A UPLC method development and validation study of Upadacitinib and its impurities in extended - Release oral tablet dosage forms.

OBJECTIVE: The primary objective was to develop a concomitant isocratic ultra-performance liquid chromatographic photo-diode array detection method to estimate Upadacitinib and its process-related impurities: impurity-1 and impurity-2. Further validation was conducted and studied for possible degradants under stress environments. MATERIALS AND METHODS: All the chemicals and reagents used were of HPLC (acetonitrile, methanol) and analytical grade (trifluoro acetic acid). The ultra-performance liquid chromatography (Agilent 1290 Infinity II LC system) consists of a quaternary pump, a BEH C18 (50×2.1mm, 1.7µ) column, and photo-diode array detector. The method was developed with acetonitrile: methanol: 0.1% v/v trifluoro acetic acid (50:20:30 v/v/v) mobile phase at 0.2mL/min flow rate within a run time of 5.5min The detection was carried at 231.2nm. RESULTS: The respective retention times achieved were 2.289min (Upadacitinib), 0.972min (Upadacitinib impurity-1), and 3.508min (Upadacitinib impurity-2). The optimized method was validated further, and the linearity range was best fit at 15.0-180.0µg/mL for Upadacitinib and 1.0-12.0µg/mL for both Upadacitinib impurity-1 and 2 respectively. The detection and quantification limits were 4.50µg/mL, 15.00µg/mL (Upadacitinib) and 0.30µg/mL, 1.0µg/mL (Upadacitinib impurity-1 and 2). CONCLUSION: A fast, isocratic, specific, and reproducible ultra-performance liquid chromatographic method was developed and validated for various parameters according to the ICH Q2 (R1) guidelines studies. Stress studies were conducted exposing the sample dilution to various treatments (acid, alkali, peroxide, HPLC water, heat, and UV light). The degradants were well-separated apart from the peaks of the active substance. The stability indicating nature was observed during the degradation. The optimized method can be applied for the separation and estimation of Upadacitinib and its process-related impurities in pharma sector in tablet dosage forms.

Neuralgia del trigémino y del glosofaríngeo concomitantes, asíncronas y refractarias. Buena respuesta al abordaje quirúrgico en un tiempo / Concomitant, asynchronous and refractory trigeminal and glossopharyngeal neuralgia. Good response to surgical approach in one time

Introducción: La cirugía de descompresión microvascular (DMV) es el tratamiento de elección de una neuralgia craneal refractaria secundaria a compresión vascular. Las neuralgias simultáneas de dos pares craneales son extremadamente infrecuentes. Describimos un caso con neuralgia concomitante del trigémino (NT) y glosofaríngeo (NG) refractarias y secundarias a cruce neurovascular abordadas quirúrgicamente en un mismo tiempo. Caso clínico: Mujer de 65 años con NT derecho (inicialmente en V2-V3) desde 2004 con control regular con carboxamidas. Diecisiete años después empeoraron los paroxismos en V2-V3, aparecieron también en V1 y en el territorio del nervio glosofaríngeo derecho (oído derecho y fosa amigdalar al hablar y deglutir). La resonancia magnética cerebral mostró contacto arterial significativo entre arteria cerebelosa superior (ACS) con origen del V par craneal derecho y de la arteria cerebelosa antero-inferior (AICA) con el origen de pares craneales bajos derechos. Se realizó DMV de ambos pares craneales en un mismo tiempo quirúrgico mediante craniectomía retrosigmoidea, y se procedió a la liberación del V par craneal, en contacto íntimo con la ACS, y del IX par craneal en contacto con la AICA derecha, para lo que se puso teflón entre ellas. La paciente tuvo una resolución inmediata de los paroxismos trigeminales y una mejoría considerable en intensidad y frecuencia de los glosofaríngeos. A los 2 años de la intervención continúa la desescalada de tratamiento neuromodulador con buena respuesta.ConclusiónLa DMV en la NT y NG simultáneas es factible y puede ofrecer un buen resultado posquirúrgico. (AU)

INTRODUCTION: Microvascular decompression (MVD) surgery is the first choice treatment for refractory cranial neuralgia secondary to vascular compression. Simultaneous neuralgia of two cranial nerves is extremely rare. We describe a case of concomitant refractory trigeminal (TN) and glossopharyngeal (GN) neuralgia secondary to neurovascular crossover, treated surgically at the same time. CASE REPORT: 65-year-old woman with right TN (initially V2-V3) since 2004 with regular control with carboxamides. Seventeen years later, paroxysms worsened in V2-V3, also appearing in V1 and in the territory of the right glossopharyngeal nerve (right ear and tonsillar fossa when speaking and swallowing). Cerebral MRI showed significant arterial contact between the superior cerebellar artery (SCA) with the origin of the right V cranial nerve and the antero-inferior cerebellar artery (AICA) with the origin of the right lower CCNN. MVD of both cranial nerves was performed at the same surgical time by means of retrosigmoid craniectomy, releasing the V cranial nerve, in intimate contact with the SCA, and the IX cranial nerve in contact with the right AICA, interposing teflon between them. The patient had an immediate resolution of the trigeminal paroxysms and a dramatic improvement in intensity and frequency of glossopharyngeal paroxysms. Two years after the intervention, de-escalation of neuromodulator treatment continues with good response. CONCLUSION. MVD in simultaneous TN and GN is feasible and can offer a good post-surgical outcome. (AU)

Caracterización del Traumatismo Dentoalveolar Concomitante a Trauma Maxilofacial en Personal Profesional de Fuerzas Armadas: Revisión Narrativa

El trauma maxilofacial es un problema de salud pública, comúnmente asociado a traumatismo dentoalveolar. Su prevalencia es alta, siendo más frecuente en poblaciones de riesgo, como personal de Fuerzas Armadas, esto por sus actividades laborales, generando gran impacto en el paciente. Caracterizar, según la literatura, el traumatismo dentoalveolar concomitante a trauma maxilofacial en el personal profesional de Fuerzas Armadas. Se realizó una revisión narrativa en cuatro bases de datos, en octubre del 2020. Se incluyeron publicaciones de máximo 5 años de antigüedad, en inglés o español, con resumen disponible, estudios primarios y revisiones sistemáticas. Se excluyó publicaciones no disponibles en texto completo y reportes de casos. Se incluyeron 15 artículos. Existe un déficit de evidencia sobre la asociación que existe entre traumatismo dentoalveolar y traumatismo maxilofacial en la población estudiada. Encontrándose que solo el 6,7 % de estos incluía en su análisis la concomitancia entre ambos tipos de traumas. Sin embargo, los diagnósticos más prevalentes consistieron en fracturas coronarias y mandibulares, respectivamente, asociadas a actividades de entrenamiento y combate. Se establece que el tipo de trauma maxilofacial más frecuente en la población profesional de Fuerzas Armadas es la fractura mandibular y en relación al traumatismo dentoalveolar, la fractura coronaria. En cuanto a la etiología, destacan las heridas de bala, explosivos y accidentes en vehículos, afectando principalmente a personal del Ejército entre 18 a 30 años. Es importante mencionar que los artículos incluidos en esta revisión que hacen referencia a la concomitancia entre el traumatismo dentoalveolar y maxilofacial son escasos y no se encuentran actualizados, por lo que, se necesita continuar investigando en esta temática.

The maxillofacial injuries are a public health issue commonly associated to dentoalveolar injuries. Its high prevalence in risk population such as the Armed Forces personnel, due to their work activities, generates a great impact on the patient. Characterize, according to the literature, dentoalveolar injuries within the maxillofacial injuries in professional Armed Forces personnel. A narrative research was conducted on October 2020 with four data bases. Only 5-year-old publications were considered both in English and Spanish, including their available summary, primary studies and systematic revisions. Publications without full access or report cases were not included. Fifteen scientific papers were included. There is a deficit of evidence between maxillofacial and dentoalveolar injuries in the target population. Only 6.7 % of the research included a joint analysis between both traumas, however the most prevalent diagnosis consisted in coronaries and mandibular fractures, in that order, associated mainly to training and combat activities. The most frequent maxillofacial injury within the Armed Forces personnel is the mandibular fracture, and in relation with dentoalveolar injuries is the coronary fracture. Regarding the etiology, gunshot wounds, explosives and car accidents are featured affecting mainly between 18 to 30 years old army personnel. It's relevant to highlight that the scientific papers included in this revision about the association between dentoalveolar and maxillofacial injuries are poor and not updated. Further research is needed in this issue.

Ejercicio aeróbico versus concurrente sobre la interleucina-6 en pacientes con enfermedad arterial coronaria: Una revisión sistemática / Aerobic Versus Concurrent Exercise on Interleukin-6 in Patients with Coronary Arterial Disease: A Systematic Review

Resumen El ejercicio aeróbico (EA) ha demostrado ser beneficioso para la supervivencia del paciente con enfermedad arterial coronaria (EAC) y la disminución de la interleucina 6 (IL-6). Sin embargo, hay poco evidencia del efecto del entrenamiento concurrente (EC). Propósito: Analizar el efecto del EA versus EC sobre la IL-6 en pacientes con EAC. Metodología: Se desarrolló con base en los acuerdos PRISMA, se realizó una búsqueda de los artículos científicos mediante bases de datos electrónicas. Los términos de búsqueda (frase booleana) fueron los siguientes: ("coronary artery disease" OR ''cardiac disease'' OR "cardiovascular disease") AND (''exercise'' OR ''training'' OR "cardiac rehabilitation") AND ("IL-6" OR "Interleukin-6" OR "inflammatory markers"). Las búsquedas se realizaron entre agosto y diciembre de 2019. Resultados: Se revisaron un total de 2516 estudios, de los cuales se incluyeron 10 estudios que cumplieron con los criterios de elegibilidad. Se analizaron un total de 413 pacientes. Se encontró una mejoría entre un 5% y un 74% con el EA y entre un 2.3% y 58.8% con el EC. Ambas modalidades disminuye significativamente la IL-6, independientemente de la edad, sesiones de entrenamiento semanales y de la etapa inicial de los pacientes con EAC, pero aquellos estudios que utilizaron una alta intensidad o un volumen superior a 30 minutos presentaron mayores beneficios. Conclusión: Tanto el EA como el EC son beneficiosos en la disminución de la IL-6 en pacientes con EAC. Esta revisión sistemática deja la posibilidad de continuar investigando el comportamiento de la alta intensidad en la disminución de la IL-6.

Abstract Aerobic exercise (AE) has been shown to be beneficial for the survival of patients with CAD and the decrease in interleukin 6 (IL-6). However, there is little evidence of the effect of concurrent training (CT). Purpose: To analyze the effect of AE versus CT on IL-6 in patients with CAD. Methodology: It was developed based on the PRISMA agreements; scientific articles were searched through electronic databases. The search terms (Boolean phrase) were the following: ("coronary artery disease" OR '' cardiac disease '' OR "cardiovascular disease") AND ('' exercise '' OR '' training '' OR "cardiac rehabilitation") AND ("IL-6" OR "Interleukin-6" OR "inflammatory markers") NOT ("animals" OR "rat"). The searches were conducted between August and December 2019. Results: A total of 2516 studies were reviewed, of which 10 studies that met the eligibility criteria were included. A total of 413 patients were analyzed. An improvement was found between 5% and 74% with the AE and between 2.3% and 58.8% with the CT. Both modalities significantly decrease IL-6, regardless of age, weekly training sessions, and the initial stage of patients with CAD; however, those studies that used a high intensity or a volume greater than 30 minutes showed greater benefits. Conclusion: Both EA and CT are beneficial in reducing IL-6 in patients with CAD. This systematic review leaves the possibility of continuing to investigate the behavior of high intensity in the decrease of IL-6.

Resumo O exercício aeróbio (EA) demonstrou beneficiar a sobrevivência dos pacientes com doença arterial coronária (DAC) e diminuir a interleucina 6 (IL-6). No entanto, há poucas evidências do efeito do treino simultâneo (TC). Objetivo: Analisar o efeito da EA versus TC na IL-6 em pacientes com DAC. Metodologia: Com base nos acordos PRISMA, foi realizada uma pesquisa de artigos científicos utilizando bases de dados eletrônicas. Os termos de busca (frase booleana) foram os seguintes: (''doença arterial coronária'' OU ''doença cardíaca'' OU ''doença cardiovascular'') E (''exercício'' OU ''treinamento'' OU ''reabilitação cardíaca'') E (''IL-6'' OU ''Interleucina-6'' OU ''marcadores inflamatórios''). As pesquisas foram realizadas entre agosto e dezembro de 2019. Resultados: Um total de 2516 estudos foram revistos, dos quais foram incluídos 10 estudos que preenchiam os critérios de elegibilidade. Foram analisados um total de 413 pacientes. A melhoria foi encontrada entre 5% e 74% com a EA e entre 2,3% e 58,8% com o TC. Ambas as modalidades diminuíram significativamente a IL-6, independentemente da idade, das sessões semanais de treinamento e do estágio inicial dos pacientes com DAC, mas os estudos que utilizaram alta intensidade ou volume superior a 30 minutos tiveram maiores benefícios. Conclusão: Tanto a EA como a TC são benéficas para a redução da IL-6 em pacientes com DAC. Esta revisão sistemática deixa espaço para uma investigação mais aprofundada sobre o comportamento de baixa intensidade da IL-6.

Final results of the IFCT-0803 study, a phase II study of cetuximab, pemetrexed, cisplatin, and concurrent radiotherapy in patients with locally advanced, unresectable, stage III, non-squamous, non-small-cell lung cancer.

PURPOSE: Roughly 20% of patients with non-small-cell lung cancer exhibit locally advanced, unresectable, stage III disease. Concurrent platinum-based chemoradiotherapy is the backbone treatment, which is followed by maintenance immunotherapy, yet with poor long-term prognosis. This phase II trial (IFCT-0803) sought to evaluate whether adding cetuximab to cisplatin and pemetrexed chemoradiotherapy would improve its efficacy in these patients. MATERIALS AND METHODS: Eligible patients received weekly cetuximab (loading dose 400mg/m2 day 1; subsequent weekly 250mg/m2 doses until two weeks postradiotherapy). Chemotherapy comprised cisplatin (75mg/m2) and pemetrexed (500mg/m2), both delivered on day 1 of a 21-day cycle of maximally four. Irradiation with maximally 66Gy started on day 22. Disease control rate at week 16 was the primary endpoint. RESULTS: One hundred and six patients were included (99 eligible patients). Compliance exceeded 95% for day 1 of chemotherapy cycles 1 to 4, with 76% patients receiving the 12 planned cetuximab doses. Maximal grade 3 toxicity occurred in 63% patients, and maximal grade 4 in 9.6%. The primary endpoint involving the first 95 eligible patients comprised two (2.1%) complete responses, 57 (60.0%) partial responses, and 27 (28.4%) stable diseases. This 90.5% disease control rate (95% confidence interval [95% CI]: 84.6%-96.4%) was achieved at week 16. After median 63.0-month follow-up, one-year and two-year survival rates were 75.8% and 59.5%. Median overall survival was 35.8months (95% CI: 23.5-NR), and median progression-free survival 14.4months (95% CI: 11.2-18.8), with one-year and two-year progression-free survival rates of 57.6% and 34.3%. CONCLUSION: These survival rates compare favourably with published data, thus justifying further development of cetuximab-based induction chemoradiotherapy.

Management of oropharyngeal squamous cell carcinoma.

This article reviews the various treatment options, by primary or postoperative external radiotherapy and by brachytherapy for the p16-negative oropharyngeal squamous cell carcinoma. Dose levels, fractionation and association with systemic treatments are presented. The need for neck node dissection post local treatment is discussed, as well as specificities for the management of p16-positive tumours. Guidelines for target volume selection and delineation are thoroughly elaborated. Last, the management by radiotherapy of locoregional recurrences is discussed.

A simple stability indicating RP-HPLC-DAD method for concurrent analysis of Tenofovir Disoproxil Fumarate, Doravirine and Lamivudine in pure blend and their combined film coated tablets.

OBJECTIVES: The main aim of the study was to develop an economical, insightful, accurate and simple RP-HPLC-DAD method with high precision and good sensitivity for concurrent determination of Tenofovir disoproxil fumarate, Doravirine and Lamivudine in blended bulk form and their combined tablet form. MATERIAL AND METHODS: A method with Ascentis C18 (150×4.6mm, 5µm) column, mobile phase ratio of 0.1% ortho phosphoric acid and Acetonitrile in 70:30 (v/v), 1mL/min flow rate and detection wavelength of 260nm was highly proficient in effective separation of all three drugs. The developed method was validated in accordance with ICH specifications. RESULTS: The retention times of Doravirine, Lamivudine and Tenofovir disoproxil fumarate observed were 2.4, 2.9, and 3.6min, respectively. The linear responses were observed for Doravirine, Lamivudine and Tenofovir disoproxil fumarate in the range of 12.5-75µg/mL, 75-225µg/mL and 75-225µg/mL, respectively. The limit of detection and quantification values were calculated to be 0.36µg/mL and 0.11µg/mL for Lamivudine, 0.55µg/mL and 1.66µg/mL for Tenofovir disoproxil fumarate and 0.03µg/mL and 0.09µg/mL for Doravirine. The % RSD values of the intra-day and inter-day precision were calculated in the range of 0.134-1.749. The mean percentage recovery of all three analytes was in the range of 98.85-100.18%. The statistical results of the validation parameters ensured that the method was accurate, specific, and precise with good sensitivity. Investigation of analytes under different stressed conditions ensures the stability of analytes reflecting the stability indication of the method. The developed method has high proficiency in separation of Tenofovir disoproxil fumarate, Doravirine and Lamivudine. The degradation products generated due to stress conditions also separated with good resolution. CONCLUSION: The current method is a stability-indicating assay method consisting of appropriate specificity, accuracy, precision and sensitivity. The developed method has a good potential to be adopted by the pharmaceutical industrial sector.

[Concomitant radiotherapy and trastuzumab: Rational and clinical implications]. / Association radiothérapie et trastuzumab : rationnel et implications cliniques.

The HER2 receptor (Human Epidermal Growth Receptor 2) is a transmembrane receptor with tyrosine kinase activity that is over-expressed in 25-30 % of breast carcinomas. Its activation is associated with an exaggeration of cell proliferation with an increase in repair capacity resulting in increased radioresistance. On cardiac tissues, HER2 receptor activation plays a cardio-protective role. Trastuzumab, the first anti-HER2 drug used to treat patients with breast cancer overexpressing HER2 receptor , inhibits the cascade of reactions resulting in the proliferation of tumor cells, thus restoring cellular radiosensitivity. However, the combination of Trastuzumab with radiation therapy also removes HER2 receptor cardio-protective role on myocardial cells which increases the risk of cardiotoxicity. Thus, the concomitant association of these two modalities has long been a subject of controversy. Recent advances in radiation therapy technology and early detection of cardiac injury may limit the cardiotoxicity of this combination. Through this review, we developed the biological basis and the benefit-risk of concomitant combination of radiotherapy and Trastuzumab in adjuvant treatment of breast cancers overexpressing HER2 and we discuss the modalities of its optimization.

In vitro effects of Trastuzumab Emtansine (T-DM1) and concurrent irradiation on HER2-positive breast cancer cells.

BACKGROUND: To determine the effects of concurrent irradiation and T-DM1 on HER2-positive breast cancer cell lines. METHODS: Five human breast cancer cell lines (in vitro study) presenting various levels of HER2 expression were used to determine the potential therapeutic effect of T-DM1 combined with radiation. The toxicity of T-DM1 was assessed using viability assay and cell cycle analysis was performed by flow cytometry after BrdU incorporation. HER2 cells were irradiated at different dose levels after exposure to T-DM1. Survival curves were determined by cell survival assays (after 5 population doubling times). RESULTS: The results revealed that T-DM1 induced significant lethality due to the intracellular action of DM1 on the cell cycle with significant G2/M phase blocking. Even after a short time incubation, the potency of T-DM1 was maintained and even enhanced over time, with a higher rate of cell death. After irradiation alone, the D10 (dose required to achieve 10% cell survival) was significantly higher for high HER2-expressing cell lines than for low HER2-expressing cells, with a linearly increasing relationship. In combination with irradiation, using conditions that allow cell survival, T-DM1 does not induce a radiosensitivity. CONCLUSIONS: Although there is a linear correlation between intrinsic HER2 expression and radioresistance, the results indicated that T-DM1 is not a radiation-sensitizer under the experimental conditions of this study that allowed cell survival. However, further investigations are needed, in particular in vivo studies before reaching a final conclusion.

[Radiochemotherapy for the treatment ofmuscle invasive bladder tumors in a west african radiotherapy service]. / Radiochimiotherapie pour le traitement des tumeurs de vessie infiltrant lemuscle dans un service de radiotherapie ouest africaine.

OBJECTIF: The aim of this study was to describe the results of radiochemotherapy in patients after transurethral resection of muscle invasive bladder tumors. MATERIAL AND METHODS: A retrospective study from May 2014 to May 2016 in the radiotherapy department of the Mali Hospital. Have been included, all patients with bladder cancer infiltrating the muscle. Secondary cancers of the bladder and metastatic forms have been excluded from our study. Transurethral resection of bladder was performed. Neoadjuvant chemotherapy with paclitaxel- carboplatin was administered every three weeks in all patients, then external phototherapy 6 MV at a dose of 66 Gy due to 2 Gy of 5 sessions per week 6MV photon of external beam radiotherapy at a dose of 66 Gy due to 2 Gy of 5 sessions per week associated with concomitant cisplatin at dose of 40mg / m2 / week. RESULTS: Eight patients were included in ourstudy. The average age of 53.75 ± 14.84 years. The male sex was predominant 87.5% (n = 7). The history of chronic smoking wasfound in four patients. The main carcinogenic risk factor identified in our patients was urogenital bilharzia (6 cases / 8).The histological type found was urothelial carcinomain 12.5% (n = 1) and invasive squamous cell carcinomain 87.5% (n = 7). Transurethral resection of the tumor was performed in 62.5% (n = 5). Endoscopic biopsy was performed in 37.5% (n = 3). The tumor was classified pT2N0M0 in 50% (n = 4), pT3aN0M0 in 37.5% (n = 3) and pT3bN0M0 in 12.5% (n = 1). Neoadjuvant chemotherapy with paclitaxel - carboplatin every three weeks was administered to all patients. The results of radiochemotherapy (see Table: evolution). CONCLUSION: Concomitant radiochemotherapy is a conservative curative treatment that can be proposed as a replacement for cystectomy, for non-metastatic infiltrating tumors after the most complete endoscopic resection.

OBJECTIF: Le but de cette étude était de décrire les résultats d'une radiochimiothérapie chez les patients après résection transurétrale des tumeurs de vessie infiltrant le muscle. MATÉRIEL ET MÉTHODES: Une étude rétrospective allant de mai 2014 à mai 2016 au service de radiothérapie de l'hôpital du Mali. Ont été inclus, tous les patients présentant un cancer de vessie infiltrant le muscle. Les cancers secondaires de la vessie ainsi que les formes métastatiques ont été exclus de notre étude. La résection transurétrale de vessie a été réalisée. La chimiothérapie néoadjuvante à base de paclitaxel ­ carboplatine a été administrée toutes les trois semaines. La radiothérapie externe au photon 6MV à la dose de 66 Gy en raison de 2 Gy de 5 séances par semaine associée à la chimiothérapie concomitante à base de cisplatine (CDDP) 40mg/m2/semaine a été réalisée. RÉSULTATS: Au total huit patients ont été inclus dans notre étude. L'âge moyen de 53,75±14,84 ans. Le sexe masculin était prédominant 87.5% (n=7). L'antécédent de tabagisme chronique était retrouvé chez quatre patients. Le principal facteur de risque cancérigène identifié chez nos patients était la bilharziose urogénitale (6cas/8). Le type histologique retrouvé était le carcinome urothelial dans 12.5% (n=1) et le carcinome épidermoïde infiltrant dans 87.5% (n=7). La résection transurétrale de la tumeur a été réalisée dans 62.5% (n=5). La biopsie par voie endoscopique été réalisée dans 37.5% (n=3). La tumeur été classée pT2N0M0 dans 50% (n= 4), pT3aN0M0 dans 37.5% (n=3) et pT3bN0M0 dans 12.5% (n= 1). La chimiothérapie néoadjuvante à base de paclitaxel ­ carboplatine chaque trois semaines a été administrée chez tous les malades.Les résultats de la radiochimiothérapie (cf. Tableau: évolution). CONCLUSION: La radiochimiothérapie concomitante est un traitement curatif conservateur qui peut être proposée en remplacement à la cystectomie pour les tumeurs infiltrantes non métastatiques après une résection endoscopique la plus complète possible.

Outcome of multidisciplinary treatment in laryngeal cancer. Retrospective study with 10-years follow-up.

BACKGROUND: In laryngeal cancer, multidisciplinary treatment improves the patient's quality of life and the possibility of preserving the larynx. Most cases occur in a locally advanced stage. The aim is to present the results according to the stage. METHOD: A retrospective study which analyzed the clinical stage, type of primary treatment, outcomes, and survival were analyzed. RESULTS: 451 patients were included. The median age was 66 years. The majority of the tumors presented in advanced stage (72%) and the most affected subsite was the glottis (84.5%). In the early stage the most frequent treatment was radiotherapy as the only treatment modality. In stages III and IVA, 65% were resectable. In stage IVB the management was non-surgical, with control in 26% of the cases. Survival at 10 years was related to the clinical stage: 81.7% for stage I and 0% for stages IVB and IVC. CONCLUSIONS: Patients with laryngeal cancer should be treated according to the clinical stage, through a multidisciplinary approach. Long-term follow-up showed a worse prognosis for advanced clinical stages.

ANTECEDENTES: En cáncer de laringe, el tratamiento multidisciplinario mejora la calidad de vida del paciente y la posibilidad de preservar la laringe. La mayor parte de estos cánceres se presentan localmente avanzados. El objetivo es presentar los resultados de acuerdo con la etapa. MÉTODO: Estudio retrospectivo en el que se analizaron la etapa clínica, el tipo de tratamiento primario, los resultados y la sobrevida. RESULTADOS: Se incluyeron 451 pacientes. La mediana de edad fue de 66 años. El mayor porcentaje de los tumores se presentó en etapa avanzada (72%) y el sitio más afectado fue la glotis (84.5%). En etapa temprana, el tratamiento más frecuente fue la radioterapia. En las etapas III y IVA, el 65% fueron operables. En la etapa IVB el manejo fue no quirúrgico, con control en el 26% de los casos. La supervivencias a 10 años se relacionaron con la etapa clínica: 81.7% para la etapa I y 0% para las etapas IVB y IVC. CONCLUSIONES: Los pacientes con cáncer de laringe deben ser tratados de acuerdo con la etapa clínica y mediante un abordaje multidisciplinario. El seguimiento a largo plazo demostró un peor pronóstico para las etapas clínicas avanzadas.

Effect on the adherence to concomitant medications after initiation of treatment with direct-acting antiviral agents against hepatitis C virus.

INTRODUCTION: Many patients with hepatitis C virus (HCV) have associated comorbidities that require complex treatments. We sought to determine the impact of treatment with direct-acting antiviral agents (DAAs) for HCV on adherence to prescribed concomitant medications for associated comorbidities and to identify predictors of non-adherence to comedications. PATIENTS AND METHODS: HCV-infected patients treated with DAAs in a Spanish hospital between January 2015 and December 2016 and followed-up by the pharmacy unit were included in the study. Adherence to concomitant comedication prescribed before and during HCV therapy with DAAs was compared to adherence during the same number of weeks before DAA initiation. Demographic, clinical and pharmacotherapy variables were analyzed to determine factors associated with non-adherence. A multivariate regression model was created for prediction of non-adherence to concomitant medication. RESULTS: Data from 214 patients using prescribed concomitant therapies were analyzed. Significant reduction on adherence to comedications was observed after initiation of DAA treatment compared with a similar period before therapy initiation (29.9% vs. 36.9%, p=0.032). The univariate analysis showed that polypharmacy and presence of vascular disease were associated negatively with adherence to concomitant medications (87.8%, p=0.006 and 84.7%, p<0.001, respectively). Multivariate analysis indicated that HIV/HBV coinfection was associated with adherence (OR 0.19; 95% CI 0.09-0.39), while polypharmacy was a predictor for non-adherence (OR 4.54; 95% CI 1.48-13.92). DISCUSSION: Adherence to concomitant medications decreases in HCV-infected patients when DAA therapy is initiated. Polypharmacy is a predictor for non-adherence, while HIV/HBV coinfection reduce non-adherence rates. Polymedicated patients on DAAs might benefit from close follow-up and educational programmes to improve their adherence.

Survival comparision of three-dimensional radiotherapy alone with concurrent chemoradiotherapy for non-surgical esophageal carcinoma.

PURPOSE: Radiotherapy is the main treatment method for patients with locally advanced, unresectable esophageal cancer. The aim of this study is to compare overall survival (OS) using 3D radiotherapy (3DRT) alone with concurrent chemoradiotherapy (CCRT) in 296 non-surgical esophageal carcinoma patients. PATENTS AND METHODS: Over 10 years, of the 480 patients with esophageal carcinoma treated with 3DRT with or without chemotherapy, 148 patients each comprised 3DRT and CCRT groups after propensity score matching. RESULTS: The 5- and 10-year OS (P=0.337) and PFS (P=0.715) rates for 3DRT alone were 22.0%, 14.4% and 26.1%, 23.2%, respectively, compared with 28.8%, 18.6% and 34.7%, 29.1% for CCRT, respectively. CCRT did not improve 5-year and 10-year OS or PFS in 60-70Gy group (OS: 27.5% and 25.2%; 17.9% and 17.0%, P=0.938; PFS: 38.3% and 31.8%; 31.9% and 27.8%, P=0.890) nor reduce 10-year hematogenous metastasis (31.7% and 28.3%, P=0.698). CCRT improved 5-year OS and PFS of 50.0-59.9Gy group (OS: 33.3% and 12.0%, P=0.029; PFS: 33.1% and 10.6%, P=0.081). For 3DRT, the 5-year OS and PFS rates were significantly better in the 60-70Gy group (P=0.017) compared with 50.0-59.9Gy group (P=0.002). For CCRT group, 5-year OS and PFS favored the 50.0-59.9Gy group, but the difference was insignificant. Major toxicities were greater with CCRT compared with 3DRT. CONCLUSION: For non-surgical esophageal carcinoma patients, 3DRT combined with CCRT was effective in prolonging both OS and PFS.

Factors infuencing the sensitivity of ultrasound and gamma location of the parathyroid adenoma. / Factores que condicionan la sensibilidad de la ecografía y la gammagrafía en la localización del adenoma paratiroideo.

INTRODUCTION: The treatment of choice for primary hyperparathyroidism (PHPT) when there is proper preoperative localization of the adenoma is minimally invasive parathyroidectomy. However, imaging techniques are not always able to provide the exact location. The objective is to identify potential factors that might influence the sensitivity and concordance of ultrasound (US) and 99mTc-methoxy-isonitrile parathyroid scintigraphy (MIBI-PS) and the actual location of the adenoma. METHODS: We reviewed the data of patients who underwent parathyroidectomies for PHPT. All patients had undergone ultrasound and 99mTc-MIBI scintigraphy as a preoperative location study. Multiple endocrine neoplasms, other hyperplasias and non-cervical ectopic adenomas were excluded. The sensitivity, PPV and concordance have been estimated for the location of the gland in both tests compared with the intraoperative location, using a multivariable analysis of the factors that might influence their localization capacity. RESULTS: 139 patients (82% women) have been analysed. The US sensitivity was 56.7%, concordance (Kappa index) 0.387 and PPV 96.3%. The MIBI-PS sensitivity was 81.6%, the concordance (Kappa index) 0.669 and the PPV 97.4%. The factor that improved localization of the glands by US in the multivariable analysis was the absence of a concomitant thyroid pathology. The factor that improved the MIBI-PS results was a gland weight greater than 600mg. CONCLUSIONS: US sensitivity improves when there is no concomitant thyroid pathology. MIBI-PS sensitivity improves when the gland weight is greater than 600mg.

[Neoadjuvant chemotherapy in locally advanced cervical cancer in patients receiving a concomitant chemoradiotherapy in a low income country]. / Chimiotherapie neo adjudante dans les cancers localement avances du col uterin chez des patientes recevant une radiochimiotherapie concomitante dans pays aux ressources limitees.

PURPOSE: Delays to access to radiotherapy are long in our context. The purpose of this study was to analyze the effect of neoadjuvant chemotherapy to concomitant chemoradiotherapy in locally advanced cervical cancers. PATIENTS AND METHODS: We conducted a retrospective study from April 2014 to April 2016 at the radiotherapy center of "Hopital du Mali" in Bamako, Mali. Patients were allocated according to age, histological type, tumor size and the 2002 classification of the FIGO. Experimental protocol was the administration of a neoadjuvante chemotherapy with association of Paclitaxel 175mg/m2 + Carboplatine AUC 5 every 3 weeks and radiothérapy cure with avec linac 6 MV at 70 Gy due to 5 sessions of 2 Gy per week associated with a concomitant chemotherapy with cisplatin at 40 mg/m2/week. The clinical response was assessed at the end of neoadjuvant chemotherapy and of concomitant chemoradiotherapy. RESULTS: Thirty patients were included in the study. The mean age was 53.63 ± 8.9 years. The mean size of the tumor was 5.17 cm (2 to 7 cm). According to the 2002 classification of the FIGO stages IIB were 33% (n = 10); IIIB were 57% (n = 17) and IVA were 10% (n = 3). Clinical evaluation at the end of neoadjuvant chemotherapy found: complete response 17 % (n = 5), partial response 10% (n = 3) and stable disease 73 % (n = 22). Evaluation at the end of the concomitant chemoradiotherapy had found the complete response in 90% (n = 27) and stable disease in 10% (n = 3). CONCLUSION: Neoadjuvant chemotherapy to concomitant chemoradiotherapy in locally advanced cervical cancer allows stabilization of the tumor and improves local control. Due to long delays to access to radiotherapy treatment in our context; neoadjuvant chemotherapy is an alternative to stabilize the disease and prevent distant metastasis from locally advanced cervical cancers.

OBJECTIF: Les délais d'attente pour accéder à la radiothérapie sont longs dans note contexte. L'objet de cette étude était d'analyser le résultat de la chimiothérapie néo adjuvante à la radiothérapie dans les cancers localement avancés du col utérin. PATIENTS ET MÉTHODES: Nous avons réalisé une étude rétrospective allant d'avril 2014 à avril 2016 au centre de radiothérapie de l'hôpital du Mali. Les patients ont été regroupés selon l'âge, le type histologique, la taille de la tumeur, la classification de la FIGO 2002. Le schéma thérapeutique était une chimiothérapie néo adjuvante associant Paclitaxel 175 mg/m2 et Carboplatine AUC 5 toutes les 3 semaines suivie d'une radiothérapie avec linac 6 MV à la dose de 70 Gy en raison de 5 séances de 2 Gy par semaine faite concomitamment à une chimiothérapie avec du cisplatine à la dose de 40 mg/m2/semaine. La réponse clinique était évaluée à la fin de la chimiothérapie néoadjuvante et de la radiochimiothérapie concomitante. RÉSULTATS: Trente patientes ont été incluses dans l'étude. L'âge moyen était de 53.63 ± 8.9 ans. La taille moyenne de la tumeur était de 5,17 cm (2 à 7 cm). Selon la classification FIGO 2002, 10 (33%) étaient en stade IIB distal, 17 (57%) étaient en stade IIIB et 3 (10%) en stade IVA. L'évaluation clinique à la fin de la chimiothérapie néo adjuvante avait retrouvé 17 % de réponses complètes (n=5), 10% de réponses partielles (n=3) 73 % d'évolutions stables (n=22). L'évaluation à la fin de la radiochimiothérapie concomitante avait trouvé une réponse complète chez 27 patientes (90%) et une maladie stable chez 3 (10%). CONCLUSION: La chimiothérapie néo adjuvante à la chimioradiothérapie concomitante dans les cancers localement avancés du col utérin permet la stabilisation de la tumeur et améliore le control local. En raison des délais d'attente longs pour accéder à la radiothérapie, la chimiothérapie néo adjuvante est une alternative pour stabiliser la maladie et réduire le risque de métastases à distance des cancers du col utérin localement avancés.

Susceptibility of Biomphalaria glabrata submitted to concomitant infection with Angiostrongylus costaricensis and Schistosoma mansoni / Suscetibilidade de Biomphalaria glabrata submetida à infecção concomitante com Angiostrongylus costaricensis e Schistosoma mansoni

Abstract The easy adaptation of Angiostrongylus costaricensis, nematode responsible for abdominal angiostrongyliasis to several species of terrestrial and freshwater molluscs and the differences observed in the interactions of trematodes with their intermediate hosts have induced us to study the concomitant infection of Biomphalaria glabrata with Schistosoma mansoni and A. costaricensis. Prior exposure of B. glabrata to A. costaricensis (with an interval of 48 hours), favored the development of S. mansoni, observing higher infection rate, increased release of cercariae and increased survival of molluscs, when compared to molluscs exposed only to S. mansoni. Prior exposure of B. glabrata to A. costaricensis and then to S. mansoni also enabled the development of A. costaricensis since in the ninth week of infection, higher amount of A. costaricensis L3 larvae was recovered (12 larvae / mollusc) while for molluscs exposed only to A. costaricensis, the number of larvae recovered was lower (8 larvae / mollusc). However, pre-exposure of B. glabrata to S. mansoni (with an interval of 24 hours), and subsequently exposure to A. costaricensis proved to be very harmful to B. glabrata, causing extensive mortality of molluscs, reduced pre-patent period to release cercariae and greater recovery of L3 A. costaricensis larvae.

Resumo A facilidade de adaptação do Angiostrongylus costaricensis, nematódeo responsável pela angiostrongiliase abdominal, a diversas espécies de moluscos terrestres e dulciaquícolas e as divergências observadas nas interações dos trematódeos com seus hospedeiros intermediários nos induziu a estudar a infecção concomitante de Biomphalaria glabrata com Schistosoma mansoni e A. costaricensis. A exposição prévia de B. glabrata ao A. costaricensis (com intervalo de 48 horas), favoreceu o desenvolvimento do S. mansoni observando-se elevação da taxa de infecção, maior liberação de cercárias e maior sobrevivência dos moluscos, quando comparado com os moluscos expostos somente ao S. mansoni. A exposição de B. glabrata previamente ao A. costaricensis e posteriormente ao S. mansoni também facilitou o desenvolvimento do A. costaricensis uma vez que na nona semana de infecção foi recuperada maior quantidade de larvas L3 de A. costaricensis, enquanto nos moluscos expostos somente ao A. costaricensis, o número de larvas recuperadas foi menor . Entretanto a pré-exposição de B. glabrata ao S. mansoni (com intervalo de 24 horas), e posteriormente a exposição ao A. costaricensis mostrou-se muito prejudicial à B. glabrata provocando grande mortalidade dos moluscos, redução do período pré-patente para liberação de cercárias e maior recuperação de larvas L3 de A. costaricensis.

Susceptibility of Biomphalaria glabrata submitted to concomitant infection with Angiostrongylus costaricensis and Schistosoma mansoni

Abstract The easy adaptation of Angiostrongylus costaricensis, nematode responsible for abdominal angiostrongyliasis to several species of terrestrial and freshwater molluscs and the differences observed in the interactions of trematodes with their intermediate hosts have induced us to study the concomitant infection of Biomphalaria glabrata with Schistosoma mansoni and A. costaricensis. Prior exposure of B. glabrata to A. costaricensis (with an interval of 48 hours), favored the development of S. mansoni, observing higher infection rate, increased release of cercariae and increased survival of molluscs, when compared to molluscs exposed only to S. mansoni. Prior exposure of B. glabrata to A. costaricensis and then to S. mansoni also enabled the development of A. costaricensis since in the ninth week of infection, higher amount of A. costaricensis L3 larvae was recovered (12 larvae / mollusc) while for molluscs exposed only to A. costaricensis, the number of larvae recovered was lower (8 larvae / mollusc). However, pre-exposure of B. glabrata to S. mansoni (with an interval of 24 hours), and subsequently exposure to A. costaricensis proved to be very harmful to B. glabrata, causing extensive mortality of molluscs, reduced pre-patent period to release cercariae and greater recovery of L3 A. costaricensis larvae.

Resumo A facilidade de adaptação do Angiostrongylus costaricensis, nematódeo responsável pela angiostrongiliase abdominal, a diversas espécies de moluscos terrestres e dulciaquícolas e as divergências observadas nas interações dos trematódeos com seus hospedeiros intermediários nos induziu a estudar a infecção concomitante de Biomphalaria glabrata com Schistosoma mansoni e A. costaricensis. A exposição prévia de B. glabrata ao A. costaricensis (com intervalo de 48 horas), favoreceu o desenvolvimento do S. mansoni observando-se elevação da taxa de infecção, maior liberação de cercárias e maior sobrevivência dos moluscos, quando comparado com os moluscos expostos somente ao S. mansoni. A exposição de B. glabrata previamente ao A. costaricensis e posteriormente ao S. mansoni também facilitou o desenvolvimento do A. costaricensis uma vez que na nona semana de infecção foi recuperada maior quantidade de larvas L3 de A. costaricensis, enquanto nos moluscos expostos somente ao A. costaricensis, o número de larvas recuperadas foi menor . Entretanto a pré-exposição de B. glabrata ao S. mansoni (com intervalo de 24 horas), e posteriormente a exposição ao A. costaricensis mostrou-se muito prejudicial à B. glabrata provocando grande mortalidade dos moluscos, redução do período pré-patente para liberação de cercárias e maior recuperação de larvas L3 de A. costaricensis.

Thoracic irradiation in 3weeks for limited-stage small cell lung cancer: Is twice a day fractionation really needed?

PURPOSE: Many Canadian institutions treat limited-disease small cell lung cancer with 40Gy in 15 fractions delivered once-a-day in 3weeks concomitantly with chemotherapy. This regimen is convenient and seems to be effective. Here, we report and compare with a literature review the outcomes of patients with limited-stage small cell lung cancer treated in our institution with this hypofractionated regimen. PATIENTS AND METHODS: From January 2004 to December 2012, patients with limited-stage small cell lung cancer treated curatively with platinum-based chemotherapy and concurrent thoracic radiotherapy at a dose of 40Gy in 16 fractions once-a-day were eligible for this review. RESULTS: Sixty-eight patients fit the analysis criteria, including ten patients with small pleural effusion. The median age was 66years old. After a median follow-up of 77months for those alive, the median survival was 28months. At 3 and 5years respectively, the locoregional control rates were 67 and 64%, while the overall survival rates were 40 and 35%. Prophylaxis cranial irradiation was delivered to 68% of the patients. Grade 2 and 3 acute esophagitis occurred in respectively 49 and 9% of the patients. There was no grade 4 radiation-induced toxicity. All patients, except for one, completed their thoracic irradiation course without interruption. CONCLUSION: Once-a-day hypofractionated radiation with concurrent chemotherapy followed by prophylactic cranial irradiation is a practical regimen. Based on our experience and the published literature, it appears to be similarly effective as regimens using twice-daily fractionation in 3weeks, or once-daily in 6 to 7weeks with higher radiotherapy doses. Further prospective comparisons of hypofractionation with the current recommendations are needed.

Freud, Brentano e a Concomitância Dependente / Freud, Brentano and Dependent Concomitance

RESUMO No campo das interações entre o corporal e o anímico, a noção de concomitância dependente é um dos principais pilares capazes de sustentar a soberania não apenas da psicanálise, mas da psicologia de um modo geral. Formulada por Freud em seu manuscrito sobre as afasias, de 1891, ela é comumente associada à contribuição do neurologista britânico John Hughlings Jackson. Não contrariando este julgamento, o presente trabalho visa examiná-la ainda à luz dos ensinamentos do filósofo Franz Brentano, professor de Freud durante sua graduação em medicina. Com isso, pretende-se elevar a noção de concomitância para além da condição de imperativo metodológico.

ABSTRACT In the field of interactions between the physical and the mental, the notion of dependent concomitance is one of the main pillars able to sustain not only Psychoanalysis' sovereignty, but also that of Psychology as a whole. Formulated by Freud in his manuscript from 1891 regarding aphasias, it is usually associated with the contribution of the British neurologist John Hughlings Jackson. Not contradicting this judgement, the present work aims to examine this notion further in the light of the teachings of the philosopher Franz Brentano, Freud's professor during his graduation in Medicine. In so doing, we intend to elevate the notion of concomitance beyond its condition of methodological imperative.

Prevalencia de interacciones medicamentosas con fármacos anti-retrovirales en Buenos Aires, Argentina / Prevalence of potential drug-drug interactions involving antiretroviral drugs in Buenos Aires, Argentina

Introduction: Antiretroviral agents (ARVs) have a high potential for drug interactions. However, the prevalence and risk factors for clinically significant drug-drug interactions (CSDDIs) with ARVs from Latin American countries is unknown. Aim: To evaluate the prevalence and risk factors for CSDDIs in HIV outpatients attending at two centers in Buenos Aires, Argentina. Methods: Descriptive cross-sectional study (september to november 2012). HIV-1 infected patients under ARV treatment at the time of the study were randomly assessed for concomitant medication. CSDDIs were screened using the University of Liverpool Drug Interactions Program (www.hiv-druginteractions.org). Results: A total of 217 patients were included. Male sex: 64% (CI 95: 57-70). Median age (IQR): 41 (36-48). Presence of comorbidities: 19%. ARV regimen: NNRTI-based: 48%, PI-based: 50% and NNRTI plus PI: 2%. Median of CD4 T-cell count (IQR): 402 cells/mL (235-588). Viral load < 50 copies/mL: 78%. Overall, 64% (CI 95: 57-70) of patients had > 1 co-medication of whom a 49% had at least one CSDDI. Two patients had a CSDDI between ARVs. The most frequent co-medications observed were antimicrobial (40%), cardiovascular (25%) and gastrointestinal agents (22%). In the multivariate analysis the number of co-medications and use of CNS agents were associated with the presence of CSDDIs. Conclusions: Co-medications and CSDDIs were common in our setting. In this context, training of HIV physicians in drug interactions is of major importance for adequate management of these patients.

Introducción: Los fármacos anti-retrovirales (ARVs) tienen un alto potencial de interaccionar farmacológicamente con otros medicamentos. Sin embargo, los datos sobre la prevalencia y los factores de riesgo para la presencia de interacciones medicamentosas clínicamente significativas (IMCS) con ARVs en países latinoamericanos son limitados. Objetivo: Evaluar la prevalencia y los factores de riesgo para estas IMCS en dos centros de atención ambulatoria en Buenos Aires, Argentina. Métodos: Estudio transversal y descriptivo (septiembre-noviembre de 2012). Se evaluó la presencia de medicación concomitante en pacientes infectados por VIH bajo tratamiento ARV. Para evaluar la presencia de IMCS se utilizó la base de datos de interacciones de la Universidad de Liverpool (www.hiv-druginteractions.org). Resultados: Se incluyeron 217 pacientes. Sexo masculino: 64% (IC 95: 57-70). Mediana de edad (IQR): 41 (36-48). Presencia de co-morbilidades: 19%. Tratamiento ARV basado en INNTI: 48%, basado en IP: 50% y basado en INNTI más IP: 2%. Mediana de linfocitos T-CD4 (IQR): 402 céls/ml (235-588). Carga viral < 50 copias/ml: 78%. El 64% (IC 95: 57-70) de los pacientes tenían > 1 medicación concomitante: antimicrobianos (40%), fármacos cardiovasculares (25%) y gastrointestinales (22%). De los pacientes que presentaban medicación concomitante 68 (49%) tenían > 1 IMCS y sólo tres (2%) presentaban una asociación contraindicada. Además, dos pacientes tenían una IMCS entre ARVs. En el análisis multivariado, el número de medicamentos concomitantes y el uso psicofármacos se asociaron con una mayor chance de presentar IMCS. Conclusiones: La presencia de medicación concomitante e IMCS fue común en nuestra población. En este contexto, la formación de profesionales de la salud en la detección de interacciones medicamentosas es de suma importancia para un manejo adecuado de pacientes con infección por VIH que reciban tratamiento ARV.