Efficacy and safety of recombinant human lymphotoxin-α derivative with cisplatin and fluorouracil in patients with metastatic esophageal squamous cell carcinoma: A randomized, multicenter, open-label, controlled, phase 2b trial.

BACKGROUND: Recombinant human lymphotoxin-α derivative (rhLTα-Da) is a lymphotoxin-α derivative that is missing 27 N-terminal amino acid residues. Previous studies indicated a benefit from the addition of rhLTα-Da to cisplatin-based treatment in patients with metastatic esophageal squamous cell carcinoma. The current study was conducted to evaluate the efficacy and safety of rhLTα-Da plus cisplatin and fluorouracil (PF) in patients with mESCC. METHODS: Patients from 15 centers in China were randomly assigned (1:1:1) to 3 arms (arm A, PF plus 10 µg/m2 daily rhLTα-Da; arm B, PF plus 20 µg/m2 daily rhLTα-Da; arm C, PF alone). The primary endpoints included progression-free survival (PFS) and the confirmed overall response rate (ORR). An exploratory analysis was performed to evaluate the role of serum tumor necrosis factor receptor II (TNFR II) in predicting the efficacy of rhLTα-Da. RESULTS: Between September 2010 and May 2013, 150 patients were enrolled. No significant differences in either PFS or ORR were observed between the 3 arms. However, in a small subset of patients who had low serum TNFR II levels, the median PFS was significantly longer for those in arm B than for these in other 2 arms (7.2 months [95% confidence interval, 5.1-8.6 months] for arm B vs 3.5 months [95% confidence interval, 1.7-5.5 months] for arm A [P = .022] and 4.0 months [95% confidence interval, 3.2-6.3 months] for arm C [P = .027]). The addition of rhLTα-Da significantly increased the incidence of chills (P < .001). CONCLUSIONS: rhLTα-Da combined with the PF regimen failed to improve PFS and ORR in patients with mESCC, except in a small subset that had low serum TNFR II concentrations. Cancer 2017;123:3986-94. © 2017 American Cancer Society.

Gene polymorphisms in the TNF locus and the risk of myocardial infarction.

We investigated two genetic polymorphisms in the tumor necrosis factor locus (TNF-alpha -308 G-->A and LT-alpha +252 A-->G) as risk factors for coronary atherothrombotic disease (CAD) by determining its prevalence in 148 survivors of myocardial infarction (MI) with angiographically-proven severe CAD, and in 148 age-, gender- and race-matched controls. The odds ratio (OR) for MI related to the mutant TNF-alpha and LT-alpha alleles was 0.8 (CI95: 0.4-1.3) and 1. 3 (CI95: 0.8-2.0), respectively. We also sought interaction of smoking and metabolic risk factors for MI with each mutant genotype. Smokers not carrying the LT-alpha +252 A-->G mutation had a risk of MI of 2.7 (CI95: 1.4-5.4) whereas in smoking carriers the risk was 6. 9 (CI95: 3.4-14.1). An interactive effect of the LT-alpha mutation may also exist with dyslipidemia (OR for MI in non-carriers was 12 [CI95: 3.2-41.3] and in carriers the OR was 39, [CI95: 5.1-301] and with obesity (OR for MI was 2.7, [CI95: 1-7.2] in non-carriers and in carriers the OR was 6 [CI95: 2.1-16.8]). Lastly, the OR for MI in obese non-carriers of TNF-alpha -308 G-->A was 2.8 (CI95: 1.3-6) and in obese carriers the OR was 14.5 (CI95: 1.8-113). Although significant interactive effects could not be detected, the findings suggest that interaction of polymorphisms in the TNF locus with major risk factors for CAD may exist, and should be explored in larger studies.

[Results of Befnorin clinical trails in healthy volunteers]. / Rezul'taty klinicheskogo ispytaniia preparata benforina na zdorovykh dobrovol'tsakh.

Clinical trails of Befnorin based on the human recombinant TNF-beta elaborated at the Research Design and Technology Institute of Biologically Active Substances, "Vector" State Research Center of Virology and Biotechnology, were carried out on healthy volunteers in compliance with a decision passed by the Committee of Medical and Immunobiological Preparations, Russia's Health Ministry. Single Befnorin doses of 5-10(4) U, 10(5) U, 5-10(5) U, and 10(6) U were administered as intramuscular injections. Clinical, biochemical and immunological parameters were registered for 7 days after a single dose. The drug had an impact on the below immunity indices: Fc-phagocytosis of monocytes, migration index and migration inhibition index. The dose of 10(5) U was proven to be most effective and safe. Supposedly, the drug can be effective in the treatment of herpetic diseases.

[Phase I clinical trial of intravenous recombinant human lymphotoxin-alpha derivative].

BACKGROUND & OBJECTIVE: Intravenous recombinant human lymphotoxin-alpha derivative (rhLTalpha-Da) is a novel biological antitumor reagent developed in China. This study was to evaluate the tolerance of tumor patients to rhLTalpha-Da, confirm its maximum tolerable dose (MTD) in vivo, and to provide recommending dose for phase II trial. METHODS: The dose escalation of rhLTalpha-Da was as follows: 10 microg.(m2.day)-1, 20 microg.(m2.day)-1, and 33 microg.(m2.day)-. Each group contained at least 3 patients. rhLTalpha-Da was solved in 5% GS (100 ml), and intravenously infused over 30 minutes daily for 5 consecutive days. RESULTS: A total of 24 patients were enrolled. Grade I-III chill and fever were the most common adverse events, with the occurrence rate of 79.2% (19/24). Other adverse events observed were dyspnea (3/24), nausea/vomiting (3/24), headache (4/24), fatigue (2/24), hypotension (2/24), and skin discomfort at irradiation region (2/24). No obvious abnormity of liver and renal functions was observed. The dose-limiting toxicities (DLT), which occurred at dose level of 33 microg.(m2.day)-1, were grade III chill, grade III fever, and grade III dyspnea. Although there was no definite efficacy showed in this primary study, initial response to rhLTalpha-Da was seen on a minority of patients with cancers, including malignant melanoma, mycosis fungoides, and renal carcinoma. CONCLUSIONS: The MTD of rhLTalpha-Da is 33 microg.(m2.day)-1. The recommended dose for phase II clinical trial is 20 microg.(m2.day)-1.

Are cytokines in platelet concentrates responsible for febrile transfusion reactions?

In recent years, several studies have identified the leukocyte content and the age of the blood components as dominant factors in febrile transfusion reactions (FTRs). At present, extensive efforts are being made to reduce adverse effects by implementation and/or introduction of new methods for leuko-depletion of blood components and by studying the mechanisms responsible for these phenomena. A recent approach has been the evaluation of cytokines in platelet concentrates and this issue has been addressed with some detail in this review. Comparative data currently available on levels of cytokines in the different platelet concentrates is provided along with the functional role of the detected cytokines in including adverse reactions.

Human lymphotoxin mutein lacks hypotensive activity but has higher in vivo antitumor activity than lymphotoxin or tumor necrosis factor.

A serious drawback of tumor necrosis factor alpha (TNF) as a clinical antitumor agent is that it also has hypotensive activity. To overcome this problem, derivatives of its sister cytokine lymphotoxin (TNF-beta or LT) were prepared. One of them, mutein 2 (Mut2) has a deletion of amino acids 1-7 but contains substituted amino acids, Met-Phe-Pro at positions 8-10 of the mature human LT. This mutein has no hypotensive activity at the maximum dose (10 mg/kg) tested on rats. In contrast, a much lower dose (1 mg/kg) of TNF and LT caused a significant blood pressure drop. In vivo studies revealed that Mut2 was more effective than TNF or LT against MethA (a mouse tumor line) as judged by the therapeutic ratio [calculated as LD50 (dose that kills 50% of the animals)/ED50 (dose that reduces the tumor size by 50%)]. With five other different mouse tumors and two different human tumors, Mut2 was also effective and the effectiveness was comparable or superior to that of TNF or LT. These results suggest the possibility that this derivative may be usable as a clinical antitumor agent without the serious side effects associated with TNF.

In vivo effects of recombinant human lymphotoxin on human medulloblastoma xenograft: enhancement of antitumor activity of etoposide.

The authors investigated the antitumor activities of rHuLT alone and in combination with etoposide on human meduloblastoma xenografts growing subcutaneously in nude mice. Intravenous administration of rHuLT (1.0 x 10(5) U/kg, 5.0 x 10(5)U/kg, 2.5 x 10(6)U/kg, three times a week for three weeks) suppressed medulloblastoma growth depending on the dose. However, the highest dosage caused serious side effects. Combining rHuLT (intravenously, 5.0 x 10(5)U/kg, three times a week for three weeks) with etoposide (intraperitoneally, 20mg/kg, once a week for three weeks) increased the antitumor activity without causing serious toxicity. Microscopically, tumor specimen showed thrombosed tumor vessels and massive necrosis 3 weeks after rHuLT treatment. Ultrastructural examination revealed that 120 minutes after the administration of rHuLT alone, disruption of interendothelial junctions was evident, and that the endothelial cells were destroyed at 240 minutes. Concentration of etoposide in tumor tissue peaked 30 minutes after intraperitoneal administration, and then decreased with time. When etoposide was administered in combination with rHuLT, the concentration of etoposide in tumor tissue after 60 to 240 minutes was significantly higher than when etoposide was given alone, and the area under the concentration versus time curve was also greater for the tumors of mice with combination treatment. The findings suggest that the proper combination of rHuLT and etoposide may have synergistic antitumor activities. Histological changes suggest that increased concentrations of etoposide within the tumor after combination therapy may occur due to increased vascular permeability and/or decreased etoposide clearance which is the result of blood statis in the tumor vasculature.

Eficacia y seguridad de ustekinumab y secukinumab en pacientes adultos con psoriasis vulgar severa, con falla terapéutica a terapia sistémica convencional, fototerapia y terapia biológica con antagonistas del factor de necrosis tumoral disponibles en EsSalud / Efficacy and safety of ustekinumab and secukinumab in adult patients with severe psoriasis vulgaris, with therapeutic failure to conventional systemic therapy, phototherapy and biological therapy with tumor necrosis factor antagonists available in EsSalud

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad de ustekinumab y secukinumab para el tratamiento de pacientes adultos con psoriasis vulgar severa, con falla terapéutica a terapia sistémica convencional, fototerapia y terapia biológica con antagonistas del factor de necrosis tumoral (anti-FNT) disponibles, en comparación con la mejor terapia de soporte paliativo (MTSP). La psoriasis es la enfermedad auto inflamatoria crónica dermatológica más frecuente, la cual tiene una prevalencia cercana al 2.5 % en el Perú. La psoriasis vulgar es la forma clínica más común, la cual puede clasificarse, según la severidad, en leve, moderada y severa, de acuerdo a los instrumentos de medición clínica, tales como el Psoriasis Area and Severity Index (PASI), el Dermatology Life Quality Index (DLQI) y el grado de afectación de la superficie corporal total (SCT). La psoriasis severa se define como aquella que cuenta con un PASI ≥ 10, o un DLQI ≥ 10 o la afectación ≥ 10 % del área de SCT. La importancia clínica de la clasificación de acuerdo a la severidad de la psoriasis radica en el tratamiento, el cual requiere de medidas sistémicas para las formas severas. El Petitorio Farmacológico de EsSalud cuenta con terapia tópica, fototerapia, y terapia sistémica convencional (i. e. metotrexato, ciclosporina y acitretina), para el tratamiento de pacientes con psoriasis vulgar severa. Luego de falla terapéutica a los tratamientos mencionados, se cuenta con terapia biológica con los antagonistas del factor de necrosis tumoral (anti-FNT), tales como infliximab, etanercept y adalimumab. La mejor terapia de soporte paliativa (MTSP) se utiliza en los pacientes con psoriasis vulgar severa que presentan falla terapéutica a todos los tratamientos antes mencionados, y consiste en el uso de terapia tópica, fototerapia y terapia sistémica convencional de forma paliativa. METODOLOGÍA: Se llevó a cabo una búsqueda bibliográfica exhaustiva y jerárquica de la literatura con respecto a la eficacia y seguridad de ustekinumab y secukinumab para el tratamiento de pacientes adultos con psoriasis vulgar severa con falla terapéutica a terapia tópica, fototerapia, terapia sistémica convencional y terapia biológica anti-FNT (i. e. infliximab, etanercept, y adalimumab); comparados con el placebo o la MTSP. La búsqueda se inició revisando la información sobre el uso del medicamento de acuerdo con entidades reguladoras como FDA, EMA y DIGEMID en el Perú. Además, se realizó una búsqueda sistemática en las principales bases de datos, tales como MEDLINE vía PubMed y en Cochrane Library. Asimismo, se realizó una búsqueda manual en las páginas web de grupos dedicados a la investigación y educación en salud que elaboran guías de práctica clínica y/o evaluación de tecnologías sanitarias: National Institute for Health and Care Excellence (NICE), Canadian Agency for Drugs and Technologies in Health (CADTH), Scottish Medicines Consortium (SMC), Haute Authorité de Santé (HAS), la Institute for Quality and Efficiency in Health Care (IQWiG), la Institute for Clinical and Economic Review (ICER) y el Ministerio de Salud del Perú (MINSA). Además, se realizó una búsqueda de las guías de las principales sociedades o instituciones especializadas en dermatología y en psoriasis, tales como la American Academy of Dermatology (AAD), la British Association of Dermatologists (BAD), la European Academy of Dermatology and Venereology (EADV), y la International Psoriasis Council (IPC). Por último, se buscaron ensayos clínicos en desarrollo o que no hayan sido publicados en la página web www.clinicaltrials.gov que contengan información acerca de las tecnologías evaluadas, y así disminuir el sesgo de publicación. RESULTADOS: De acuerdo con la pregunta PICO, se llevó a cabo una búsqueda de evidencia científica relacionada al uso de ustekinumab y secukinumab como tratamiento de pacientes adultos con psoriasis vulgar severa con falla terapéutica a terapia tópica, fototerapia, terapia sistémica convencional y terapia biológica anti-FNT (i. e. infliximab, etanercept, y adalimumab); comparados con el placebo o la MTSP. En la presente sinopsis se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad (GPC, ETS, RS, MA y ECA fase III). Los ECA fueron agrupados en tres comparaciones: (i) ustekinumab vs. placebo o la MTSP; (ii) secukinumab vs. placebo o la MTSP; (iii) secukinumab vs. ustekinumab. CONCLUSIONES: El presente dictamen evaluó la evidencia científica disponible a la actualidad en relación a la eficacia y seguridad de secukinumab y ustekinumab comparados con la MTSP y el placebo en pacientes adultos con psoriasis vulgar severa con falla terapéutica a terapia tópica, fototerapia, terapia sistémica convencional, y terapia biológica anti-FNT disponibles en EsSalud, en términos de PASI 75, DLQI, SCT, y EA. Nuestra revisión de la evidencia disponible hasta agosto del 2019, agrupadas en tres comparaciones (ustekinumab vs. placebo, secukinumab vs. placebo y secukinumab vs. ustekinumab) permitió identificar una GPA de la BAD del Reino Unido y nueve ECA como las principales fuentes de información para la evaluación de los efectos de secukinumab y ustekinumab en nuestra población de interés. El Equipo Técnico del IETSI llevó a cabo un MA con los ECA incluidos para derivar las conclusiones del presente dictamen. Respecto a la comparación ustekinumab vs. placebo, se evidenció un balance riesgo beneficio favorable para ustekinumab en la población de la pregunta PICO a corto plazo (12 semanas), en vista que presentó diferencias clínicamente relevantes y estadísticamente significativas respecto al PASI 75, DLQI 0-1 y DLQI, en la población total de los estudios incluidos. Además, ustekinumab mostró un similar riesgo de presentar EAT, EAS, TII y TIS que el placebo, mientras que presentó un menor riesgo de DT a causa de EA. El MA de la comparación de secukinumab vs. placebo mostró un balance riesgo beneficio favorable para secukinumab en la población de la pregunta PICO a corto plazo (12 semanas), dado que se evidenciaron diferencias clínicamente relevantes y estadísticamente significativas respecto al PASI 75 y DLQI 0-1, a favor de secukinumab, mientras que secukinumab y placebo presentaron un similar riesgo de desenlaces clave de seguridad, tales como EAS, DT por EA y TIS en la población total de los estudios incluidos. Para la comparación de secukinumab vs. ustekinumab, se realizó un MA de los resultados a corto plazo (12 semanas) y se analizaron los resultados del ECA CLEAR a largo plazo (52 semanas). Los resultados de eficacia mostraron que tanto a corto como a largo plazo, las diferencias entre secukinumab y ustekinumab respecto al PASI 75 y al DLQI 0-1 fueron estadísticamente significativas, pero con intervalos de confianza cercanos al punto de no diferencia, y estuvieron sujetas a las limitaciones que presentan los desenlaces de naturaleza subjetiva (PASI y DLQI) que luego de ser ajustadas para convertirlos en desenlaces categóricos (PASI 75 y DLQI 0-1) podrían representar diferencias espurias. Es decir, tanto a corto como a largo plazo, se tiene que secukinumab y ustekinumab presentarían una eficacia similar en la población de la pregunta PICO. Asimismo, el análisis de los EA mostró que secukinumab y ustekinumab presentarían un perfil de seguridad similar en la población de la pregunta PICO. En vista que, tanto a corto como a largo plazo, no se presentaron diferencias respecto al riesgo de presentar desenlaces clave de seguridad, tales como EAS y DT por EA. Los resultados muestran que secukinumab y ustekinumab presentan un balance riesgo beneficio comparable en la población de la pregunta PICO del presente dictamen preliminar. En vista que, el impacto presupuestario sería menor con el uso de secukinumab que con ustekinumab (diferencia en alrededor de S/ 12,053.80, a favor de secukinumab), la aprobación de secukinumab sería la decisión más costo-oportuna para un sistema de salud público como EsSalud. Por lo expuesto, el Instituto de Evaluaciones de Tecnologías en Salud e Investigación ­ IETSI aprueba el uso de secukinumab para el manejo de los pacientes con psoriasis vulgar severa con falla terapéutica a terapia tópica, fototerapia, terapia sistémica convencional y terapia biológica anti-FNT disponibles en EsSalud.

Fibrosis pulmonar mortal, con etanercept como posible desencadenante / Etanercept as a possible trigger of fatal pulmonary fibrosis

La fibrosis pulmonar es una enfermedad que puede estar causada por agentes externos como determinados fármacos. Desde hace un tiempo se utilizan fármacos antagonistas del factor de necrosis tumoral (TNF) para ciertas enfermedades autoinmunitarias, siendo un ejemplo de estos fármacos el etanercept. Las fibrosis secundarias a medicamentos se caracterizan por la respuesta a la retirada del fármaco y a esteroides. En muy raras ocasiones se produce una fibrosis irreversible. Presentamos el caso de un paciente que desarrolló una fibrosis pulmonar tras iniciar tratamiento con etanercept y que tuvo un curso clínico nefasto a pesar de la retirada del anti-TNF y dosis altas de esteroides

Pulmonary fibrosis can be caused by external agents, including certain drugs. For some time now, tumor necrosis factor antagonists such as etanercept have been used to treat certain autoimmune diseases. Fibrosis caused by medication responds to withdrawal of the drug and treatment with corticosteroids. Very rarely, fibrosis is irreversible. We present the case of a patient who developed pulmonary fibrosis after initiating treatment with etanercept. The clinical course was fulminant despite withdrawal of the drug and high doses of corticosteroids (AU)

Factor de necrosis tumoral y terapéutica / Tumor necrosis factor and therapeutic

El factor de necrosis tumoral (TNF) alfa (caquectina) y beta (linfotoxina) son citoquinas involucradas en un amplio espectro de actividades biológicas. La inflamación, reparación tisular, coagulación, crecimiento y diferenciación de células hematopoyéticas progenitoras, mecanismos efectores de la respuesta inmune, bacteremia por gram negativos, choque séptico, actividad antitumoral, reacción injerto versus huésped están relacionadas a la bioactividad de TNF. Sus efectos secundarios han sido neutralizados terapéuticamente mediante el uso de anticuerpos monoclonales antilipopolisacáridos y anti TNF, inmunoadhesina contra el receptor TNF, Pentoxifilina, Cloroquina, Dexametasona y Colchicina. Debido a sus eficaces resultados in vitro, el TNF ha sido usado en enfermedadesmalignas en forma regional mediante la infusión arterial o como inmunoquimioterapia sistémica