Biologic therapies for refractory juvenile dermatomyositis: five years of experience of the Childhood Arthritis and Rheumatology Research Alliance in North America.

BACKGROUND: The prognosis of children with juvenile dermatomyositis (JDM) has improved remarkably since the 1960's with the use of corticosteroid and immunosuppressive therapy. Yet there remain a minority of children who have refractory disease. Since 2003 the sporadic use of biologics (genetically-engineered proteins that usually are derived from human genes) for inflammatory myositis has been reported. In 2011-2016 we investigated our collective experience of biologics in JDM through the Childhood Arthritis and Rheumatology Research Alliance (CARRA). METHODS: The JDM biologic study group developed a survey on the CARRA member experience using biologics for Juvenile DM utilizing Delphi consensus methods in 2011-2012. The survey was completed online by the CARRA members interested in JDM in 2012. A second survey was similarly developed that provided more opportunity to describe their experiences with biologics in JDM in detail and was completed by CARRA members in Feb 2013. During three CARRA meetings in 2013-2015, nominal group techniques were used for achieving consensus on the current choices of biologic drugs. A final survey was performed at the 2016 CARRA meeting. RESULTS: One hundred and five of a potential 231 pediatric rheumatologists (42%) responded to the first survey in 2012. Thirty-five of 90 had never used a biologic for Juvenile DM at that time. Fifty-five of 91 (denominators vary) had used biologics for JDM in their practice with 32%, 5%, and 4% using rituximab, etanercept, and infliximab, respectively, and 17% having used more than one of the three drugs. Ten percent used a biologic as monotherapy, 19% a biologic in combination with methotrexate (mtx), 52% a biologic in combination with mtx and corticosteroids, 42% a combination of a biologic, mtx, corticosteroids (steroids), and an immunosuppressive drug, and 43% a combination of a biologic, IVIG and mtx. The results of the second survey supported these findings in considerably more detail with multiple combinations of drugs used with biologics and supported the use of rituximab, abatacept, anti-TNFα drugs, and tocilizumab in that order. One hundred percent recommended that CARRA continue studying biologics for JDM. The CARRA meeting survey in 2016 again supported the study and use of these four biologic drug groups. CONCLUSIONS: Our CARRA JDM biologic work group developed and performed three surveys demonstrating that pediatric rheumatologists in North America have been using multiple biologics for refractory JDM in numerous scenarios from 2011 to 2016. These survey results and our consensus meetings determined our choice of four biologic therapies (rituximab, abatacept, tocilizumab and anti-TNFα drugs) to consider for refractory JDM treatment when indicated and to evaluate for comparative effectiveness and safety in the future. Significance and Innovations This is the first report that provides a substantial clinical experience of a large group of pediatric rheumatologists with biologics for refractory JDM over five years. This experience with biologic therapies for refractory JDM may aid pediatric rheumatologists in the current treatment of these children and form a basis for further clinical research into the comparative effectiveness and safety of biologics for refractory JDM.

Conocimiento, aceptación y uso de medicina tradicional peruana y de medicina alternativa/complementaria en usuarios de consulta externa en Lima Metropolitana / Knowdlege, aceptation and use of peruvian traditional medicine and complementary/alternative medicine in users from outpatient services in Lima Metropolitana

Objetivo: Determinar los conocimientos, aceptación y uso de la Medicina Tradicional Peruana y la Medicina Alternativa/Complementaria en usuarios de consulta externa de en establecimientos de salud de Lima Metropolitana. Materiales y Métodos: Se realizó una encuesta validada en 351 usuarios de consulta externa de ocho establecimientos de salud pertenecientes al Ministerio de Salud (MINSA) y Seguro Social de Salud (EsSalud) donde se evaluaron los patrones de uso, conocimiento y aceptación de terapias de Medicina Tradicional Peruana (MTC) y Medicina Complementaria/Alternativa (MAC). Resultados: La terapia de MTP más conocida, aceptada y usada fue la pasada de huevo (71.5%, 67.5% y 58.1%) mientras que en el caso de las terapias de MAC fue la fitoterapia (63.8%, 72.1% y 59.5%), La MTP mayormente fue usada solo 1-2 veces y un 29.6% refirió el uso de MAC, como la fitoterapia, en todos sus episodios de enfermedad. La razón más frecuente de aceptación es la "integración a la medicina convencional" (20.5% en MTP y 29.9% en MAC) y las de no aceptación fueron el no tener bases científicas (14.8% en MTP) o no estar reconocida legalmente (29.9% en MAC). Conclusión: La terapia de MTP más conocida, aceptada y usada fue la pasada de huevo, mientras que en el caso de MAC fue la fitoterapia. Las terapias de MTP suelen ser menos usadas que las terapias MAC por los encuestados. Estos procedimientos suelen ser realizados en el domicilio del paciente y son aceptados por la posibilidad de integración con la medicina convencional.

Results of induction chemotherapy in children older than 18 months with stage-4 neuroblastoma treated with an adaptive-to-response modified N7 protocol (mN7)

Purpose. We report the response rate in children older than 18 months with stage 4 Neuroblastoma, using a modified dose-intensive, response-adaptive, induction mN7 protocol. Methods. From 2005 to 2012, 24 patients were treated with the mN7 protocol. Phase 1 included five MSKCC N7 cycles and surgery and two high-dose cyclophosphamide-topotecan (HD-CT) cycles for those who did not achieve complete remission (CR) and negative bone marrow (BM) minimal residual disease (MRD) status (CR+MRD-). Phase 2 consisted of myeloablative doses of topotecan, thiotepa and carboplatin plus hyperfractionated RT. Phase 3 included isotretinoin and 3F8 immunotherapy plus GM-CSF. BM MRD was monitored using GD2 synthase, PHOX2B and cyclin D1 mRNAs. Results. After 3 cycles, all patients showed BM complete histological clearance and 6 (25 %) were MRD-. Twenty of 21 s-look surgeries achieved macroscopic complete resection. After 5 cycles and surgery, 123I-MIBG scan was negative in 15 (62.5 %) cases, BM disease by histology was negative in 23 (96 %) and 10 (42 %) patients were MRD-. Twelve (50 %) pts were in CR, 2 in very good partial response (VGPR), 9 partial response (PR) and one had progressive disease. With 2 HD-CT extra cycles, 17 (71 %) pts achieved CR+MRD- status moving to phase 2. Overall and event-free survival at 3 years for the 17 patients who achieved CR+MRD- is 65 and 53 %, respectively, median follow-up 47 months. Seven (29 %) patients never achieved CR+MRD-. Univariate Cox regression analysis shows CR+MRD- status after mN7 induction as the only statistically significant prognostic factor to predict overall survival. Conclusions. mN7 induction regimen produced a CR+MRD- rate of 71 %. CR+MRD- status following induction was the only predictive marker of long-term survival (AU)

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Results of induction chemotherapy in children older than 18 months with stage-4 neuroblastoma treated with an adaptive-to-response modified N7 protocol (mN7).

PURPOSE: We report the response rate in children older than 18 months with stage 4 Neuroblastoma, using a modified dose-intensive, response-adaptive, induction mN7 protocol. METHODS: From 2005 to 2012, 24 patients were treated with the mN7 protocol. Phase 1 included five MSKCC N7 cycles and surgery and two high-dose cyclophosphamide-topotecan (HD-CT) cycles for those who did not achieve complete remission (CR) and negative bone marrow (BM) minimal residual disease (MRD) status (CR+MRD-). Phase 2 consisted of myeloablative doses of topotecan, thiotepa and carboplatin plus hyperfractionated RT. Phase 3 included isotretinoin and 3F8 immunotherapy plus GM-CSF. BM MRD was monitored using GD2 synthase, PHOX2B and cyclin D1 mRNAs. RESULTS: After 3 cycles, all patients showed BM complete histological clearance and 6 (25 %) were MRD-. Twenty of 21 s-look surgeries achieved macroscopic complete resection. After 5 cycles and surgery, (123)I-MIBG scan was negative in 15 (62.5 %) cases, BM disease by histology was negative in 23 (96 %) and 10 (42 %) patients were MRD-. Twelve (50 %) pts were in CR, 2 in very good partial response (VGPR), 9 partial response (PR) and one had progressive disease. With 2 HD-CT extra cycles, 17 (71 %) pts achieved CR+MRD- status moving to phase 2. Overall and event-free survival at 3 years for the 17 patients who achieved CR+MRD- is 65 and 53 %, respectively, median follow-up 47 months. Seven (29 %) patients never achieved CR+MRD-. Univariate Cox regression analysis shows CR+MRD- status after mN7 induction as the only statistically significant prognostic factor to predict overall survival. CONCLUSIONS: mN7 induction regimen produced a CR+MRD- rate of 71 %. CR+MRD- status following induction was the only predictive marker of long-term survival.

Comparative feeding value of distillers dried grains plus solubles as a partial replacement for steam-flaked corn in diets for calf-fed Holstein steers: characteristics of digestion, growth performance, and dietary energetics.

Two experiments were conducted to examine the effect of level of dried distillers grains plus solubles (DDGS) supplementation (0, 10, 20, and 30%; DM basis), replacing steam-flaked (SF) corn in finishing diets, on characteristics of digestion (Exp. 1) and growth performance (Exp. 2) in calf-fed Holstein steers. In Exp.1, 4 cannulated Holstein steers (349 ± 12 kg) were used to evaluate treatment effects on characteristics of digestion. Ruminal NDF digestion tended to increase (quadratic effect, P = 0.09) and ruminal OM digestion decreased (linear effect, P = 0.01) with DDGS substitution. There were no treatment effects on duodenal flow of microbial N (MN). Substitution with DDGS increased (linear effect, P < 0.01) N flow to the small intestine. The undegradable intake protein (UIP) value of DDGS was 35%. Postruminal digestion of OM (linear effect, P = 0.04) and fatty acids (linear effect, P = 0.03) and total tract digestion of OM and GE decreased (linear effect, P < 0.03) with increasing level of DDGS substitution. Substitution with DDGS did not affect (P = 0.80) ruminal pH but increased (linear effect, P = 0.01) acetate:propionate molar ratio. In Exp.2, 144 Holsteins steer (112 ± 6 kg) were used in a 305-d trial to evaluate treatment effects on growth performance and carcass characteristics. During the initial 126 d, DDGS substitution increased ADG (linear effect, P = 0.03), G:F (quadratic effect, P = 0.03), and dietary NE (quadratic effect, P = 0.02), maximal for both at 20% DDGS inclusion rate. Based on estimated indispensable AA supply to the small intestine as a percentage of requirements during the initial 126-d period, histidine was first limiting followed by methionine. During the final 179-d period and overall (305-d feeding period), treatment effects on ADG and G:F were small (P ≥ 0.22). Compared with the other treatments, HCW was greater (3.4; P = 0.03) at the 20% level of DDGS substitution. The NE value for DDGS in SF corn-based diets for the calf-fed Holstein are consistent with current tabular standards. Extra-caloric value of DDGS as a metabolizable AA source is apparent during the initial growing phase. The UIP value of DDGS used in this study (35%) was considerably less than current tabular estimates (52%; NRC, 2000).

Feeding value of dried shredded sugarbeets as a partial replacement for steam-flaked corn in finishing diets for feedlot cattle.

Two experiments were conducted to evaluate the comparative feeding value of dried shredded sugarbeets (DSSB; 0, 20, and 40% of diet DM) as a replacement for steam-flaked corn (SFC) in finishing diets for feedlot cattle. In Exp. 1, 60 calf-fed Holstein steers (476 ± 6.3 kg) were used in a 97-d finishing trial. Substitution of SFC with DSSB did not affect ADG or DMI (P > 0.20). Increasing DSSB decreased gain efficiency (ADG:DMI; linear effect, P = 0.04) and dietary NE (linear effect, P = 0.03). Given that SFC has a NE(m) value of 2.38 Mcal/kg, the replacement NE(m) and NE(g) values for DSSB were 1.94 and 1.29 Mcal/kg, respectively. There were no treatment effects (P > 0.20) on carcass characteristics. In Exp. 2, 6 cannulated Holstein steers (205 kg) were used in a replicated 3 × 3 Latin square design to evaluate treatment effects on digestion. Ruminal digestion of starch, NDF, and feed N were not affected (P > 0.10) by DSSB, although ruminal OM digestion tended to increase (linear effect, P < 0.08). Replacing SFC with DSSB decreased flow of starch to the small intestine, but it increased flow of microbial N (linear effect, P = 0.05). There were no treatment effects (P > 0.14) on postruminal digestion of OM, NDF, starch, or feed N or total tract digestion of OM, starch, and N. Substitution of DSSB increased (linear effect, P = 0.05) total tract NDF digestion and decreased (linear effect, P = 0.05) dietary DE (Mcal/kg). Given that SFC has a DE value of 4.19 Mcal/kg, the replacement DE value of DSSB was 3.68 Mcal/kg. There were no treatment effects (P > 0.12) on ruminal pH or total VFA; however, DSSB decreased propionate (linear effect, P = 0.05) and increased acetate (linear effect, P = 0.07), butyrate (linear effect, P = 0.05), valerate (linear effect, P = 0.04), and estimated methane production (linear effect, P = 0.05). We concluded that DSSB may replace SFC in finishing diets at levels of up to 40% without detrimental effects on ADG and carcass characteristics. The NE value of DSSB is 82% that of SFC (DM basis). Partial replacement of SFC with DSSB alters ruminal VFA patterns, increasing estimated methane energy loss and slightly decreasing the efficiency of DE utilization.

Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma.

Cyclin D dysregulation and overexpression is noted in the majority of multiple myeloma (MM) patients, suggesting its critical role in MM pathogenesis. Here, we sought to identify the effects of targeting cyclin D in MM. We first confirmed cyclin D mRNA overexpression in 42 of 64 (65%) patient plasma cells. Silencing cyclin D1 resulted in >50% apoptotic cell death suggesting its validity as a potential therapeutic target. We next evaluated P276-00, a clinical-grade small-molecule cyclin-dependent kinase inhibitor as a way to target the cyclins. P276-00 resulted in dose-dependent cytotoxicity in MM cells. Cell-cycle analysis confirmed either growth arrest or caspase-dependent apoptosis; this was preceded by inhibition of Rb-1 phosphorylation with associated downregulation of a range of cyclins suggesting a regulatory role of P276-00 in cell-cycle progression through broad activity. Proliferative stimuli such as interleukin-6, insulin-like growth factor-1 and bone-marrow stromal cell adherence induced cyclins; P276-00 overcame these growth, survival and drug resistance signals. Because the cyclins are substrates of proteasome degradation, combination studies with bortezomib resulted in synergism. Finally, in vivo efficacy of P276-00 was confirmed in an MM xenograft model. These studies form the basis of an ongoing phase I study in the treatment of relapsed/refractory MM.

Yodo y embarazo: resultados de un estudio en una población de mujeres embarazadas sanas del sureste andaluz / Iodine and pregnancy: Results of a population’s study of healthy pregnant women in the south-est of Andalucia (Spain)

En España estudios recientes han demostrado que la ingesta de yodo en las mujeres embarazadas es baja, incluso en zonas donde teóricamente hay programas institucionales para promover el consumo de sal yodada para la prevención de la deficiencia de yodo. Nuestro estudio muestra que en la población de mujeres gestantes de Málaga la ingesta de yodo está por debajo de las recomendaciones nutricionales. La eliminación de yodo por la orina va aumentando a lo largo del embarazo, produciéndose un incremento del tamaño del volumen tiroideo al final del mismo. Aunque no se encontró una correlación individual entre el volumen tiroideo y la eliminación de yodo por la orina, los resultados sugieren claramente que el incremento en el volumen tiroideo es la consecuencia de una disfunción tiroidea a lo largo del embarazo. Esta disfunción del tiroides se corresponde con lo esperado en una situación de yododeficiencia. A pesar de existir en distintas zonas de España unas campañas de salud pública recomendando la utilización de sal yodada, los resultados de distintos estudios nos muestran que este aporte es insuficiente en las mujeres gestantes, con el consecuente riesgo que conlleva para el desarrollo fetal. Los resultados del presente estudio apoyan la conveniencia de instaurar programas sistemáticos de suplementación de yodo durante el embarazo

In Spain several studies have demonstrated that iodine intake of pregnant women is low. Our study shows that in the south-west (Malaga), the intake of iodine in the population of pregnant women is under the nutritional recommendations. The iodine urine elimination increases during the pregnancy with an increasing of the thyroid volume during pregnancy. There is no individual correlation between thyroid volume and urine iodine elimination, but the results suggest the origin of the thyroid dysfunction thought the pregnancy is the increased thyroid volume. Besides the health public campaign of using iodine salt in several zones of Spain, the results of some studies shown that this supplementation is inadequate, with the risk for the fetal development. The results of this study support the necessity of systematic programmes of iodine supplementation during the pregnancy