMZ) and everolimus (RAD001) therapy for metastatic melanoma: a North Central Cancer Treatment Group study, N0675.

OBJECTIVE: Mammalian target of rapamycin (mTOR) pathway is activated in malignant melanoma and in situ lesions as opposed to benign nevi. Inhibition of PI3K-Akt-mTOR signaling is implicated in sensitization of melanoma cells to alkylating agents (temozolomide [TMZ]) and inhibition of tumor angiogenesis. METHODS: We conducted a single-arm phase II multi-institution cooperative group study to assess the antitumor activity and safety profile of the combination of TMZ and the rapamycin derivative everolimus in patients with metastatic unresectable malignant melanoma. Patients received 10 mg/d of RAD001 for 5 of 7 days (ie, 50 mg/wk) and 200 mg/m/d of TMZ for 5 days each cycle. RESULTS: Of the first 39 eligible patients, 17 were PFS-9 successes, for a predetermined threshold of 18/39 patients for a positive trial. Overall, 21 of 48 patients were progression free at 9 weeks, for an event-free survival rate of 44% (95% confidence interval, 29%-59%). The median progression-free survival was 2.4 months and the median overall survival was 8.6 months. Four patients achieved a partial response; the median duration of response was 15.1 months. No complete remissions were observed. Treatment was in general well tolerated with only 1 patient discontinuing therapy due to toxicity (hyperlipidemia). CONCLUSIONS: The combination of TMZ and RAD001 was well tolerated but failed to meet/exceed our study threshold for promising clinical activity in patients with metastatic melanoma.

Adverse events during the titration phase of interferon-beta in remitting-relapsing multiple sclerosis are not predicted by body mass index nor by pharmacodynamic biomarkers.

BACKGROUND: This study aimed to correlate body mass index or biomarkers with the frequency of common adverse events (AEs) with subcutaneous IFN ß-1a during treatment titration in patients with relapsing-remitting multiple sclerosis previously naïve to IFN ß. METHODS: Eighty-four patients (66.3% females) were followed up during 8 weeks, 25.3% were overweight and 14.5% were obese. RESULTS: Biomarkers steadily increased during all study period by 45.3% for ß2-microglobulin, 262.8% for olygoadenylate synthetase-1, and 92.8% for neopterin. Overall AE reporting did not vary with the dose or treatment duration. CONCLUSIONS: BMI was not predictive of increased risk for AEs. Biomarkers did not discriminate on the frequency of any AE either.

A randomized phase 2 study of temozolomide and bevacizumab or nab-paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV melanoma : a North Central Cancer Treatment Group study, N0775.

BACKGROUND: Increasing evidence shows chemotherapy in combination with vascular endothelial growth factor (VEGF) inhibition is a clinically active therapy for patients with metastatic melanoma (MM). METHODS: A phase 2 trial was conducted in chemotherapy-naive patients with unresectable stage IV MM who were randomized to temozolomide (200 mg/m(2) on days 1 through 5) and bevacizumab (10 mg/kg intravenously on days 1 and 15) every 28 days (Regimen TB) or nab-paclitaxel (100 mg/m(2) , or 80 mg/m(2) post-addendum 5 secondary to toxicity, on days 1, 8, and 15), bevacizumab (10 mg/kg on days 1 and 15), and carboplatin (area under the curve [AUC] 6 on day 1, or AUC 5 post-addendum 5) every 28 days (Regimen ABC). Accrual goal was 41 patients per regimen. The primary aim of this study was to estimate progression-free survival rate at 6 months (PFS6) in each regimen. A regimen would be considered promising if its PFS6 rate was > 60%. RESULTS: Ninety-three eligible patients (42 TB and 51 ABC) were enrolled. The majority of patients had M1c disease (20 TB and 26 ABC). The median PFS and overall survival times with ABC were 6.7 months and 13.9 months, respectively. Median PFS time and median overall survival with TB were 3.8 months and 12.3 months, respectively. The most common severe toxicities (≥ grade 3) in both regimens were cytopenias, fatigue, and thrombosis. Among the first 41 patients enrolled onto each regimen, PFS6 rate was 32.8% (95% confidence interval: 21.1%-51.2%) for TB and 56.1% (90% confidence interval: 44.7%-70.4%) for ABC. CONCLUSIONS: The addition of bevacizumab to nab-paclitaxel and carboplatin shows promising activity despite tolerability issues.

Epratuzumab with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated diffuse large B-cell lymphoma.

Approximately 60% of patients with diffuse large B-cell non-Hodgkin lymphoma (DLBCL) are curable with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemoimmunotherapy. Epratuzumab (E) is an unlabeled anti-CD22 monoclonal antibody with efficacy in relapsed DLBCL. This phase 2 trial tested the safety and efficacy of combining E with R-CHOP (ER-CHOP) in untreated DLBCL. A secondary aim was to assess the efficacy of interim positron emission tomography (PET) to predict outcome in DLBCL. Standard R-CHOP with the addition of E 360 mg/m(2) intravenously was administered for 6 cycles. A total of 107 patients were enrolled in the study. Toxicity was similar to standard R-CHOP. Overall response rate in the 81 eligible patients was 96% (74% CR/CRu) by computed tomography scan and 88% by PET. By intention to treat analysis, at a median follow-up of 43 months, the event-free survival (EFS) and overall survival (OS) at 3 years in all 107 patients were 70% and 80%, respectively. Interim PET was not associated with EFS or OS. Comparison with a cohort of 215 patients who were treated with R-CHOP showed an improved EFS in the ER-CHOP patients. ER-CHOP is well tolerated and results appear promising as a combination therapy. This study was registered at www.clinicaltrials.gov as #NCT00301821.

Phase 2 trial of carboplatin, weekly paclitaxel, and biweekly bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N047A.

BACKGROUND: Vascular endothelial growth factor (VEGF) plays an important role in the growth and metastatic progression of melanoma. Exposure of melanoma cells to chemotherapy induces VEGF overproduction, which in turn may allow melanoma cells to evade cell death and become chemotherapy resistant. Therefore, in patients with metastatic melanoma, the combination of chemotherapy with an agent that specifically targets VEGF might be able to control tumor growth and progression more effectively than chemotherapy alone. METHODS: A 2-stage phase 2 clinical trial was conducted in patients with unresectable stage IV (metastatic) melanoma to assess antitumor activity and the toxicity profile of the combination of carboplatin (area under the curve 6 iv on Day 1 of a 28-day cycle), paclitaxel (80 mg/m2 iv on Days 1, 8, and 15), and bevacizumab (10 mg/kg iv on Days 1 and 15). Treatment was continued until progression or intolerable toxicity. RESULTS: Fifty-three patients (62.3% male) were enrolled. Nine (17%) patients achieved partial remission, and another 30 (57%) achieved stable disease for at least 8 weeks. Median progression-free survival and median overall survival were 6 months and 12 months, respectively. One patient died after 8 treatment cycles from intracranial hemorrhage into undiagnosed brain metastases. The most common severe (grade>or=3) toxicities were neutropenia (53%), thrombocytopenia (11%), hypertension (9%), and anemia (8%). CONCLUSIONS: This combination of carboplatin, paclitaxel, and bevacizumab appears to be moderately well tolerated and clinically beneficial in patients with metastatic melanoma. Further study of this combination is warranted.

Very long-term objective evaluation of heller myotomy plus posterior partial fundoplication in patients with achalasia of the cardia.

OBJECTIVE: To present the objectively assessed very long-term results of a prospective study of 149 patients with achalasia of the cardia who underwent Heller myotomy and posterior partial fundoplication. SUMMARY BACKGROUND DATA: Very few studies evaluate objectively the very long-term results to analyze whether the effectiveness of Heller myotomy is maintained with the passing of time. METHODS: The study group consisted of 149 patients who underwent a Heller myotomy plus a posterior partial fundoplication through a laparotomy. The median follow-up was 6 years (range, 1-27 years). Follow-up period was over 10 years in 53 patients and over 15 in 36. Clinical, radiologic, endoscopic, manometric, and pHmetric evaluations were performed postoperatively. RESULTS: Satisfactory results were higher than 90% up to 5 years. From that time on results gradually decreased to a 75% rate after 15 years (P < 0.001) due to either heartburn or dysphagia. Both the esophageal diameter and the mean resting pressure of the lower esophageal sphincter decreased postoperatively with no significant changes during follow-up. Esophagitis appeared in 11% of the patients (47% of them being asymptomatic) and 24-hour pH monitoring showed pathologic rates of acid reflux in 14% of patients, 58% of them being asymptomatic. Both esophagitis and pathologic rates of reflux appeared in >40% of the patients late in the follow-up. CONCLUSION: Results after Heller myotomy plus posterior partial fundoplication deteriorate with time, although we achieved a 75% of satisfactory results after >15 years of follow-up. Our study highlights the importance of life long follow-up and the objective assessment of the results.

Pioderma gangrenoso asociado a colitis ulcerosa y compromiso laringotraqueal / Pioderma gangrenosum associated with ulcerative colitis and airways involvement

Se describe el caso de una mujer de 63 años con lesiones ulcerosas extensas en el abdomen y enfermedad inflamatoria intestinal, que desarrolló mutilanteslesiones laringotraqueales luego de breves entubaciones orotraqueales para limpieza quirúrgica de las heridas bajo anestesia general. La grave ydesproporcionada afectación laringotraqueal de esta paciente fue secundaria al fenómeno de patergia subyacente, por lo cual debemos manejar concuidado las vías aéreas en este tipo de enfermedades

A 63 year-old woman with extensive ulcerative lesions in the abdominal area and inflammatory bowel disease who developed mutilating airwayslesions after short period of orotracheal intubation for surgical cleanliness of wounds under general anesthesia is reported. The extensive and severelaringotracheal involvement in this case was secondary to the pathergy phenomena, for this reason we have to manage carefully the airways in thiscondition