Reações adversas medicamentosas em pacientes em quimioterapia e estratégias de intervenções / Adverse drug reactions in chemotherapy patients and intervention strategies / Reacciones adversas a medicamentos en pacientes quimioterápicos y estrategias de intervención

A quimioterapia do câncer pode ocasionar reações adversas medicamentosas (RAM), podendo resultar de interações medicamentosas (IM) e impactar na adesão. O presente estudo relatou as RAM apresentadas por pacientes em quimioterapia (QT) e propôs estratégias de intervenções. Este trabalho foi aprovado em comité de ética (5.160.503), sendo incluídos 23 pacientes em quimioterapia (oral- VO e/ou endovenosa- EV) e todos foram entrevistados. Recebiam apenas o QTEV, 20 pacientes e 2 QTEV e VO, a maioria em tratamento paliativo (50%), predomínio de estadiamento IV, sendo as doenças mais presentes de pâncreas (27,3%), estômago (22,7%) e mama (18,2%) e esquema mais usado foi Carboplatina + Paclitaxel. As principais comorbidades foram diabetes e hipertensão arterial. As interações medicamentosas foram classificadas em graves (45%), moderadas (55%) e intencional (75%), sendo necessário introdução de medicamentos de suporte (61%). Houve RAM de maior gravidade, neutropenia, sendo necessário a suspensão temporária, e de menor gravidade náuseas. Houve um óbito relacionado a evolução de doença e, talvez, o tratamento possa ter contribuído. Ao final, foram feitas as intervenções para cada caso e validado o formulário para a consulta farmacêutica a pacientes oncológicos.

Cancer chemotherapy can cause adverse drug reactions (ADRs), which can result from drug interactions (IM) and impact adherence. The present study reported the ADRs presented by patients undergoing chemotherapy (CT) and proposed intervention strategies. This work was approved by the ethics committee (5,160,503), and 23 patients on chemotherapy (oral-VO and/or intravenous-IV) were included and all were interviewed. Only received CTIV, 20 patients and 2 CTIV and VO, most in palliative treatment (50%), predominance of stage IV, being the most common diseases of pancreas (27.3%), stomach (22.7%) and breast (18.2%) and the most used regimen was Carboplatin + Paclitaxel. The main comorbidities were diabetes and arterial hypertension. Drug interactions were classified as severe (45%), moderate (55%) and intentional (75%), requiring the introduction of supportive drugs (61%). There were more severe ADRs, neutropenia, requiring temporary suspension, and less severe nausea. There was one death related to the evolution of the disease and, perhaps, the treatment may have contributed. At the end, interventions were made for each case and the form for the pharmaceutical consultation to cancer patients was validated.

La quimioterapia contra el cáncer puede causar reacciones adversas a los medicamentos (RAM), que pueden ser consecuencia de interacciones farmacológicas (IM) y repercutir en la adherencia. El presente estudio reportó las RAM presentadas por pacientes en quimioterapia (QT) y propuso estrategias de intervención. Este trabajo fue aprobado en comité de ética (5.160.503), se incluyeron 23 pacientes en quimioterapia (oral- VO y/o endovenosa-EV) y todos fueron entrevistados. Recibieron sólo QTEV, 20 pacientes y 2 QTEV y VO, la mayoría en tratamiento paliativo (50%), predominio de estadiaje IV, siendo las enfermedades más presentes las de páncreas (27,3%), estómago (22,7%) y mama (18,2%) y el esquema más utilizado fue Carboplatino + Paclitaxel. Las principales comorbilidades fueron la diabetes y la hipertensión arterial. Las interacciones farmacológicas se clasificaron como graves (45%), moderadas (55%) e intencionadas (75%), requiriendo la introducción de fármacos de apoyo (61%). La RAM más grave fue la neutropenia, que requirió la suspensión temporal, y la menos grave las náuseas. Hubo una muerte relacionada con la evolución de la enfermedad y, tal vez, el tratamiento pudo haber contribuido. Al final, se realizaron intervenciones para cada caso y se validó el formulario de consulta farmacéutica a pacientes oncológicos.

Low-dose paclitaxel modulates the cross talk between the JNK and Smad signaling in primary biliary fibroblasts

SUMMARY OBJECTIVE: The objective of this study was to explore the molecular mechanism underlying the occurrence of benign bile duct stricture and the target of low-dose paclitaxel in the prevention of benign bile duct stricture. METHODS: Under the stimulation of transforming growth factor beta 1, the expression of collagen type I and connective tissue growth factor were detected on isolated primary fibroblasts. The phosphorylation levels of JNK and Smad2L were detected using Western blot. The effect of low-dose paclitaxel on the transforming growth factor beta 1-induced inhibition of type I collagen and connective tissue growth factor expression and JNK and Smad2L phosphorylation was also observed. RESULTS: Transforming growth factor beta 1 induced the secretion of type I collagen and connective tissue growth factor as well as JNK phosphorylation in biliary fibroblasts. The JNK inhibitor or siRNA-Smad2 inhibited the transforming growth factor beta 1-induced secretion of type I collagen and connective tissue growth factor. Low-dose paclitaxel inhibited the expression of type I collagen induced by transforming growth factor beta 1 and may inhibit the secretion of collagen in biliary fibroblasts. CONCLUSION: The activation of JNK/Smad2L induced by transforming growth factor beta 1 is involved in the occurrence of benign bile duct stricture that is mediated by the overexpression of type I collagen and connective tissue growth factor, and low-dose paclitaxel may inhibit the phosphorylation of JNK/Smad2L.

Avaliação do tratamento quimioterápico paliativo com o esquema LDE- paclitaxel em pacientes portadores de metástases ósseas por neoplasia maligna / Evaluation of palliative chemotherapy treatment with the LDEpaclitaxel regimen in patients with bone metastases from malignant neoplas

Introdução: Pacientes com câncer em estádios avançados e metástases ósseas frequentemente não apresentam condições clínicas para a realização de esquemas quimioterápicos convencionais subsequentes, restringindo as opções de tratamento. Anteriormente, demonstramos que nanopartículas artificiais lipídicas (LDE), semelhantes à lipoproteína de baixa densidade (LDL) rica em colesterol, são captadas por tecidos malignos, e quando associadas aos quimioterápicos, após injeção pela via endovenosa, reduz drasticamente a toxicidade do tratamento. Os objetivos deste presente estudo foram avaliar a resposta clínica ao tratamento quimioterápico com paclitaxel (PTX) associado à LDE; avaliar as toxicidades clínicas e laboratorial, e a capacidade da associação LDE-PTX em reduzir a dor oncológica relacionada às metástases ósseas em pacientes com carcinoma de mama, próstata e pulmão, previamente tratados e não elegíveis para tratamento quimioterápico convencional subsequente. Métodos: Dezoito pacientes (8 com câncer de mama, 5 de próstata e 5 de pulmão) com metástases ósseas foram incluídos. O tratamento consistiu no esquema LDE-PTX na dose convencional do PTX (175 mg/m2 de superfície corpórea de 3/3 semanas) e os pacientes foram avaliados por resposta clínica, redução da dor óssea, uso de medicamentos opióides, e ocorrência de fraturas ósseas patológicas. Resultados: No total, 104 ciclos de quimioterapia foram realizados, e nenhum paciente apresentou toxicidade clínica, laboratorial, assim como não houve fraturas patológicas. Dos 18 pacientes incluídos, 9 tiveram sobrevida livre de progressão de doença 6 meses. Houve em todos os pacientes redução da dor óssea, permitindo substituição da medicação opióide por analgésico não opióide. Conclusão: A melhora significativa na dor óssea sem que tenha ocorrido toxicidade do tratamento, e o tempo de não progressão de doença 6 meses na metade dos pacientes sugere que esses pacientes tenham se beneficiado consistentemente do tratamento com a LDE-PTX. Portanto, a LDE-PTX pode tornar- se uma opção terapêutica interessante em pacientes com carcinomas de próstata, mama ou pulmão em estágios avançados e sem condições clínicas de se submeterem a outros esquemas quimioterápicos convencionais

Introduction: Patients with advanced cancer and bone metastases usually do not have clinical conditions to perform additional conventional chemotherapy regimens, restricting treatment options. Previously, we showed that lipid core nanoparticles (LDE), similar to cholesterol-rich low-density lipoprotein (LDL), are taken up by malignant tissues, and when associated to chemotherapy, after endovenous injection, it drastically decreases the toxicity of the treatment. The objectives of this study were to evaluate the clinical response to chemotherapy treatment with paclitaxel (PTX) associated with LDE; to evaluate the clinical and laboratorial toxicities, and the ability of the LDE-PTX to reduce cancer pain related to bone metastases in patients with breast, prostate or lung carcinoma, previously treated and not eligible for subsequent conventional chemotherapy treatment. Methods: Eighteen patients (8 with breast cancer, 5 with prostate and 5 with lung) with bone metastases were included. Treatment consisted of the LDE-PTX regimen at a conventional dose of PTX (175 mg/m2 body surface area, 3/3 weeks) and patients were evaluated for clinical response, reduction in bone pain, use of opioid medications, and the occurrence of pathological bone fractures. Results: In total, 104 chemotherapy cycles were performed, and none of the patients showed clinical or laboratorial toxicities, as well as there were no pathological fractures. Of the 18 patients evaluated, 9 had progression-fee survival 6 months. Patients had decrease in bone pain allowing replacement of opioid medication by another non-opioid analgesic. Conclusion: Significant improvement in bone pain without treatment toxicity, and time to disease progression of 6 months in half of the patients suggest that these patients have consistently benefited with LDE-PTX treatment. Therefore, LDE-PTX may become an interesting therapeutic option in patients with advanced stage of prostate, breast or lung carcinomas and without clinical conditions to undergo other conventional chemotherapy regimens

Is paclitaxel less cardiotoxic in the treatment of breast cancer before or after doxorubicin? / Qual estratégia terapêutica é menos cardiotóxica no tratamento do câncer de mama: uso de paclitaxel antes ou depois da doxorrubicina?

Background: The combination of doxorubicin (DOX) with paclitaxel (PTX) effectively treats breast cancer (BC). However, DOX-associated cardiotoxicity (CTX) is aggravated by the use of PTX. Consensus is lacking about which drug sequence involves the most CTX. Objectives: To evaluate whether DOX followed by PXT or the reverse sequence has the greatest cardiotoxic potential in the treatment of BC. Methods: Prospective study of women with primary BC who received four cycles of DOX and 12 infusions of PTX. Participants were divided into Group 1 (G1; PXT before DOX) and Group 2 (G2; DOX before PXT) at the discretion of the oncologist. CTX was defined as an absolute reduction in left ventricular ejection fraction (LVEF) > 10% to a value <53%. Patients underwentclinical evaluations and echocardiography before treatment (Phase 1) and one year after treatment (Phase 2). Results: Sixty-nine women were evaluated: 19 in G1 and 50 in G2. The groups had similar clinical characteristics. The doses of radiation, DOX, and PTX used were similar. Eight (11.6%) patients developed CTX: two (10.5%) in G1 and six (12.0%) in G2 (p=0.62). The mean LVEF was similar between groups in Phase 1 (G1=65.1±3.5%; G2=65.2±3.9%; p=0.96), with a significant reduction noted after one year in both groups: G1=61.4±8.1% (p=0.021) and G2=60.8±7.6% (p<0,001). Although lower, mean LVEF remained similar between groups after Phase 2 (p=0.79). Conclusions: In women with BC who underwent chemotherapy, the incidence of CTX at the end of the first year of treatment was similar regardless of whether DOX was used before or after PTX. (AU)

Investigation of effect of paclitaxel on netrin 1 and factor 8 in Ehrlich solid tumors / Investigación del efecto del paclitaxel en netrina 1 y factor 8 en tumores sólidos de Ehrlich

SUMMARY: Cancer known as a malignant tumor, is a class of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. The Ehrlich tumor is a mammary adenocarcinoma of mice developed in solid and ascitic forms. This study was aimed to investigate the effects of paclitaxel on Netrin 1 and Factor 8 expression and also in tumor cell proliferation, apoptosis, angiogenesis, and development of tumor in Ehrlich solid tumors treated with paclitaxel. In this study, 26 adult Balb/C male mice were used. 6 of them were used as stock. Ehrlich ascites cells taken from animals in stock were injected subcutaneously from the neck area to all animals. The mice were randomly assigned to two groups of ten rats per group. Paclitaxel treatment group 10 mg/kg were administered to mice intraperitoneally (i.p.) 4,9, and 14th days. 15th day the animals were sacrificed and tumor tissues were taken. Paraffin-embedded solid tumor sections were stained Hematoxylin & Eosin, Masson's Trichrome. Also solid tumor sections were stained immunohistochemically with Netrin1 and Factor 8. Tunel method was applied to determine apoptosis. Paclitaxel applied as a therapeutic Ehrlich solid tumor reduced the volume of tumors in the treatment groups. At the end of the experiments, in the treatment groups' significantly reduced the Netrin 1 expression and microvessel density compared to the group control. Also paclitaxel in the treatment group increased the number of apoptotic cells. We suggest that decreasing the expression of Netrin 1 would be reduced vessel density and increased apoptosis.

RESUMEN: El cáncer, conocido como tumor maligno, es una clase de enfermedad que involucra un crecimiento celular anormal con potencial de invadir o diseminarse a otras partes del cuerpo. El tumor de Ehrlich es un adenocarcinoma mamario de ratones desarrollado en formas sólidas y ascíticas. Este estudio tuvo como objetivo investigar los efectos del paclitaxel en la expresión de Netrin 1 y Factor 8 y también en la proliferación de células tumorales, apoptosis, angiogénesis y desarrollo de tumores sólidos de Ehrlich tratados con paclitaxel. En esta investigación se utilizaron 26 ratones machos Balb / C adultos. Seis de ellos se utilizaron como stock. Se inyectaron por vía subcutánea células de ascitis de Ehrlich tomadas de animales en la zona del cuello. Los ratones se asignaron aleatoriamente a dos grupos de diez ratas por grupo. Se administraron 10 mg/kg del grupo de tratamiento con paclitaxel a ratones por vía intraperitoneal (i.p.) 4, 9 y 14 días. El día 15 se sacrificaron los animales y se extrajeron los tejidos tumorales. Las secciones de tumor sólido incluidas en parafina se tiñeron con hematoxilina y eosina y tricrómico de Masson. También se tiñeron inmunohisto-químicamente secciones de tumor sólido con Netrin1 y Factor 8. Se aplicó el método Tunel para determinar la apoptosis. El paclitaxel aplicado como tumor sólido terapéutico de Ehrlich redujo el volumen de tumores en los grupos de tratamiento. Al final de los experimentos, en los grupos de tratamiento se redujo significativamente la expresión de Netrin 1 y la densidad de microvasos en comparación con el grupo control. Además, el paclitaxel en el grupo tratamiento aumentó el número de células apoptóticas. Sugerimos que la disminución de la expresión de Netrin 1 reduciría la densidad de los vasos y aumentaría la apoptosis.

LXYL-P1-2 immobilized on magnetic nanoparticles and its potential application in paclitaxel production

BACKGROUND: LXYL-P1-2 is the first reported glycoside hydrolase that can catalyze the transformation of 7-b-xylosyl-10-deacetyltaxol (XDT) to 10-deacetyltaxol (DT) by removing the D-xylosyl group at the C7 position. Successful synthesis of paclitaxel by one-pot method combining the LXYL-P1-2 and 10- deacetylbaccatin III-10-b-O-acetyltransferase (DBAT) using XDT as a precursor, making LXYL-P1-2 a highly promising enzyme for the industrial production of paclitaxel. The aim of this study was to investigate the catalytic potential of LXYL-P1-2 stabilized on magnetic nanoparticles, the surface of which was modified by Ni2+-immobilized cross-linked Fe3O4@Histidine. RESULTS: The diameter of matrix was 20­40 nm. The Km value of the immobilized LXYL-P1-2 catalyzing XDT (0.145 mM) was lower than that of the free enzyme (0.452 mM), and the kcat/Km value of immobilized enzyme (12.952 mM s 1 ) was higher than the free form (8.622 mM s 1 ). The immobilized form maintained 50% of its original activity after 15 cycles of reuse. In addition, the stability of immobilized LXYL-P1-2, maintained 84.67% of its initial activity, improved in comparison with free form after 30 d storage at 4 C. CONCLUSIONS: This investigation not only provides an effective procedure for biocatalytic production of DT, but also gives an insight into the application of magnetic material immobilization technology.

Design, manufacture and initial tests of a drug-eluting coronary stent / Diseño, fabricación y pruebas iniciales de una endoprótesis coronaria liberadora de fármaco

Abstract Introduction: A drug-eluting coronary stent is being developed at the National Institute of Cardiology of Mexico for the treatment of ischemic heart disease. Objective: To establish the best animal model for the tests, to show the advances in the drug-eluting stent prototype, to assess two drugs’ antiproliferative activity and histological results. Method: Smooth muscle cell culture tests were performed in order to assess sirolimus and paclitaxel antiproliferative properties. The drugs were encapsulated inside the polymeric matrix of the stents. Rabbits and pigs were used as animal models. Results: Sirolimus and paclitaxel showed an inhibitory effect, which was higher for the latter. Infrared spectroscopy and light and optical microscopy showed that the drug/polymer layer properly adhered to the stent. At a four-week follow-up, both animal models showed satisfactory clinical evolution and adequate histological response, although the porcine model was shown to be more suitable for future protocols. Conclusions: Preliminary tests of the drug-eluting stent provided bases for the development of a study protocol with an adequate number of pigs and with clinical angiographic and histopathological three-month follow-up.

Resumen Introducción: En el Instituto Nacional de Cardiología de México se desarrolla una endoprótesis (stent) coronaria liberadora de fármacos para el tratamiento de la cardiopatía isquémica. Objetivo: Establecer el mejor modelo animal para las pruebas, mostrar los avances en el prototipo del stent liberador de fármacos, evaluar la actividad antiproliferativa de dos fármacos y los resultados histológicos. Método: Se realizaron cultivos de células de músculo liso para evaluar las propiedades antiproliferativas de sirolimus y paclitaxel. Los fármacos fueron encapsulados en el interior de la matriz polimérica de los stents. Se emplearon conejos y cerdos como modelos animales. Resultados: Sirolimus y paclitaxel mostraron efecto inhibitorio, mayor en el segundo. La espectroscopia infrarroja y la microscopia óptica y electrónica mostraron que la capa del polímero con el fármaco se adhería adecuadamente al stent. A las cuatro semanas de seguimiento, ambos modelos animales mostraron evolución clínica satisfactoria y adecuada respuesta histológica, si bien el modelo porcino resultó más conveniente para protocolos futuros. Conclusiones: Las pruebas preliminares del stent liberador de fármaco brindó bases para desarrollar el protocolo con un número adecuado en cerdos y con seguimiento clínico angiográfico e histopatológico a tres meses.

Treatment with ß-elemene combined with paclitaxel inhibits growth, migration, and invasion and induces apoptosis of ovarian cancer cells by activation of STAT-NF-κB pathway

In this study, we aimed to analyze the anti-cancer effects of β-elemene combined with paclitaxel for ovarian cancer. RT-qPCR, MTT assay, western blot, flow cytometry, and immunohistochemistry were used to analyze in vitro and in vivo anti-cancer effects of combined treatment of β-elemene and paclitaxel. The in vitro results showed that β-elemene+paclitaxel treatment markedly inhibited ovarian cancer cell growth, migration, and invasion compared to either paclitaxel or β-elemene treatment alone. Results demonstrated that β-elemene+paclitaxel induced apoptosis of SKOV3 cells, down-regulated anti-apoptotic Bcl-2 and Bcl-xl gene expression and up-regulated pro-apoptotic P53 and Apaf1 gene expression in SKOV3 cells. Administration of β-elemene+paclitaxel arrested SKOV3 cell cycle at S phase and down-regulated CDK1, cyclin-B1, and P27 gene expression and apoptotic-related resistant gene expression of MDR1, LRP, and TS in SKOV3 cells. In vivo experiments showed that treatment with β-elemene+paclitaxel significantly inhibited ovarian tumor growth and prolonged the overall survival of SKOV3-bearing mice. In addition, the treatment inhibited phosphorylated STAT3 and NF-κB expression in vitro and in vivo. Furthermore, it inhibited migration and invasion through down-regulation of the STAT-NF-κB signaling pathway in SKOV3 cells. In conclusion, the data suggested that β-elemene+paclitaxel can inhibit ovarian cancer growth via down-regulation of the STAT3-NF-κB signaling pathway, which may be a potential therapeutic strategy for ovarian cancer therapy.

Analgesic and side effects of intravenous recombinant Ph alfa 1 beta

Background: Intrathecal injection of voltage-sensitive calcium channel blocker peptide toxins exerts analgesic effect in several animal models of pain. Upon intrathecal administration, recombinant Phα1β exerts the same analgesic effects as the those of the native toxin. However, from a clinical perspective, the intrathecal administration limits the use of anesthetic drugs in patients. Therefore, this study aimed to investigate the possible antinociceptive effect of intravenous recombinant Phα1β in rat models of neuropathic pain, as well as its side effects on motor, cardiac (heart rate and blood pressure), and biochemical parameters. Methods: Male Wistar rats and male Balb-C mice were used in this study. Giotto Biotech® synthesized the recombinant version of Phα1β using Escherichia coli expression. In rats, neuropathic pain was induced by chronic constriction of the sciatic nerve and paclitaxel-induced acute and chronic pain. Mechanical sensitivity was evaluated using von Frey filaments. A radiotelemeter transmitter (TA11PA-C10; Data Sciences, St. Paul, MN, USA) was placed on the left carotid of mice for investigation of cardiovascular side effects. Locomotor activity data were evaluated using the open-field paradigm, and serum CKMB, TGO, TGP, LDH, lactate, creatinine, and urea levels were examined. Results: Intravenous administration of recombinant Phα1β toxin induced analgesia for up to 4 h, with ED50 of 0.02 (0.01-0.03) mg/kg, and reached the maximal effect (Emax = 100% antinociception) at a dose of 0.2 mg/kg. No significant changes were observed in any of the evaluated motor, cardiac or biochemical parameters. Conclusion: Our data suggest that intravenous administration of recombinant Phα1β may be feasible for drug-induced analgesia, without causing any severe side effects.

Paclitaxel and spirulina co-loaded polymeric nanoparticles: in-vitro and in-vivo anticancer study

Paclitaxel spirulina nanoparticles were said to have promising anticancer activity against gastric cancer. Nanoparticles of paclitaxel-spirulina were prepared for treating gastric cancer using precipitation technique. The synergistic anticancer efficiency againstMKN45 cells retains when the paclitaxel and spirulina were encapsulated into nanoparticles. To increase the site specific delivery, intra-tumoral administration was carried in the in vivo evaluation. There was an increase in overall survival in an MKN45-transplanted mice model and notable improvement in anti-tumour efficacy when paclitaxel-spirulina nanoparticles were delivered through intra-tumoral administration. The further investigation of overall anticancer mechanism of these nanoparticles is made as a major part in this research. Hence, the conjecture of this research is that, the paclitaxel-spirulina encapsulated nanoparticles could be an effective chemotherapeutic formulation for gastric cancer.

Upregulation of miR-129-5p increases the sensitivity to Taxol through inhibiting HMGB1-mediated cell autophagy in breast cancer MCF-7 cells

Although Taxol has improved the survival of cancer patients as a first-line chemotherapeutic agent, an increasing number of patients develop resistance to Taxol after prolonged treatment. The potential mechanisms of cancer cell resistance to Taxol are not completely clear. It has been reported that microRNAs (miRNAs) are involved in regulating the sensitivity of cancer cells to various chemotherapeutic agents. In this study, we aimed to explore the role of miR-129-5p in regulating the sensitivity of breast cancer cells to Taxol. Cell apoptosis and autophagy, and the sensitivity of MCF-7 cells to Taxol were assessed with a series of in vitro assays. Our results showed that the inhibition of autophagy increased the Taxol-induced apoptosis and the sensitivity of MCF-7 cells to Taxol. Up-regulation of miR-129-5p also inhibited autophagy and induced apoptosis. Furthermore, miR-129-5p overexpression increased the sensitivity of MCF-7 cells to Taxol. High mobility group box 1 (HMGB1), a target gene of miR-129-5p and a regulator of autophagy, was negatively regulated by miR-129-5p. We found that interference of HMGB1 enhanced the chemosensitivity of Taxol by inhibiting autophagy and inducing apoptosis in MCF-7 cells. Taken together, our findings suggested that miR-129-5p increased the chemosensitivity of MCF-7 cells to Taxol through suppressing autophagy and enhancing apoptosis by inhibiting HMGB1. Using miR-129-5p/HMGB1/autophagy-based therapeutic strategies may be a potential treatment for overcoming Taxol resistance in breast cancer.

Evolução Clínica e Preditores da Neuropatia Periférica Induzida por Quimioterapia / Clinical Evolution and Predictors of Chemotherapy-Induced Peripheral Neuropathy / Evolución Clínica y Predictores de la Neuropatía Periférica Inducida por Quimioterapia

Introdução: Drogas antineoplásicas neurotóxicas estão frequentemente associadas à neuropatia periférica induzida por quimioterapia (NPIQ). Objetivo: Avaliar a evolução clínica dos pacientes expostos a tratamento antineoplásico potencialmente neurotóxico e identificar possíveis preditores clínicos e sociodemográficos para o desenvolvimento da NPIQ. Método: Estudo de coorte prospectiva com pacientes com diagnóstico de câncer de mama, ovário ou intestino em tratamento quimioterápico com paclitaxel, docetaxel ou oxaliplatina. Foram avaliados antes da quimioterapia (T1), no terceiro mês (T2) e 30-60 dias após interrupção do tratamento (T3). Todos responderam ao questionário de perfis sociodemográfico e clínico, foram avaliados por meio de exame clínico neurológico, pela escala de performance ECOG, escala hospitalar de ansiedade e depressão (HAD), escala de dor Short-cGuill, autorrelato de sintomas de NPIQ e avaliação com o questionário de neurotoxicidade induzida por antineoplásicos (CINQ). Resultados: Por meio de autorrelato, 75% da dos pacientes informaram apresentar sintomas de NPIQ. O CINQ evidenciou que 90% apresentaram algum grau de NPIQ em T2, enquanto 82,5% ainda persistiam em T3. Dor neuropática acometeu 42% da população (RR=1,429; IC95%=1,130-1,806). Os escores de ansiedade e depressão reduziram significativamente quando comparados ao início de tratamento (redução de 2,5 pontos na escala HAD, p<0,05). A capacidade funcional da população não mostrou alterações significativas. No T2, a escolaridade foi considerada preditora para autorrelato de sintomas de NPIQ (OR=1,314, IC95%=1,002-1,723, p=0,048). Conclusão:A baixa escolaridade pode comprometer a capacidade do paciente em relatar os sintomas da NPIQ. Este estudo chama a atenção para a necessidade de utilização de instrumentos específicos para detecção precoce da NPIQ.

Introduction: Neurotoxic antineoplastic drugs are frequently associated to chemotherapy-induced peripheral neuropathy (CIPN). Objective: To evaluate the clinical evolution of patients exposed to potentially neurotoxic antineoplastic treatment and to identify possible clinical and sociodemographic predictors for the development of CIPN. Method: Cohort prospective study with patients with breast, ovary or intestine diagnosis of cancer in chemotherapy treatment with paclitaxel, docetaxel or oxaliplatin. They were assessed before the chemotherapy (T1), in the third month (T2) and 30-60 days after the interruption of the treatment (T3). All the patients responded to the questionnaire of clinical and sociodemographic profiles, were evaluated through neurologic clinical exam, by the performance scale ECOG, by the Hospital Anxiety and Depression Scale - HAD, pain scale of Short-cGuill, self-report of symptoms of CIPN and evaluation with the questionnaire of antineoplastic-induced neurotoxicity (QAIN). Results: Through self-report, 75% of the patients presented symptoms of CIPN. The QAIN showed that 90% presented a certain degree of CIPN in T2, while 82.5% still persisted in T3. Neuropathic pain affected 42% of the population (RR = 1.429, CI95% = 1.130-1.806). Anxiety and depression scores significantly reduced when compared with the beginning of the treatment (reduction of 2.5 points in the scale HAD, p < 0.05). The functional capacity of the population did not show any significant change. The school level was considered a predictor of self-report of CIPN symptoms in T2 (OR = 1.314, CI95% = 1.002-1.723, p = 0.048). Conclusion: The low school level may taint the patient capacity to report CIPN symptoms. This study draws attention for the necessity to use specific instruments for early detection of CIPN.

Introducción: Los fármacos antineoplásicos neurotóxicos a menudo se asocian con neuropatía periférica inducida por quimioterapia (CIPN). Objetivo: Evaluar la evolución clínica de pacientes expuestos a tratamientos antineoplásicos potencialmente neurotóxicos e identificar posibles predictores clínicos y sociodemográficos para el desarrollo de CIPN. Método: Estudio de cohorte prospectivo con pacientes diagnosticadas con cáncer de mama, ovario o intestino sometidos a quimioterapia con paclitaxel, docetaxel u oxaliplatino. Se evaluaron antes de la quimioterapia (T1), en el tercer mes (T2) y 30-60 días después de la interrupción del tratamiento (T3). Todos respondieron el cuestionario de perfil sociodemográfico y clínico, se evaluaron mediante un examen neurológico clínico, la escala de rendimiento ECOG, la escala de ansiedad y depresión hospitalaria (HAD), la escala de dolor Short-cGuill, el autoinforme de los síntomas de CIPN y la evaluación con el cuestionario de neurotoxicidad inducida por antineoplásicos (CINQ). Resultados: Por autoinforme, el 75% de la población informó presentar síntomas de CIPN. El CINQ mostró que el 90% tenía algún grado de NPIQ en T2, mientras que el 82.5% aún persistía en T3. El dolor neuropático afectó al 42% de la población (RR = 1.429; IC del 95% = 1.130-1.806). Las puntuaciones de ansiedad y depresión disminuyeron significativamente en comparación con el valor inicial (reducción de 2.5 puntos HAD, p <0.05). La capacidad funcional de la población no mostró cambios significativos. En T2, la educación se consideró un predictor de síntomas CIPN autoinformados (OR=1.314, IC 95%=1.002-1.723, p=0,048). Conclusión: La baja educación puede comprometer la capacidad del paciente para informar los síntomas de CIPN. Este estudio llama la atención sobre la necesidad de utilizar instrumentos específicos para la detección temprana de CIPN.

The clinical efficacy and safety of paclitaxel combined with avastin for NSCLC patients diagnosed with malignant pleural effusion

Summary Objective: The current study aimed to investigate the clinical efficacy of paclitaxel combined with avastin for non-small cell lung cancer (NSCLC) patients diagnosed with malignant pleural effusion (MPE). Method: Total of 33 patients diagnosed with NSCLC as well as malignant pleural effusion were included. All of them received paclitaxel (175 mg/m2) and avastin (5 mg/kg). Clinical efficacy was evaluated using the total response rate, overall survival, progression-free survival and changes in MPE volume. Adverse events and rates of toxicities were examined as well. Results: The total response rate reached 77% while the overall survival and the median progression-free survival were respectively 22.2 months and 8.4 months. Toxicities of grade 3-4 consisted of neutropenia in 57% of patients, anemia in 17% of them, febrile neutropenia in 11%, as well as anorexia in 7%. No treatment-correlated deaths were found. Conclusion: Paclitaxel combined with avastin decreased MPE volume and increased survival rate of NSCLC patients via inhibiting vascular endothelial growth factor expression.

Citorreducción óptima en cáncer de ovario avanzado tratado con paclitaxel a dosis densa y carboplatino seguido de cirugía de intervalo en el Instituto Nacional de Enfermedades Neoplásicas del Perú / Optimal cytoreduction in advanced ovarian cancer treated with dose-dense paclitaxel and carboplatin followed by interval surgery at the Peruvian National Institute of Neoplastic Diseases

RESUMEN Objetivos. Determinar la tasa de citorreducción óptima en pacientes con cáncer de ovario avanzado que recibieron quimioterapia neoadyuvante con carboplatino y paclitaxel dosis densa seguido de cirugía de citorreducción de intervalo (CCI). Materiales y métodos. Estudio de una serie de casos retrospectiva de mujeres peruanas tratadas con quimioterapia neoadyuvante con carboplatino (AUC 6 mg/ml/min) y paclitaxel (80 mg/m2 semanal) seguido de CCI, en el Instituto Nacional de Enfermedades Neoplásicas durante el período 2010-2014. Resultados . Los 41 pacientes que alcanzaron cirugía de intervalo, tuvieron una mediana de edad de 59 años (rango: 47-73 años). En 37 (90,2%) pacientes se reportó histología de adenocarcinoma seroso de alto grado. Treinta y cuatro (82,9%) lograron citorreducción óptima y cinco (14,7%) respuesta patológica completa. La sobrevida libre de progresión al año y 2 años fueron 74,7% y 51,8%, respectivamente. La sobrevida global al año y 2 años fue 85,2% y 71,4%, respectivamente. El riesgo de progresión y muerte fue mayor en pacientes sin citorreducción óptima y pacientes con niveles de dosaje del antígeno carcinoembrionario 125 postoperatorio > 30 U/ml. Conclusiones . La neoadyuvancia con carboplatino y paclitaxel dosis densa logró una frecuencia elevada de citorreducción óptima. Los niveles de antígeno carcinoembrionario 125 postoperatorios y citorreducción óptima resultaron factores independientes de sobrevida libre de progresión y sobrevida global.

ABSTRACT Objectives. To determine the rate of optimal cytoreduction in patients with advanced ovarian cancer who received neoadjuvant chemotherapy with dose-dense carboplatin and paclitaxel followed by interval debulking surgery (IDS). Materials and Methods. A retrospective study of a series of cases of Peruvian women treated with neoadjuvant chemotherapy with carboplatin (6 AUC mg/mL/min) and paclitaxel (80 mg/m2 weekly) followed by IDS, at the National Institute of Neoplastic Diseases during the 2010-2014 period. Results. The 41 patients who made it to the interval surgery had a median age of 59 years (range: 47-73 years). In 37 (90.2%) patients, high-grade serous adenocarcinoma histology was reported. Thirty-four (82.9%) achieved optimal cytoreduction and five (14.7%), a complete pathological response. Progression-free survival at one year and two years was 74.7% and 51.8%, respectively. Overall survival at one year and two years was 85.2% and 71.4%, respectively. The risk of progression and death was greater in patients without optimal cytoreduction and in patients with postsurgery levels of carcinoembryonic antigen 125 > 30 U/mL. Conclusions. Neoadjuvant therapy with dose-dense carboplatin and paclitaxel achieved an elevated frequency of optimal cytoreduction. The post-surgery levels of carcinoembryonic antigen 125 and optimal cytoreduction were independent factors of progression-free survival and overall survival.

Lipid core nanoparticles resembling low-density lipoprotein and regression of atherosclerotic lesions: effects of particle size

Particles are usually polydispersed and size is an important feature for lipid-based drug delivery systems in order to optimize cell-particle interactions as to pharmacologic action and toxicity. Lipid nanoparticles (LDE) with composition similar to that of low-density lipoprotein carrying paclitaxel were shown to markedly reduce atherosclerosis lesions induced in rabbits by cholesterol feeding. The aim of this study was to test whether two LDE fractions, one with small (20-60 nm) and the other with large (60-100 nm) particles, had different actions on the atherosclerotic lesions. The two LDE-paclitaxel fractions, prepared by microfluidization, were separated by density gradient ultracentrifugation and injected (4 mg/body weight, intravenously once a week) into two groups of rabbits previously fed cholesterol for 4 weeks. A group of cholesterol-fed animals injected with saline solution was used as control to assess lesion reduction with treatment. After the treatment period, the animals were euthanized for analysis. After treatment, both the small and large nanoparticle preparations of LDE-paclitaxel had equally strong anti-atherosclerosis action. Both reduced lesion extension in the aorta by roughly 50%, decreased the intima width by 75% and the macrophage presence in the intima by 50%. The two preparations also showed similar toxicity profile. In conclusion, within the 20-100 nm range, size is apparently not an important feature regarding the LDE nanoparticle system and perhaps other solid lipid-based systems.

Screening of endophytic fungi stored in a culture collection for taxol production

Abstract In this work, four isolates of endophytic fungi (Alternaria alternata, Colletotrichum gloesporioides, Glomerella cingulata and Nigrospora sphaerica), deposited in the culture collection 'University Recife Mycologia' (URM) at the Universidade Federal de Pernambuco, were characterized for the genes ITS 1 and 4 (region 5.8 S) and evaluated for taxol production.

Sarcoma de Kaposi em Paciente Jovem Imunocompetente: uma Quinta Variante Epidemiológica? ­ Relato de Caso / Kaposi's Sarcoma in Young Immunocompetent Patient: a Fifth Epidemiological Variant? ­ Case Report / Sarcoma de Kaposi em Paciente Joven Inmunocompetente: ¿una Quinta Variante Epidemiológica? ­ Informe de Caso

Introdução: O sarcoma de Kaposi apresenta, classicamente, quatro tipos de variantes: clássico, endêmico, associado à imunossupressão (ou iatrogênico) e epidêmico (ou relacionado à Aids). Todos esses subtipos estão relacionados ao herpes-vírus humano 8. Uma quinta variante clínico-epidemiológica vem sendo proposta na literatura, que inclui uma apresentação visceral da doença no grupo de homens que fazem sexo com homens sem fatores de imunossupressão identificados. Relato de caso: Descreve-se o caso de um paciente masculino de 24 anos de idade, de orientação homossexual, sem fatores de imunossupressão, com apresentação linfonodal de sarcoma de Kaposi, e sem outros fatores que o incluam dentro das classificações da doença atualmente conhecidas. O paciente recebeu tratamento quimioterápico com paclitaxel, atingindo resposta completa e mantida até o momento, 42 meses após o término do tratamento. Conclusão: Esse caso reforça que a patogênese do sarcoma de Kaposi ainda é pouco clara, e que provavelmente múltiplos fatores, tanto do vírus como do hospedeiro, interajam entre si para desencadear a carcinogênese. É possível que o hábito sexual não encerre relação com essa patogênese, comportando-se apenas como fator confundidor. O paciente apresentou toxicidade mínima durante o tratamento com paclitaxel e atingiu resposta completa e mantida.

Introduction: Kaposi sarcoma classically presents four types of variants: classic, endemic, immunosuppression-associated (or iatrogenic) and epidemic (or AIDS-associated). All subtypes are invariably linked to human herpesvirus-8. A fifth clinical-epidemiological variant has been proposed in the literature, which includes a visceral presentation of the disease in the group of men who have sex with men without detected immunosuppressive factors. Case Report: We report the case of a 24-year-old male patient with a homosexual orientation without immunosuppressive factors, diagnosed with KS, with lymph node involvement, and without other disease characteristics that could include him within the currently known four types of Kaposi sarcoma classification. The patient received chemotherapy with paclitaxel, evolving with complete and sustained reponse until now, 42 months after the ending of treatment. Conclusion: This case reinforces that the pathogenesis of KS is still unclear, and that probably multiple factors, both virus and host, interact with each other to trigger carcinogenesis. It is possible that the sexual habit does not influence this pathogenesis, behaving only as a confounding factor. The patient had minimal toxicity during treatment with paclitaxel and achieved a complete and sustained response.

Introducción: El sarcoma de Kaposi presenta, clásicamente, cuatro tipos de variantes: clásico, endémico, asociado a inmunosupresión (o iatrogénico) y epidémico (o relacionado a SIDA). Todos estos subtipos están relacionados con el virus del herpes humano tipo 8 (HHV-8). Una quinta variante clínica-epidemiológica está en estudio, incluye una presentación visceral de la enfermedad en un grupo de hombres que tienen sexo con hombres sin factores de inmunosupresión de causa detectada. Informe de Caso: Se desarrolló un estudio sobre un paciente masculino de 24 años de edad, de orientación homosexual, sin factores de inmunosupresión, presentando diagnóstico de sarcoma de Kaposi con característica linfonodal de la enfermedad, y sin otros factores que incluyan dentro de las clasificaciones de sarcoma de Kaposi actualmente conocidas. El paciente recibió tratamiento quimioterápico con paclitaxel, alcanzando respuesta completa y sostenida hasta el momento, 42 meses después del término del tratamiento. Conclusión: Este caso refuerza que la patogénesis del sarcoma de Kaposi es poco clara, y que probablemente múltiples factores, tanto del virus y del hospedador, interactúan entre sí para desencadenar La carcinogénesis. Es posible que el hábito sexual no encierre relación con esa patogénesis, comportándose apenas como factor confundidor. El paciente presentó toxicidad mínima durante el tratamiento y alcanzó una respuesta completa y sostenida hasta el momento, pudiendo, el paclitaxel, ser considerado una opción sólida para el tratamiento del sarcoma de Kaposi en ese grupo de pacientes con esa variante de presentación.

Impact of Paclitaxel-Eluting Balloons Compared to Second-Generation Drug-Eluting Stents for of In-Stent Restenosis in a Primarily Acute Coronary Syndrome Population / Impacto dos Balões de Eluição de Paclitaxel Comparados a Stents Farmacológicos de Segunda Geração para Reestenose Intra-Stent em uma População com Síndrome Coronária Aguda Primária

Abstract Background: The place of drug-eluting balloons (DEB) in the treatment of in-stent restenosis (ISR) is not well-defined, particularly in a population of all-comers with acute coronary syndromes (ACS). Objective: Compare the clinical outcomes of DEB with second-generation drug-eluting stents (DES) for the treatment of ISR in a real-world population with a high proportion of ACS. Methods: A retrospective analysis of consecutive patients with ISR treated with a DEB compared to patients treated with a second-generation DES was performed. The primary endpoint was a composite of major adverse cardiovascular events (MACE: all-cause death, non-fatal myocardial infarction, and target lesion revascularization). Comparisons were performed using Cox proportional hazards multivariate adjustment and Kaplan-Meier analysis with log-rank. Results: The cohort included 91 patients treated with a DEB and 89 patients treated with a DES (74% ACS). Median follow-up was 26 months. MACE occurred in 33 patients (36%) in the DEB group, compared to 17 patients (19%) in the DES group (p log-rank = 0.02). After multivariate adjustment, there was no significant difference between the groups (HR for DEB = 1.45 [95%CI: 0.75-2.83]; p = 0.27). Mortality rates at 1 year were 11% with DEB, and 3% with DES (p = 0.04; adjusted HR = 2.85 [95%CI: 0.98-8.32]; p = 0.06). Conclusion: In a population with a high proportion of ACS, a non-significant numerical signal towards increased rates of MACE with DEB compared to second-generation DES for the treatment of ISR was observed, mainly driven by a higher mortality rate. An adequately-powered randomized controlled trial is necessary to confirm these findings.

Resumo Fundamento: O papel de balões farmacológicos (BFs) no tratamento de reestenose intra-stent (RIS) não está bem definido, particularmente em na síndrome coronária aguda (SCA). Objetivo: Comparar desfechos clínicos do uso de BF com stents farmacológicos (SFs) de segunda geração no tratamento de RIS em uma população real com alta prevalência de SCA. Métodos: Foi realizada uma análise retrospectiva de pacientes consecutivos com RIS tratados com um BF comparados a pacientes tratados com SF de segunda geração. O desfecho primário incluiu eventos cardiovasculares adversos importantes (morte por todas as causas, infarto do miocárdio não fatal, e revascularização da lesão alvo). As comparações foram realizadas pelo modelo proporcional de riscos de Cox ajustado e análise de Kaplan-Meier com log-rank. Resultados: A coorte incluiu 91 pacientes tratados com BF e 89 pacientes tratados com um SF (75% com SCA). O tempo mediano de acompanhamento foi de 26 meses. Eventos cardiovasculares adversos importantes ocorreram em 33 pacientes (36%) no grupo BF, e em 17 (19%) no grupo SF (p log-rank = 0,02). Após ajuste multivariado, não houve diferença significativa entre os grupos (HR para BF = 1,45 [IC95%: 0,75-2,83]; p = 0,27). As taxas de mortalidade de 1 ano foram 11% com BF, e 3% com SF (p = 0,04; HR ajustado = 2,85 [IC95%: 0,98-8,32; p = 0,06). Conclusão: Em uma população com alta prevalência de SCA, observou-se um aumento não significativo nas taxas de eventos cardiovasculares adversos importantes com o uso de BF comparado ao uso de SF de segunda geração para o tratamento de RIS, principalmente pelo aumento na taxa de mortalidade. É necessário um ensaio clínico controlado, randomizado, com poder estatístico adequado para confirmar esses achados.

O tratamento oncológico e a doença arterial coronariana / Cancer treatment and coronary artery disease

A concomitância de doença arterial coronariana e câncer é uma apresentação frequente na prática da cardiologia. Além de compartilharem os mesmos fatores de risco para seu desenvolvimento e, portanto, os mesmos grupos demográficos, a toxicidade vascular da quimioterapia e da radioterapia torna mais alta a incidência da doença no grande grupo de sobreviventes do câncer. No ciclo do tratamento oncológico, a ocorrência de eventos cardíacos maiores, secundários ou não à cardiotoxicidade, é determinante de alteração ou interrupção de tratamento, com efeito importante na sobrevida. O objetivo da assistência especializada é retornar o paciente ao tratamento o mais precocemente possível e, na fase tardia, evitar a morte por doença cardiovascular. As peculiaridades da apresentação da doença coronariana e do diagnóstico e tratamento percutâneo são aqui discutidas

Concomitant coronary artery disease and cancer is a common presentation in current cardiovascular practice. Besides sharing the same risk factors for their development, and accordingly, the same demographic groups, vascular toxicity from chemotherapy and radiotherapy make the incidence of the disease higher in the large group of cancer survivors. During the cancer treatment cycle, the occurrence of major cardiac events, whether due to cardiotoxicity or not, is responsible for changes or interruption of treatment, with important effects on survival. The goal of specialized care is to return the patient to treatment as early as possible and in the later phase, to avoid death from cardiovascular disease. The specific characteristics of coronary disease and percutaneous diagnosis and treatment are discussed here