Purpose
To evaluate incidence and predictive factors for the vascular lake phenomenon (VLP), as well as to compare local and overall tumor response in patients with and without VLP induced during ...DEB-TACE for HCC.
Methods
A total of 200 consecutive patients with 323 HCC nodules underwent first-session DEB-TACE from 2011 to 2014. Patients were divided in two groups, according to the presence of the VLP during DEB-TACE. Pre- and post-treatment imaging studies (CT or MRI) were performed. Primary endpoint was assessment of tumor response, evaluated by mRECIST. Comparison of response rates between the VLP group and the non-VLP group was performed. Secondary endpoints were the determination of incidence rate and predictive factors for the VLP.
Results
The VLP was observed in 39/323 (12.1%) of the nodules treated. At multivariate logistic regression analysis, tumor size ≥3 cm in diameter (OR 13.95; 95% CI 3.60–54.05), presence of a pseudocapsule (OR 6.67; 95% CI 1.45–30.59) and alpha-fetoprotein levels (OR 1.004; 95% CI 1.000–1.007) remained predictive for the VLP occurrence. On a nodule-based analysis (
p
< 0.001), target lesion response analysis (
p
= 0.003) and overall response analysis (
p
= 0.004) the VLP group presented a higher objective response rate than the non-VLP group.
Conclusion
VLP is observed in 12% of the patients and happens more frequently in large and encapsulated tumors. It seems to be associated with better local and overall responses in HCC patients who underwent DEB-TACE.
We have established a link between the global ac response and the local flux distribution of superconducting films by combining magnetic ac susceptibility, dc magnetization, and magneto-optical ...measurements. The investigated samples are three Nb films: a plain specimen, used as a reference sample, and other two films patterned with square arrays of antidots. At low temperatures and small ac amplitudes of the excitation field, the Meissner screening prevents penetration of flux into the sample. Above a certain ac drive threshold, flux avalanches are triggered during the first cycle of the ac excitation. The subsequent periodic removal, inversion, and rise of flux occurs essentially through the already-created dendrites, giving rise to an ac susceptibility signal weakly dependent on the applied field. The intradendrite flux oscillation is followed, at higher values of the excitation field, by a more drastic process consisting of creation of new dendrites and antidendrites. In this more invasive regime, the ac susceptibility shows a clear field dependence. At higher temperatures a smooth penetration occurs, and the flux profile is characteristic of a critical state. We have also shown that the regime dominated by vortex avalanches can be reliably identified by ac susceptibility measurements.
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Introduction. Observational studies from patients treated outside controlled clinical trials offer real life information and are relevant to understand whether data derived from prospective trials ...are reproducible in the clinical practice. A retrospective observational study was carried out by the GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) group in order to evaluate the clinical characteristics and outcome of patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib in Italy within a Named Patient Program (NPP). The NPP was intended to offer free and early drug access to CLL patients until ibrutinib became available on the Italian market.
Methods. Patients included in the NPP program had refractory or relapsed (R/R) disease with progression within 24 months after prior chemo-immunotherapy, and/or 17p deletion/TP53 mutations. Patients were also required to have an ECOG performance status ≤2; serum creatinine ≤2 times, liver enzymes ≤3 times and total bilirubin ≤1.5 times the upper limit of normal. Key exclusion criteria were: the need of a concomitant treatment with a strong CYP3A inhibitor or warfarin, an allogeneic stem cell transplantation within the past 6 months or an ongoing active infection. All patients included in the program received ibrutinib orally as a single agent at the standard dose of 420 mg daily. Clinical data of 110 patients included in the NPP program between January 2014 and November 2014 have so far been collected and analyzed using the Research Electronic Data Capture (REDCap) system. Patients were managed at 20 Italian centers and received at least one dose of ibrutinib. Clinical data were reported by the treating physicians.
Results. The median age of patients was 69.9 years (range 49.8-83.3); 53% were in Rai stage III-IV, 32% in stage II and 15% in stage 0-I. Sixty-two percent of patients had relapsed disease, 38% were refractory to prior treatment. The presence of a 17p deletion and/or TP53 mutations was recorded in 51 R/R patients. Eighty-six percent of patients had an unmutated IGHV gene profile. The median number of prior treatments was 3 and included allogeneic stem cell transplantation in 4 cases. Two or more comorbidities were reported in 57 patients (52%) and included atrial fibrillation (AF) in 10 (9.1%) and hypertension in 40 (36.4%). After a median follow-up of 12.1 months (range, 1.6-24.6), 87 patients (79%) were still on ibrutinib. A response to ibrutinib was reported in 98/110 patients (89.1%). The best recorded response was a CR/CRi in 19 patients (17.3%), while a PR was reported in 79 patients (72%; PR-L 21.1%). Similar response rates were observed in patients with unmutated IGHV genes (91.9%) and in those with 17p deletion/TP53 mutations (90.3%). At 12 months, the progression-free survival (PFS) and overall survival (OS) were 92.9% (95%CI: 87.9-98.2) and 95.2% (95%CI: 91.1-99.4), respectively. PFS at 12 months of patients who achieved a response was 96.3%, 98.9% in unmutated IGHV patients, 90.7% in those with 17p deletion/TP53 mutations. Five patients (4.5%) died during the NPP program (1 patient each for sepsis, heart failure, ileus perforation, cancer, unknown cause). Adverse events (AE) were recorded in 75 patients (68.2%); in 47 (42.7%) they were grade ≥3. Any grade AEs recorded in ≥5% of patients were: infections (35%; grade ≥3, 22%), granulocytopenia (18.8%; grade ≥3, 17.2%), bleeding (15.5%; grade ≥3, 2.7%), fever of unknown origin or febrile neutropenia (12%; grade ≥3, 5.4%), AF (10.9%; grade ≥3, 4.5%), diarrhoea (8.3; grade ≥3, 2%), hypertension (7.2%; grade ≥3, 5.4%). A new event of AF occurred in 1/10 patients with a prior history of AF. Warfarin was required in 1 patient with AF and this was the reason for ibrutinib discontinuation.
Conclusions. The results of the first interim analysis of this retrospective, real life study confirms that ibrutinib, as a single agent, is an effective treatment for patients with poor-prognosis CLL. Our data also suggest that ibrutinib given to unselected patients, in a compassionate-use program, shows a clinical activity and a safety profile comparable to those reported in prospective trials. Data collection is ongoing in order to complete the analysis of this large NPP cohort in Italy.
Marasca:Roche: Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria. Coscia:Karyopharm: Research Funding; ROCHE: Honoraria, Other: Advisory board; Janssen: Honoraria; Gilead: Honoraria; Mundipharma: Honoraria. Zinzani:Abbvie: Membership on an entity’s Board of Directors or advisory committees; Roche: Membership on an entity’s Board of Directors or advisory committees; Janssen: Membership on an entity’s Board of Directors or advisory committees; MorphoSys: Membership on an entity’s Board of Directors or advisory committees; Takeda: Membership on an entity’s Board of Directors or advisory committees; Celegene: Membership on an entity’s Board of Directors or advisory committees. Molica:Jansen: Membership on an entity’s Board of Directors or advisory committees; Abbvie: Membership on an entity’s Board of Directors or advisory committees; Roche Italy: Membership on an entity’s Board of Directors or advisory committees; Gilead Sciences: Speakers Bureau. Orlandi:Ariad: Honoraria; BMS: Honoraria; Novartis: Honoraria. Ghia:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria; Adaptive Biotechnology: Consultancy; Roche: Honoraria, Research Funding. Foà:Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; BMS: Consultancy; Genentech: Consultancy; Pfizer: Speakers Bureau; Ariad: Speakers Bureau.
This paper describes the development process of the Pesquisa Nacional sobre Acesso, Utilização e Promoção do Uso Racional de Medicamentos (PNAUM - National Survey on Access, Use and Promotion of ...Rational Use of Medicines) based on an integrated approach to pharmaceutical services, science, technology and innovation. It starts by contextualizing health and development in Brazil and features elements of the National Policy for Science, Technology and Innovation in Health in Brazil and the National Policy for Pharmaceutical Services. On presenting pharmaceutical policy guidelines, it stresses the lack of nationwide data. This survey, commissioned by the Brazilian Ministry of Health, has two components: household survey and evaluation of pharmaceutical services in primary care. The findings point to perspectives that represent, besides the enhancement of public policy for pharmaceutical services and public health, results of government action aimed at developing the economic and industrial health care complex to improve the health conditions of the Brazilian population. RESUMO O artigo apresenta o processo de construção da Pesquisa Nacional sobre Acesso, Utilização e Promoção do Uso Racional de Medicamento a partir de uma concepção integradora da Assistência Farmacêutica, Ciência, Tecnologia e Inovação. Inicia-se contextualizando a saúde e o desenvolvimento no País e apresenta elementos da Política Nacional de Ciência Tecnologia e Inovação em Saúde no Brasil e da Política Nacional de Assistência Farmacêutica. Ao apresentar as diretrizes das Políticas Farmacêuticas, destaca-se a carência de dados de abrangência nacional. A presente pesquisa, encomendada pelo Ministério da Saúde, foi estruturada em dois componentes: inquérito domiciliar e avaliação dos serviços de assistência farmacêutica na atenção básica. As perspectivas dos resultados representam, além do incremento das políticas públicas farmacêuticas e de saúde pública, resultados de ações governamentais voltadas ao desenvolvimento do complexo econômico-industrial da saúde, visando a melhoria das condições de saúde da população brasileira.
To verify the association between the presence of specific anti-52 Ro/SSA-p200 antibodies and congenital heart block (CHB).
207 pregnant Italian women carrying anti-Ro/SSA Ab were retrospectively ...evaluated. Anti-p200 Ab were investigated in the mothers' sera by ELISA (Euro-Diagnostica,Wieslab SS-A p200).
CHB occurred in 42 children (34 complete CHB), whereas 165 were not affected. All CHB cases were previously identified with an ELISA screening for anti-Ro/SSA 60 kD Ab. Anti-p200 Ab were more frequently positive (81.0% vs. 59.1%, p=0.013) and at a higher titer in CHB mothers (Absorbance ratio: 2.030 (0.208-4.052) vs. 0.925 (0.200-3.816); p=0.017). This association was maintained even when the 42 mothers of children with CHB were compared with a control group matched for age and diagnosis (80.9% vs. 50.0%; p=0.006). The presence of anti-p200 Ab provided an odds ratio (OR) for CHB of 2.98 (CI: 1.30-6.83), which was higher than that of other variables, such as maternal disease and other antibody specificities. CHB risk significantly decreased in the absence of this fine specificity (OR:0.34, CI: 0.15-0.77). However, while the negative predictive value related to anti-Ro/SSA 60 kD Ab ELISA was 100%, almost 20% of mothers negative for anti-p200 Ab delivered babies with CHB.
Anti-p200 antibodies seem to be associated with CHB with a higher probability than anti-Ro/SSA Ab, and therefore may be an additional test to identify mothers at higher risk to deliver affected children. An ELISA screening for anti-Ro/SSA 60 kD Ab is nevertheless mandatory given the probability of developing CHB also in the absence of anti-p200 Ab.
Rheumatic autoimmune diseases have a higher prevalence in women, particularly during their childbearing age. Due to improved management, an increasing number of patients plan and carry out one or ...more pregnancies. Therefore, a growing interest is being paid to the possible consequences of maternal disease and associated treatment on the fetus and newborn infant. If maternal disease is characterized by the presence of IgG isotype autoantibodies, these can cross the placenta with possible antibody-mediated damage to the fetus. This is typically the case of the so called neonatal lupus erythematosus (NLE); a similar mechanism has been shown in infants of patients with immune thrombocytopenic purpura (ITP) and, less frequently, in those from mothers with antiphospholipid syndrome (APS). Indeed, this last condition is often responsible for placental, rather than neonatal, pathology. In addition, immunosuppressive and other drugs administered to the mothers during pregnancy and lactation might affect the fetal and neonatal immune system development. Finally, mothers disease and/or treatment could be related to neuropsychological alteration reported in some of their children.
Because the real benefit of pulmonary valve replacement (PVR) in patients with repaired tetralogy of Fallot who develop pulmonary insufficiency remains unclear, it is necessary to analyze the ...evidence published around the world. We performed a systematic review of studies that reported data about the effect of PVR in patients with repaired tetralogy of Fallot that developed pulmonary insufficiency, until December 2012. The variables chosen to represent the benefit were both right ventricular (RV) and left ventricular measures, QRS duration, and functional class. The principal summary measures were difference in means with 95% confidence interval and p values (considered statistically significant when p < 0.05). The differences in means were combined across studies with the weighted DerSimonian-Laird random effects model. Meta-analysis, sensitivity analysis, and meta-regression were completed with the software Comprehensive Meta-Analysis (version 2, Biostat, Inc., Englewood, New Jersey). Forty-eight studies involving 3,118 patients met the eligibility criteria. The pooled 30-day mortality was 0.87% (47 studies; 27 of 3,100 patients); the pooled 5-year mortality was 2.2% (24 studies; 49 of 2,231 patients); the pooled 5-year re-PVR was 4.9% (15 studies; 88 of 1,798 patients). The results of this meta-analysis demonstrate that after PVR: 1) the RV experiences improvement of its volumes and function; 2) the left ventricle experiences improvement of its function; 3) QRS duration decreases; 4) symptoms improve; 5) pre-operative RV geometry modulates the effect of PVR; and 6) there is important heterogeneity of the effects among the studies, and few publication biases. In conclusion, PVR seems to be a positive approach in the analyzed scenario.
In the last two decades, RNA interference pathways have been employed as a useful tool for reverse genetics in trypanosomatids. Angomonas deanei is a nonpathogenic trypanosomatid that maintains an ...obligatory endosymbiosis with a bacterium related to the Alcaligenaceae family. Studies of this symbiosis can help us to understand the origin of eukaryotic organelles. The recent elucidation of both the A. deanei and the bacterium symbiont genomes revealed that the host protozoan codes for the enzymes necessary for RNAi activity in trypanosomatids. Here, we tested the functionality of the RNAi machinery by transfecting cells with dsRNA to a reporter gene (green fluorescent protein), which had been previously expressed in the parasite and to α-tubulin, an endogenous gene. In both cases, protein expression was reduced by the presence of specific dsRNA, inducing, respectively, a decreased GFP fluorescence and the formation of enlarged cells with modified arrangement of subpellicular microtubules. Furthermore, symbiont division was impaired. These results indicate that the RNAi system is active in A. deanei and can be used to further explore gene function in symbiont-containing trypanosomatids and to clarify important aspects of symbiosis and cell evolution.
The possible existence of a humoral communication between glial cells and LHRH-secreting neurons has been studied using the LHRH-secreting GT1-1 cell line and type 1 astrocytes. Two different designs ...have been adopted: 1) GT1-1 cells were coincubated with purified cultures of type 1 rat astrocytes, and 2) GT1-1 cells were exposed to the conditioned medium (CM) in which type 1 rat astrocytes had been grown for 24 h. LHRH was measured by RIA in the medium of the GT1-1 cell cultures at different time intervals. The data show that short periods (1, 3, and 6 h) of either coculture or exposure to previously frozen CM significantly increase the release of LHRH from the GT1-1 cells. However, more prolonged times of coculture (e.g. 2 and 5 days) or exposure to CM (e.g. 48 h) induce a significant decrease in the amount of LHRH in the medium. The stimulatory effect on LHRH release appears to be specific for type 1 astrocytes (either cortical or hypothalamic), because neither the CM of oligodendrocytes nor the CM of LNCaP cells (a cell line derived from a human prostatic cancer) possess stimulating activities. Heating the type 1 astrocyte-CM to 100 C for 10 min does not eliminate the ability of the CM to significantly increase the release of LHRH from GT1-1 cells at 1, 3, and 6 h. Because of the opposite effects encountered in the short and long term experiments, it was hypothesized that the CM might contain, in addition to LHRH-releasing principle(s), LHRH-degrading properties. Known amounts of standard LHRH were then added to type 1 astrocyte-CM, either untreated or submitted to heating at 100 C for 10 min. The amount of LHRH added to untreated CM decreases progressively; on the contrary, the amount of LHRH added to heated CM remains unchanged. These results confirm that one or more heat-sensitive enzymes able to degrade LHRH may be present in the type 1 astrocyte-CM. As previously mentioned, the experiments reported so far were performed using type 1 astrocyte-CM that had been kept frozen for various periods of time, before being tested for its LHRH-releasing activity. Surprisingly, fresh CM proves to be inactive, whereas heated CM is effective; this suggests that the factor involved might be activated by the two opposite experimental procedures.
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