Adverse reactions to oncologic drugs: spontaneous reporting and signal detection

Oncology is one of the areas of medicine with the most active research being conducted on new drugs. New pharmacological entities frequently enter the clinical arena, and therefore, the safety profile of anticancer products deserves continuous monitoring. However, only very severe and (unusual) suspected adverse drug reactions (ADRs) are usually reported, since cancer patients develop ADRs very frequently and some practical selectivity must be used. Notably, a recent study was able to identify 76 serious ADRs reported in updated drug labels of oncologic drugs and 50% of them (n = 38) were potentially fatal. Of these, 49 and 58%, respectively, were not described in initial drug labels. The aims of this article are to provide an overview about spontaneous reporting of ADRs of oncologic drugs and to discuss the available methods to analyze the safety of anticancer drugs using databases of spontaneous ADR reporting

Acute portal vein thrombosis precipitated by indomethacin in a HCV-positive elderly patient

BACKGROUND: An increased risk of venous thromboembolism has been reported in patients treated with non-steroidal anti-inflammatory drugs (NSAIDs). We describe a case of acute portal vein thrombosis (PVT) in a hepatitis C virus (HCV)-positive elderly patient following administration of indomethacin. CASE PRESENTATION: A 79-year-old HCV-positive man was hospitalized for severe abdominal pain, nausea and vomiting, 15 days after starting indomethacin for back pain. Clinical signs and imaging evaluations disclosed a picture of PVT. Indomethacin was discontinued, and the patient was started on fondaparinux and antithrombin. He was discharged 15 days later due to improvement of his clinical conditions. Thirty days later, a follow-up ultrasound did not show appreciable signs of PVT. The time elapsing between the start of analgesic therapy and PVT onset suggests a role of indomethacin as the triggering agent. Indomethacin could have precipitated PVT by a combination of at least two detrimental mechanisms: 1) direct action on liver vascular endothelium by inhibition of prostacyclin biosynthesis; 2) damage to the intestinal mucosa, followed by inflammatory and pro-coagulant activation of portal endothelium upon exposure to bacterial endotoxins. CONCLUSIONS: This case can be of interest to physicians, who should exert caution when prescribing NSAIDs for inflammatory pain in patients with background inflammatory dysfunctions of the portal vein endothelium

Neonatal Adaptation Issues After Maternal Exposure to Prescription Drugs: Withdrawal Syndromes and Residual Pharmacological Effects

Exposure to drugs during pregnancy has the potential to harm offspring. Teratogenic effects are the most feared adverse outcomes in newborns; however, a wide spectrum of less known, usually reversible and often acute, neonatal adverse events can also occur due to drug intake by mothers during pregnancy, particularly in close proximity to delivery. This narrative review is aimed at the description of drugs and drug classes for which licit maternal use in the predelivery period has been associated with neonatal non-teratogenic disorders. For each drug class, epidemiology, clinical features, biological mechanism and management of these adverse reactions have been discussed in detail. Although these adverse reactions have been described mainly for substances used illicitly for recreational purposes, several prescription drugs have also been involved; these include mainly psychotropic medications such as opioids, antidepressants, antiepileptics and antipsychotics. These effects can be partly explained by withdrawal syndromes (defined also as 'neonatal abstinence syndrome') caused by the delivery-related discontinuation of the drug disposition from the mother to the fetus, with symptoms that may include feeding disorders, tremors, irritability, hypotonia/hypertonia, vomiting and persistent crying, occurring a few hours to 1 month after delivery. Otherwise, neonatal neurological and behavioral effects can also be caused by a residual pharmacological effect due to an accumulation of the drug in the blood and tissues of the newborn, with various symptoms related to the toxic effects of the specific drug class, usually developing a few hours after birth. With few exceptions, validated protocols for the assessment and management of withdrawal or residual pharmacological effects of these drugs in neonates are often lacking or incomplete. Spontaneous reporting of these adverse reactions seems limited, although it might represent a useful tool for improving our knowledge about drug-induced neonatal syndromes

O proscrito satisfeito: as obras do exílio de Victor Hugo / The satisfied proscribed: Victor Hugo’s exile works

Although Victor Hugo supported the candidacy of Louis Napoléon in the elections for president of the French Republic and helped to elect him in 1848, Hugo turned against Bonaparte after the coup d’état in December of 1851. The opposition to the government resulted in an exile wich only finished 19 years later, with the decay of Napoleón III. Victor Hugo produced nonstop for all these years: Napoléon le Petit, Les Châtiments, Les Contemplations, Les Travailleurs de la Mer, Les Chansons des Rues et des Bois, La Légende des siècles, Les Misérables, William Shakespeare, Les Travailleurs de la Mer e L’Homme qui rit are examples of an arduous and inspired work, but that doesn’t hide the sadness of the exile. This article aims to analyze the texts that Victor Hugo wrote during or after his banishment in order to comprehend in wich way it influenced his work.Apesar de ter apoiado a candidatura de Luís Napoleão nas eleições para presidente da República Francesa e ter ajudado a elegê-lo em 1848, Hugo voltou-se contra o chefe da Nação após o golpe de Estado em dezembro de 1851. A oposição ao governo resultou num exílio que só terminou 19 anos depois, com a queda de Napoleão III. Victor Hugo produziu incansavelmente nesses anos todos: Napoléon le Petit, Les Châtiments, Les Contemplations, Les Travailleurs de la Mer, Les Chansons des Rues et des Bois, La Légende des siècles, Les Misérables, William Shakespeare, Les Travailleurs de la Mer e L’Homme qui rit são exemplos de um trabalho árduo e inspirado, que não esconde a tristeza do exílio. Este artigo pretende analisar os textos de Victor Hugo escritos durante ou após o degredo a fim de compreender de que maneira ele repercutiu em sua obra

Traducir el cine, traducir el dialecto: estudio lingüístico de la película "romanzo criminale"

El presente artículo se basa en el análisis de cuatro escenas de la película italiana Romanzo criminale, dirigida por Michele Placido en 2005. El objeto principal de nuestro estudio es la traducción de la variación lingüística en el doblaje español, centrándonos sobre todo en el tratamiento del dialecto, aunque se describan y analicen todas las variedades encontradas en el texto.This article is based on the analysis of four scenes of the Italian movie Romanzo criminale, directed by Michele Placido in 2005. The aim of our article is the study of the translation of language variation in Spanish dubbing, particularly the translation of dialect, although also the other types of variation get analyzed and described

Victor Hugo: sobretudo, poeta

Victor Hugo was one of the most important writers of the French litterature. He publishied novels and plays, but he dedicated himself especially to the poetry. This article aims to describe the poetic journey of Victor Hugo and analyses how the History of France, the life of the writer and the discussions about Romantism combined and formed a work that traverses the century.Victor Hugo foi um dos mais importantes escritores da Literatura Francesa. Publicou romances e peças teatrais, mas dedicou-se, sobretudo, à poesia. Pretende-se descrever o percurso poético de Victor Hugo e analisar de que maneira a história da França, a vida do escritor e as discussões acerca do Romantismo se imbricaram de modo a formar uma obra que atravessa o século

Predictive findings of malignant evolution of nodules in cirrhotic livers at MR imaging with Gd-EOB-DTPA

ABSTRACT Purpose: the aim of this study was to evaluate the predictive findings that might suggest a rapid progression towards malignancy of pre-malignant nodules (high grade dysplastic nodules – HGDN and early hepatocellular carcinomas – early HCC) in liver cirrhosis, showing as atypical at MR dynamic vascular examination with Gd-EOB-DTPA. Furthermore, we have assessed the time to progression of such pre-malignant lesions into overt HCC. Materials and Methods: Among all patients who did perform a scheduled Magnetic Resonance (MR) follow up study between January 2013 and June 2015 at our institution, we did select 34 cirrhotic patients (Group 1; (M:23, F:11, mean age 66 years, range 48-84) who had performed two subsequent MR examinations with Gd-EOB-DTPA (Time-0 MR and Time-1 MR; within 6 months from Time-0 MR examination), with at least one atypical nodule (showing as hypovascular on arterial phase and hypointense on late dynamic and/or on hepatobiliary phase). A total of 59 atypical nodules were selected, which progressed into HCC at Time-1 MR examination, on the basis of current dynamic criteria. As control group (Group 2), we did retrospectively select 13 patients (M:8, F:5, mean age 62 years, range 43-64), who had undergone orthotopic liver transplantation (OLT) within 6 months from MR study with Gd-EOB-DTPA (pre-OLT MR) and in whom livers, at least one HGDN had been diagnosed at histological examination after OLT, with a total of 33 HGDN. Nodular signal intensities on different phases and final diagnosis were compared, in order to identify specific, early, clues suggesting evolution towards malignancy. Nodule sizes were recorded at hepatobiliary phase on both subsequent MR studies (Group 1) and on pre-OLT MR and at histological examination. Months to progression from atypical nodules to HCC were also calculated. Results: Significant association among nodule signal intensities at Time-0 MR and pre-OLT MR and nodular final diagnosis were identified: at Time-0 MR, 27/59 (45%) future HCCs did show as isointense on both T1 and T2-w.i. (p=0.03); 29/59 (49%) of future HCCs did appear as isointense on arterial phase and hypointense on late dynamic phase (p=0.03), while 34/59 (57%) of future HCCs did show as isointense on arterial phase and hypointense on hepatobiliary phase (p=0.02). No specific association at pre-OLT MR was observed for suggesting HDGN. The most significant association (p<0.0001) in suggesting nodular malignancy/pre-malignancy were the association of hypointensity both on late dynamic and on hepatobiliary phase, detected in 63/92 (68.5%) nodules (25/33 - 75% HGDNs; 38/59 - 64% future HCCs). A significant correlation was found between the sizes of nodules that progressed into HCC, evaluated at Time-0 and Time-1 MR (p= 0.0001). Moreover, nodular progression towards malignancy did result strongly time related since, if considering only nodules in whom MR studies (Time-0 MR and pre-OLT MR) had been performed between 2 and 6 months before OLT or Time-1 MR, 36 out of 46 nodules (78%) showing as hypointense on both late dynamic and hepatobiliary phase did result to progress into HCC, with an area under the curve (AUC) of 91%. Conclusion: in case of hypovascular nodules within cirrhotic liver on arterial phase, the detection of hypointensity on both late dynamic and hepatobiliary phase should be considered as the strongest clue for suggesting pre-malignancy of the nodule as well as rapid evolution towards neoplasia, that in the 60% of cases can happen within 6 months. Gd-EOB-DTPA enhanced MR surveillance of patients who do present several atypical nodules could become important in order to adequately monitor high-risk patients and to suggest and help in planning the best therapeutic approach