Differentiated thyroid carcinoma: what the nonspecialists needs to know

ABSTRACT Differentiated thyroid carcinoma (DTC) accounts for most cases of thyroid cancer, and the heterogeneity of DTC requires that management decisions be taken by a multidisciplinary team involving endocrinologists, head and neck surgeons, nuclear medicine physicians, pathologists, radiologists, radiation oncologists, and medical oncologists. It is important for nonspecialists to recognize and refer patients with DTC who will benefit from a specialized approach. Recent advances in knowledge and changes in management of DTC call for the need to raise awareness on the part of these nonspecialist physicians, including general endocrinologists and medical oncologists at large. We provide an overview of diagnostic and therapeutic principles in DTC, especially those that bear direct implication on day-to-day management of these patients by generalists. Patients with DTC may be broadly categorized as having localized, locally persistent/recurrent, or metastatic disease. Current recommendations for DTC include a three-tiered system that classifies patients with localized disease into low, intermediate, or high risk of persistent or recurrent disease. Risk stratification should be performed at baseline and repeated on an ongoing basis, depending on clinical evolution. One of the overarching goals in the management of DTC is the need to personalize treatment by tailoring its modality and intensity according to ongoing prognostic stratification, evolving knowledge about the disease, and patient characteristics and preference. In metastatic disease that is refractory to radioactive iodine, thyroid tumors are being reclassified into molecular subtypes that better reflect their biological properties and for which molecular alterations can be targeted with specific agents.

Synergistic effect of sorafenib with Platycladus orientalis (L) leaf extract on cervical cancer

The extracts of Platycladus orientalis (L.) Franco leaves have shown promising anti-cancer, anti-oxidant and anti-inflammatory potency with the traditional knowledge of healing HPV associated warts. The purpose of this research is to assess the synergistic activity of sorafenib and Platycladus orientalis (L) leaf extraction on cervical cancer cells. The cytotoxicity efficiency of different concentrations of Sorafenib and ethanol extract of Platycladus orientalis (L.) leaves were tested on HeLa cells by MTT and Trypan blue assays. The synergistic effect of the IC50 concentrations of Sorafenib and Platycladus orientalis (L.) on HeLa cell by MTT assay, and mRNA expression levels of tumor suppressor tazarotene-induced gene 3 (TIG3), proliferating cell nuclear antigen (PCNA) gene and apoptosis modulator (Bcl-2) gene by RT-PCR were evaluated with individual treatments. Combination treatment showed a relatively more expression of TIG3 and less expression of Bcl-2 and PCNA was observed. Growth factor-induced MAPKP activation was arrested by compound combination treatment, which and suppression of proliferation-induced apoptosis of cervical cancer cells. Based on the our results, the combination of sorafenib and crude leaf extract from Platycladus orientalis (L.) can effectively suppress cervical cancer cell growth, thereby providing an interesting rationale for further clinical trials and in-vivo studies.

Hepatocellular carcinoma: A real-life experience in a specialized center in Bogotá, Colombia / Hepatocarcinoma: experiencia de la vida real en un centro especializado de Bogotá, Colombia

Abstract Introduction: Hepatocellular carcinoma (HCC) is the most frequent malignant primary liver tumor globally. In 2018, it ranked sixth and represented the fourth cause of death from cancer; the five-year overall survival is 18 %. Most cases of HCC develop in patients with cirrhosis of any etiology, especially because of hepatitis B and C viruses, alcohol, and recently nonalcoholic steatohepatitis (NASH). Aim: To analyze the clinical characteristics, diagnostic methods, treatments, prognostic variables, and survival. Materials and methods: This retrospective descriptive study was conducted on a cohort of patients diagnosed with cirrhosis and treated between January 2011 and December 2020 at a health care center in Bogotá. The diagnosis of HCC was confirmed radiologically or by biopsy. We analyzed the information descriptively with absolute frequency measures in the case of categorical variables. For continuous variables, the information was summarized with measures of central tendency (mean or median) and their relevant measures of dispersion. Results: We included 152 patients diagnosed with HCC, with a mean age of 69.4 years; 51.3 % were men. The leading cause of HCC was nonalcoholic fatty liver disease (NAFLD), which accounted for almost a third of cases (32 %); other causes were alcohol (15 %) and hepatitis C virus (14 %). The median manifestation of the tumor was two nodules with a size close to 4 cm. Besides, 35 % of patients had a BCLC (Barcelona Clinic Liver Cancer) stage with curative options, and 25 % received curative treatment options. The first-line systemic therapy used in this cohort was sorafenib®, used in 35 patients (33.7 %). Survival curves showed that women, Child-Pugh class A, and BCLC stage 0 had higher median survival. Multivariate analysis showed a higher risk of death for males (hazard ratio [HR]: 2.16; confidence interval [CI]: 1.24-3.76), Child-Pugh class B (HR: 2.14; CI 1.16-3.95), and Child-Pugh class C (HR: 7.52; CI 2.88-19.57). Conclusions: NAFLD is the leading cause of HCC in this cohort. A third of patients are diagnosed in early BCLC stages with a curative treatment option, and 25 % are treated with curative therapies. Sorafenib was the first-line therapy in advanced HCC. Overall survival after diagnosis of HCC remains low, being necessary to join forces in the follow-up of patients with cirrhosis to improve these outcomes.

Resumen Introducción: el hepatocarcinoma (HCC) es el tumor hepático primario maligno más frecuente en el mundo: en 2018 ocupó la sexta posición y representó la cuarta causa de muerte por cáncer; la supervivencia global a 5 años es del 18 %. La mayoría de los casos de HCC se desarrolla en pacientes con cirrosis de cualquier etiología, especialmente por virus de la hepatitis B y C, alcohol y, recientemente, por la esteatohepatitis no alcohólica (NASH). Objetivo: analizar las características clínicas, métodos de diagnóstico, tratamientos, variables pronósticas y supervivencia. Metodología: estudio descriptivo retrospectivo de una cohorte de pacientes con diagnóstico de cirrosis atendidos entre enero de 2011 y diciembre de 2020 en un centro de atención médica de Bogotá, con diagnóstico de HCC confirmado radiológicamente o por biopsia. La información se analizó de forma descriptiva con medidas de frecuencia absoluta en el caso de las variables categóricas; para las variables continuas se resumió la información con medidas de tendencia central (media o medianas) y su respectiva medida de dispersión. Resultados: se incluyeron 152 pacientes diagnosticados con HCC, con edad promedio de 69,4 años, 51,3 % eran hombres. La principal causa de HCC fue el hígado graso no alcohólico (NAFLD), que representó casi una tercera parte de los casos (32 %); otras causas fueron el alcohol (15 %) y el virus de la hepatitis C (14 %). La mediana de presentación del tumor fue de 2 nódulos con un tamaño cercano a 4 cm. El 35 % de los pacientes tenía un estadio BCLC (Barcelona Clinic Liver Cancer) con opciones curativas y el 25 % de los pacientes recibió opciones curativas de tratamiento. La terapia sistémica de primera línea utilizada en esta cohorte fue el sorafenib®, que se utilizó en 35 pacientes (33,7 %). Las curvas de supervivencia mostraron que las mujeres, el estadio Child-Pugh A y el estadio BCLC 0 presentaron mayores medianas de supervivencia. El análisis multivariado evidenció un mayor riesgo de muerte al ser hombre (Hazard ratio [HR]: 2,16; intervalo de confianza [IC]: 1,24 a 3,76), estar en los estadios Child-Pugh B (HR: 2,14; IC: 1,16 a 3,95) y Child-Pugh C (HR: 7,52; IC: 2,88 a 19,57). Conclusiones: el NAFLD es la principal causa de HCC en la presente cohorte, una tercera parte de los pacientes se diagnostica en estadios BCLC tempranos con opción curativa de tratamiento, y un 25 % se trata con terapias curativas. El sorafenib fue la terapia de primera línea en HCC avanzado. La supervivencia global luego del diagnóstico de HCC sigue siendo baja, y es necesario aunar esfuerzos en el seguimiento de los pacientes con cirrosis para mejorar estos resultados.

Anti-proliferative effects of paroxetine alone or in combination with sorafenib in HepG2 cells

Abstract Hepatocellular carcinoma (HCC) is a common cause of cancer-related death. Sorafenib is the first approved drug for the treatment of advanced HCC. Depression is frequent in cancer patients. Moreover, sorafenib might exert depression as an adverse drug reaction and paroxetine, a selective serotonin reuptake inhibitor, is a recommended pharmacotherapy. This study aimed to investigate the potential synergistic effects of paroxetine and sorafenib on HepG2 cell proliferation and death. Paroxetine and sorafenib were administered to HepG2 cells as single-agents or in combination. Cell viability was determined with XTT cell viability assay. Cellular apoptosis and DNA content were assessed by flow cytometry. The expression of anti-apoptotic Bcl-2 was examined by immunofluorescence confocal microscopy. A lower dose of sorafenib was found to be required to inhibit cell proliferation when in combination with paroxetine. Similarly, the coadministration enhanced cellular apoptosis and resulted in cell cycle arrest. Confocal imaging revealed a remarkably lower cell density and increased expression of Bcl-2 following combined treatment of paroxetine with sorafenib. To our knowledge, this is the first study demonstrating the synergistic effect of paroxetine and sorafenib in HCC and might provide a potentially promising therapeutic strategy.

Safety and efficacy of sorafenib in patients with advanced thyroid carcinoma: a phase II study (NCT02084732)

ABSTRACT Objective: Sorafenib significantly prolonged progression-free survival in patients with iodine-refractory advanced thyroid cancer. The present study was initiated before sorafenib was approved in Colombia and therefore represents an effort by an oncology institution to evaluate its efficacy and safety in this population. Subjects and methods: This phase II clinical trial had a single treatment arm. We included adult patients with progressive metastatic iodine-refractory thyroid cancer who received treatment with sorafenib 800 mg/day (400 mg every 12 hours) up to a maximum of 24 months or until the occurrence of limiting related toxicity, the progression of the disease, or voluntary withdrawal. Results: Nineteen patients received the treatment and were included in the safety analysis. However, for the efficacy analysis, 6 patients were excluded because they received only one month of therapy. Thirteen (68%) patients were women, and the mean age at diagnosis was 61.8 years. No complete responses were observed; 5 patients had a partial response (35.7%), 6 patients had stable disease, and 3 showed progression. Mean progression-free survival was calculated at 18 months (95% CI 10.7-20.3). Overall survival was estimated at 21.3 months (95% CI 17.8-24.8). Conclusion: For the first time in Colombia, the efficacy of sorafenib was evaluated in patients with advanced and progressive thyroid carcinoma refractory to radioactive iodine, with an efficacy and a safety profile similar to those previously reported.

Efficacy and safety of sorafenib in elderly patients with advanced hepatocellular carcinoma

OBJECTIVES: To evaluate the efficacy and safety of sorafenib in elderly patients with advanced hepatocellular carcinoma (HCC). METHODS: We analyzed data from a cohort of patients with advanced HCC treated using systemic treatment according to the local institutional protocol. Patients were divided into two groups, Group A, individuals <70 years of age, and Group B, individuals 70 years of age or older at the time of treatment initiation. Efficacy, measured based on overall survival (OS) and time to treatment failure (TTF), and toxicity were compared between groups. RESULTS: A total of 238 patients with advanced HCC who received sorafenib between 2007 and 2018 were evaluated. The median age for Group A was 59.1 years and that for Group B 73.6 years. The major prognostic characteristics were balanced between the groups. There were no significant differences in OS between Group A (8.0 months, 95%CI 6.34-9.3) and Group B (9.0 months, 95%CI 5.38-12.62), p=0.433, or in TTF between Group A (3.0 months, 95%CI 2.39-3.60) and Group B (3.0 months, 95%CI 1.68-4.32), p=0.936. There were no significant differences between Groups A and B with respect to the incidence of adverse events or treatment discontinuation because of toxicity. CONCLUSION: Efficacy and safety of sorafenib did not differ significantly between younger and older patients with HCC. Our data suggest that age alone should not restrict clinical decision-making for patients with advanced HCC.

MicroRNA-92b augments sorafenib resistance in hepatocellular carcinoma via targeting PTEN to activate PI3K/AKT/mTOR signaling

Sorafenib (SOR) resistance is still a significant challenge for the effective treatment of hepatocellular carcinoma (HCC). The mechanism of sorafenib resistance remains unclear. Several microRNAs (miRNAs) have been identified as playing a role in impairing the sensitivity of tumor cells to treatment. We examined the mechanism behind the role of miR-92b in mediating sorafenib resistance in HCC cells. We detected that miR-92b expression was significantly upregulated in SOR-resistant HepG2/SOR cells compared to parental HepG2/WT cells. After transfection with miR-92b inhibitor, the proliferation of HepG2/SOR cells was remarkably weakened and rates of apoptosis significantly increased. PTEN was considered to be a functional target of miR-92b according to a luciferase reporter assay. Knockdown of PTEN significantly impaired the ability of miR-92b inhibitor on increasing sorafenib sensitivity of HepG2/SOR cells. Furthermore, we confirmed by western blotting and immunofluorescence that miR-92b can mediate sorafenib resistance by activating the PI3K/AKT/mTOR pathway in HCC cells by directly targeting PTEN. These findings further validate the mechanism of miR-92b in SOR resistance in HCC treatment.

Overall survival predictors in hepatocellular carcinoma patients treated with sorafenib

SUMMARY Malignant liver tumors are the fourth leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) accounts for 75-85% of these. Most patients are diagnosed at incurable stages. Palliative care is the appropriate treatment course in these circumstances (chemoembolization and sorafenib). There are few national studies on sorafenib. The objective is to evaluate survival predictors of HCC patients treated with sorafenib and evaluate the compliance of its indication in relation to BCLC recommendations. METHODS A total of 88 patients with an indication of sorafenib from 2010 to 2017 at the ISCMSP were retrospectively analyzed. Univariate and multivariate analyzes were performed in the search for predictors of survival. RESULTS The mean age was 61.2 years, 70.5% were men, most were classified as Child-Pugh A (69.3%), and BCLC C (94.3%). Cirrhosis was present in 84.6% and portal hypertension in 55.7%. Hepatitis C virus was the most common etiology (40.9%). Sixty-nine (78.4%) patients received the medication, with the average duration of treatment being 9.7 months. The mean overall survival was 16.8 months. Significant differences were observed in the multivariate analysis: ECOG PS (p = 0.024): Child-Pugh (p = 0.013), time of medication use (p <0.001), clinical worsening (p = 0.031) and portal thrombosis (p = 0.010). CONCLUSION Absence of portal thrombosis, Child-Pugh A, longer time of medication use, ECOG PS 0, and absence of suspension due to clinical worsening were predictors of better overall survival in the study. The drug's indication complies with BCLC guidelines in 94% of patients.

RESUMO Tumores malignos do fígado são a quarta maior causa de morte por câncer, sendo que o carcinoma hepatocelular (CHC) corresponde a 85-90% desses casos. A maioria dos doentes apresenta-se, ao diagnóstico, sem possibilidade de tratamento curativo, restando apenas as opções paliativas (quimioembolização e sorafenibe). Há poucos estudos nacionais acerca do sorafenibe. OBJETIVO Avaliar fatores preditivos de sobrevida em pacientes com CHC que tiveram indicação de tratamento com sorafenibe na Irmandade da Santa Casa de Misericórdia de São Paulo (ISCMSP) e avaliação da conformidade da indicação da medicação em relação às recomendações do BCLC. MÉTODOS Foram analisados retrospectivamente os dados de 88 pacientes que tiveram indicação de tratamento com sorafenibe no período de 2010 a 2017 na ISCMSP. Análises univariada e multivariada foram realizadas na busca de preditores de sobrevida global nos pacientes que receberam a medicação. RESULTADOS Idade média de 61,2 anos, sendo 70,5% homens. A maioria (69,3%) foi classificada como Child Pugh A e BCLC C (94,3%). A cirrose esteve presente em 84,6% e a hipertensão portal em 55,7% desses. O vírus da hepatite C foi a etiologia mais comum (40,9%) do CHC. Sessenta e nove (78,4%) pacientes receberam a medicação, sendo o tempo médio de duração do tratamento 9,7 meses e a sobrevida global média, 16,8 meses. Diferenças significativas foram observadas na análise multivariada: Ecog PS (p=0,024), CP (p=0,013), tempo de uso de medicação (p<0,001), suspensão por piora clínica (p=0,031) e trombose portal (p=0,010). CONCLUSÃO Ausência de trombose portal, Child Pugh A, Ecog PS 0, tempo maior de uso de medicação e ausência de suspensão por piora clínica foram fatores preditores de melhor sobrevida global e a indicação da medicação esteve em conformidade com as orientações do BCLC em 94% dos pacientes.

Cáncer de tiroides en estadios avanzados tratados con inhibidores de tirosina quinasa (SORAFENIB) / Advanced stage thyroid cancer treated with tyrosine kinase inhibitors (SORAFENIB)

OBJETIVO: Este estudio pretende evaluar la sobrevida global en los pacientes con carcinoma diferenciado de tiroides localmente avanzado yodo refractario. MÉTODO: Son 8 casos tratados con inhibidores de tirosina quinasa (Sorafenib) en el período comprendido entre 2014-2017. Las variables estudiadas fueron: Epidemiológicas, laboratorios tiroideos, histología, tratamiento, supervivencia posterior al tratamiento. Se tomó como significativo una P<0,05. RESULTADOS: Edad media entre los pacientes fue 51 años ± 22,1 años, el sexo prevaleciente fue femenino (75 %). El lugar de procedencia más incidente fue Estado Miranda (50 %). Los valores de laboratorio al momento del diagnóstico fueron tiroglobulina (290,2 ± 250,7), la TSH (11,3 ± 13,9) y la antitiroglobulina solo fue positiva en un paciente (87,5 %). La T predominante fue T3 (50 %), la N que prevaleció fue N1B (62 %) y M1 (62,5 %). El estadio predominante fue IVC (50 %). El grupo histológico predominante fue papilar (62,5 %). Se les realizó tiroidectomía total con vaciamiento bilateral al 75 % de los pacientes. Posteriormente recibieron 131I, para los cuales se obtuvieron una dosis media de 227,5 mCi con desviación de estándar: 188,1 mCi. La mayoría recibió radioterapia externa a región cervical (87,50 %). La sobrevida global 3 años posteriores al tratamiento fue 87,5 %. CONCLUSIONES. El control de la enfermedad a largo plazo en estos pacientes avanzados puede obtenerse con Sorafenib. En nuestro estudio evidenciamos que es un fármaco adecuado para controlar la enfermedad en pacientes con cáncer de tiroides yodo refractarios.(AU)

OBJECTIVE: This study aimed evaluates overall survival in patients with locally advanced thyroid iodine refractory differentiated carcinoma. METHOD: 8 cases treated with inhibitors of tyrosine kinase (Sorafenib) in the period 2014-2017. The variables studied were: epidemiological, laboratory thyroid histology, treatment, post-treatment survival. P was taken as meaningful < 0.05. RESULTS: Mean age among patients was 51 years ± 22.1 year, prevailing sex female (75 %). Place of origin more incident was Miranda State (50 %). At the time of the diagnostic laboratory values were thyroglobulin (290.2 ± 250.7), TSH (3 ± 13.9 11) and the single antithyroglobulin was positive in one patient (87.5 %). The predominant T was T3 (50 %), the N that prevailed was N1B (62 %) and M1 (62.5 %). The predominant stadium was IVC (50 %). The predominant histological group was papillary (62.5 %). The predominant stadium was IVC (50 %). The predominant histological group was papillary (62.5 %). He was performed in total thyroidectomy with bilateral clearing to 75 % of patients. Subsequently received 131I, for which an average dose of 227.5 mCi with standard deviation were obtained: 188.1 mCi. Most received radiotherapy external cervical region (87.50 %). Global survival 3 years after treatment was 87.5 %. CONCLUSIONS: The control of disease in long run in these advanced patients can get with Sorafenib. In our study we showed that it is a suitable drug to control the disease in patients with cancer of thyroid iodine refractory. (AU)

Rare complications of multikinase inhibitor treatment

ABSTRACT Objective: The advent of multikinase inhibitor (MKI) therapy has led to a radical change in the treatment of patients with advanced thyroid carcinoma. The aim of this manuscript is to communicate rare adverse events that occurred in less than 5% of patients in clinical trials in a subset of patients treated in our hospital. Subjects and methods: Out of 760 patients with thyroid cancer followed up with in our Division of Endocrinology, 29 (3.8%) received treatment with MKIs. The median age at diagnosis of these patients was 53 years (range 20-70), and 75.9% of them were women. Sorafenib was prescribed as first-line treatment to 23 patients with differentiated thyroid cancer and as second-line treatment to one patient with advanced medullary thyroid cancer (MTC). Vandetanib was indicated as first-line treatment in 6 patients with MTC and lenvatinib as second-line treatment in two patients with progressive disease under sorafenib treatment. Results: During the follow-up of treatment (mean 13.7 ± 7 months, median 12 months, range 6-32), 5/29 (17.2%) patients presented rare adverse events. These rare adverse effects were: heart failure, thrombocytopenia, and squamous cell carcinoma during sorafenib therapy and squamous cell carcinoma and oophoritis with intestinal perforation during vandetanib treatment. Conclusions: About 3 to 5 years after the approval of MKI therapy, we learned that MKIs usually lead to adverse effects in the majority of patients. Although most of them are manageable, we still need to be aware of potentially serious and rare or unreported adverse effects that can be life-threatening.

Respuesta parcial a lenvatinib como segunda línea de tratamiento en cáncer diferenciado avanzado de tiroides / Partial response to lenvatinib as a second line of treatment in advanced differentiated cancer of thyroid

RESUMEN Las metástasis a distancia ocurren en alrededor del 10% de los pacientes con cáncer diferenciado de tiroides (CDT), y cerca de la mitad de estos casos serán refractarios al radioyodo (RAIR). Sorafenib fue el primer inhibidor multicinasa (IMK) aprobado por la FDA para su uso en cáncer diferenciado de tiroides RAIR avanzado y progresivo, y hasta el momento es el único aprobado por la ANMAT en nuestro país para esta indicación. Lenvatinib es el segundo IMK aprobado por la FDA para este grupo de pacientes, y es una alternativa terapéutica que debe ser considerada, debido a su disponibilidad como fármaco de uso compasivo en nuestro país. Presentamos nuestra experiencia con el uso de lenvatinib como segunda línea de tratamiento en una paciente con CDT progresivo previamente tratado con sorafenib.

ABSTRACT Distant metastases occur in around 10% of patients with differentiated thyroid cancer (DTC), and half of these cases will become refractory to radioiodine therapy (RAIR). Sorafenib was the first multikinase inhibitor (MKI) approved by the FDA for patients with differentiated advanced and progressive RAIR thyroid cancer, and it is the only one approved by ANMAT in our country for this indication. Lenvatinib is the second MKI approved by the FDA for this group of patients, and is a therapeutic alternative that should be considered, due to its availability as a compassive use drug in our country. We present our experience with the use of lenvatinib as a second line of treatment in a patient with DTC with advanced and progressive disease under treatment with sorafenib.

Atividade anticarcinogênica da tributirina associada ou não ao sorafenibe em ratos Fischer-344 implantados com células JM-1 / Bimetallic nanoparticles and biocatalysts: a study about your interaction and catalytic activity

O carcinoma hepatocelular (HCC) é o sexto mais frequente e a segunda maior causa de mortalidade por câncer no mundo, além de apresentar alta taxa de recidiva. A associação de sorafenibe (SO) com agentes quimiopreventivos representa uma estratégia importante para aumentar a eficácia do tratamento e minimizar a reincidência da doença. Em estudos anteriores demonstrou-se o potencial quimiopreventivo da tributirina (TB), pró-fármaco do ácido butírico (AB), em modelo de hepatocarcinogênese experimental. A atividade da TB tem sido relacionada à inibição do desenvolvimento de lesões préneoplásicas, bem como à indução de apoptose. Assim, o presente estudo teve como objetivo avaliar a ação anticarcinogênica da TB e do SO, isoladamente ou em associação no HCC. Nesse sentido, implantes singênicos foram realizados no flanco de ratos Fischer- 344 a partir de células da linhagem neoplásica JM-1. Os animais foram distribuídos nos seguintes grupos: Grupo controle isocalórico [CO; Maltodextrina (300 mg/100 g p.c.) e solução veículo (solução de etanol a 12.5% e Cremofor a 12.5% em água estéril)]; Grupo TB (200 mg/100 g p.c. e solução veículo); Grupo SO [Maltodextrina (300 mg/100 g p.c. tosilato de SO (3 mg/100 g p.c.) em solução veículo] e Grupo associação [AS; TB (200 mg/100 g p.c) e tosilato de SO (3 mg/100 g p.c.) em solução veículo]. Os implantes de células JM-1 originaram neoplasias com características pouco diferenciadas. Os tratamentos com SO e AS retardaram (p<0,05) o desenvolvimento das neoplasias, além de reduzirem (p<0,05) suas massa e aumentem (p<0,05) a sobrevida em relação ao grupo CO. Não houve diferença na porcentagem de área necrótica das neoplasias entre os tratamentos. Porém, foi observada uma correlação negativa (p<0,05) entre o tamanho da neoplasia e a área necrótica, sendo que quanto menor a área da neoplasia maior a extensão da necrose, independente do tratamento. Foi observado aumento (p<0,05) das concentrações hepáticas de AB nos grupos TB, SO e AS. Já na neoplasia, apenas os grupos TB e SO demonstraram aumento (p<0,05) na concentração de AB. Além disso, os tratamentos com SO e AS aumentaram (p<0,05) a concentração tecidual de SO na neoplasia em relação ao CO. Nesse sentido, foi observado que grupo AS apresentou 5 vezes mais SO na neoplasia quando comparado ao grupo SO. Os tratamentos com TB e SO isoladamente ou em associação reduziram (p<0,05) a expressão de CK19 em relação ao grupo CO. Em relação à avaliação da proliferação celular, os grupos TB, SO e AS apresentaram redução (p<0,05) do índice de proliferação celular quando comparados ao grupo CO. Foi observado por meio da análise imunoistoquímica para pERK, que os animais tratados com SO e AS reduziram (p<0,05) as áreas positivas quando comparadas às dos animais do grupo CO. Além disso, também foi observada por meio de marcação imunoistoquímica uma redução (p<0,05) nas áreas positivas para CK8 nos grupos SO e AS quando comparadas às do grupo CO. Em relação à caspase-3 clivada, foi observado por imunoistoquímica que o tratamento com TB aumentou (p<0,05) o índice de células positivas para caspase-3 clivada quando comparado ao CO. Esse dado foi comprovado pela análise de western blot. Foi observado por meio da análise imunoistoquímica para H3K9, um aumento (p<0,05) da acetilação no grupo TB quando comparado ao grupo CO. Em relação à expressão em nível proteico de pAKT, foi observado por meio da análise imunoistoquímica uma redução (p<0,05) no grupo TB em comparação ao grupo CO. O presente estudo demonstrou que os implantes de células JM-1 no flanco de ratos Fischer-344 originaram neoplasias com características que lembram a organização hepatocítica de um HCC convencional. O tratamento com TB foi capaz de reduzir a proliferação celular e induzir apoptose. Os tratamentos com SO e com a AS foram capazes de retardar o desenvolvimento, aumentar a sobrevida, reduzir a massa das neoplasias, induzirem diferenciação celular e reduzirem a proliferação celular, melhorando o prognóstico da doença. Os tratamentos com SO e AS apresentaram atividade quimioterápica semelhante. No entanto, a coadministração de SO e TB foi capaz de aumentar a biodisponibilidade do SO para a neoplasia

Hepatocellular carcinoma (HCC) is the sixth most frequent and the second largest cause of cancer mortality in the world, besides presenting a high rate of recurrence. The association of sorafenib (SO) with chemopreventive agents represents an important strategy to increase the efficacy of the treatment and to minimize recurrence of the disease. In previous studies the chemopreventive potential of tributyrin (TB), a butyric acid prodrug (AB), was demonstrated in a model of experimental hepatocarcinogenesis. TB activity has been linked to inhibition of the development of pre-neoplastic lesions as well as to the induction of apoptosis. Thus, the present study aimed to evaluate the anticarcinogenic action of TB and SO, either alone or in combination in HCC. In this sense, syngeneic implants were performed on the flank of Fischer-344 rats from cells of the JM-1 neoplastic lineage. The animals were divided into the following groups: Control group [CO; Maltodextrin (300 mg / 100g p.c.) and carrier solution (12.5% ethanol solution and 12.5% Cremophor in sterile water)]; TB group (200 mg / 100 g p.c. and carrier solution); Group SO [Maltodextrin (300 mg / 100 g pc tosylate of SO (3 mg / 100 g pc) in vehicle solution] and Association group [AS; TB (200 mg / 100 g pc) and SO tosylate (3 mg / 100 (p <0.05), the development of the neoplasms, as well as the reduction (p <0.05), and the survival rate was higher (p <0.05) than the CO group. There was no difference in the percentage of necrotic area of the neoplasms between the treatments. (p <0.05) of the hepatic AB concentrations in the TB, SO and AS groups, although the size of the neoplasia and the necrotic area were higher. In the neoplasia, only the TB and SO groups showed an increase (p <0.05) in AB concentration. In addition, treatments with SO and AS increased (p <0.05) the tissue concentration of SO in the neoplasia in relation to CO. In this sense, it was observed that AS group presented 5 times more SO in the neoplasia when compared to the SO group. Treatments with TB and SO alone or in combination reduced (p <0.05) the expression of CK19 in relation to the CO group. In relation to the evaluation of cell proliferation, the TB, SO and AS groups presented a reduction (p <0.05) in the cell proliferation index when compared to the CO group. It was observed by the immunohistochemical analysis for pERK that the animals treated with SO and AS reduced (p <0.05) the positive areas when compared to the animals of the CO group. In addition, a reduction (p <0.05) in the CK8 positive areas in the SO and AS groups when compared to the CO groups was also observed by immunohistochemical labeling. In relation to the cleaved caspase-3, it was observed by immunohistochemistry that the TB treatment increased (p <0.05) the index of caspase-3 positive cells cleaved when compared to CO. This was confirmed by western blot analysis. It was observed by immunohistochemical analysis for H3K9, an increase (p <0.05) in the acetylation of the TB group when compared to the CO group. Regarding the protein level expression of pAKT, a reduction (p <0.05) in the TB group was observed through the immunohistochemical analysis when compared to the CO group. The present study demonstrated that JM-1 cell implants in the flank of Fischer-344 mice originated neoplasms with features reminiscent of the hepatocyte organization of a conventional HCC. TB treatment was able to reduce cell proliferation and induce apoptosis. SO and AS treatments were able to delay the development, increase survival, reduce the mass of neoplasms, induce cell differentiation and reduce cell proliferation, improving the prognosis of the disease. SO and AS treatments showed similar chemotherapy activity. However, co-administration of SO and TB was able to increase the bioavailability of SO to the neolasia

Atividade anticarcinogênica da tributirina associada ou não ao sorafenibe em ratos Fischer-344 implantados com células GP7TB / Evaluation of anticarcinogenic activity associated or not with sorafenib in Fischer-344 rats implanted with GP7TB cells

O câncer primário de fígado (CPF) apresenta mau prognóstico, o que torna importante sua quimioprevenção. Nesse sentido, a tributirina (TB), um pró-fármaco do ácido butírico (AB), presente em laticínios e no mel, mostrou-se um agente quimiopreventivo promissor da hepatocarcinogênese experimental. Os efeitos inibitórios da TB têm sido relacionados à inibição do desenvolvimento de lesões pré-neoplásicas, bem como indução de apoptose e hiperacetilação de histonas. A quimioterapia é uma das abordagens mais comuns para o tratamento de diversos tipos de câncer, inclusive o CPF. Neste caso, o tratamento com sorafenibe (SO) é capaz de prolongar a sobrevida média dos pacientes com a doença em fases avançadas em aproximadamente apenas três meses. Em vista disso, são necessários estudos da associação do sorafenibe com outros compostos que possam aumentar a eficácia do tratamento quimioterápico. Desta forma, a associação de fármacos anti-neoplásicos com compostos bioativos dos alimentos pode consistir em uma estratégia potencial para aumentar a eficácia contra o câncer. No presente estudo, foi avaliada a atividade anticarcinogênica da TB e do SO, isoladamente ou em associação, na etapa de progressão da hepatocarcinogênese. Para tanto, foram realizados implantes singênicos no flanco de ratos Fischer-344 a partir de células da linhagem tumoral GP7TB. Quando as neoplasias atingiram 1 cm3, os animais foram aleatorizados em grupos experimentais: Grupo controle (CO), constituído por 10 ratos Fischer 344 que receberam Maltodextrina (300mg/ 100 g. p. c.), controle isocolarico e solução de etanol à 12,5% e Cremofor à 12,5% em agua estéril; Grupo Tributirina (TB), constituído por 9 ratos Fischer 344 que receberam TB (200mg/ 100 g. p. c.) e solução de etanol à 12,5% e Cremofor à 12,5% em água estéril; Grupo sorafenibe (SO) constituído por 9 ratos Fischer 344 que receberam Maltodextrina (300 mg/ 100 g. p. c.), controle isocalorico e tosilato de sorafenibe (3mg / 100 g. p. c. ) em água estéril; Grupo associação da tributirina com o sorafenibe (AS) constituído por 9 ratos Fischer 344 que receberam TB (20 mg/ 100 g. p. c.) e tosiliato de sorafenibe (3mg/ 100 g. p. c.); tratados por administração intragástrica (i.g) diariamente por 5 semanas consecutivas. As concentrações de AB e SO foram analisadas por cromatografia gasosa associada à espectrometria de massa e as neoplasias foram caracterizadas por imunoistoquímica. Em relação à evolução do tamanho das neoplasias o grupo AS apresentou menor (p=0,009) tamanho das mesmas em relação ao grupo CO. No entanto, estas diferenças não atingiram diferenças significativas (p>0,05) entre os grupos TB e CO, bem como entre os grupos SO e CO. Contudo, quando ajustados os valores do tamanho da neoplasia pela latência, observou-se alterações significativas (p<0,05) nos diversos grupos quando comparados ao grupo CO. O grupo SO aumentou a área necrótica das neoplasias, embora esta diferença não tenha atingido diferença significativa (p>0,05), enquanto que o grupo TB reduziu essa área necrótica em relação ao grupo CO (p=0,005). O grupo TB e AS apresentaram significativamente maiores (p<0,05) concentrações hepáticas e neoplásicas de AB em relação ao grupo CO. O grupo SO e AS apresentaram significativamente maiores (p<0,05) concentrações neoplásicas de SO em relação ao grupo CO. Os grupos SO e AS reduziram a expressão de PTEN, quando comparados ao grupo CO, embora esta diferença não tenha atingido diferença significativa (p>0,05). O grupo TB por sua vez expressou maiores niveis de PTEN, embora esta diferença não tenha atigindo significância estatística (p>0,05). Todos os grupos expressaram maiores niveis de caspase 3 clivada quando comparada ao grupo CO (p>0,05). OS grupos TB e SO reduziram a expressão de pERK ½ quando comparados ao grupo CO. embora estas diferenças não tenham atingidos diferença estatística (p>0,05). O grupo AS apresentou maior expressão de pERK ½ quando comparada ao grupo CO, embora esta diferença não tenha atingido diferença significativa (p>0,05). A caracterização das neoplasias do grupo CO foi padronizada por imunoistoquímica, apresentando-se positivas para CK 7, CK8, CK19 e Arginase e negativas para HepPar1 e CK18. Assim, os resultados sugerem que as neoplasias obtidas por implantes com células da linhagem GP7TB apresentam características de CPF oriundo de células tronco neoplásicas. Além disso, os grupos experimentais TB e AS apresentaram atividade anticarcinogênica promissora no modelo de implantes singênicos com células GP7TB, que eventualmente envolvem mecanismos de ação distintos da atividade quimioterápica apresentada pelo SO

Primary liver cancer (PLC) presents poor prognosis, which makes its chemoprevention important. In this sense, tributyrin (TB), a prodrug of butyric acid (AB), present in dairy products and honey, has been shown to be a promising chemopreventive agent for experimental hepatocarcinogenesis. The inhibitory effects of TB have been related to inhibition of the development of pre-neoplastic lesions, as well as induction of apoptosis and hyperacetylation of histones. Chemotherapy is one of the most common approaches for treating various types of cancer, including PLC. In this case, treatment with sorafenib (SO) is able to prolong the average survival of patients with the disease in advanced stages in approximately three months. In view of this, studies of the association of sorafenib with other compounds that may increase the efficacy of chemotherapeutic treatment are necessary. Thus, the association of anti-neoplastic drugs with bioactive compounds in food may be a potential strategy to increase efficacy against cancer. In the present study, the anticarcinogenic activity of TB and SO was evaluated, alone or in combination, in the progression stage of hepatocarcinogenesis. For this purpose, syngenic implants were performed on the flank of Fischer-344 mice from GP7TB tumor cells. When the neoplasms reached 1 cm3, the animals were randomized into experimental groups: Control group (CO), consisting of 10 Fischer 344 rats receiving Maltodextrin (300mg / 100 g.p.c), isocaloric control and 12.5% ethanol solution, and Cremofor to 12.5% in sterile water; Tributyrin group (TB), consisting of 9 Fischer 344 rats that received TB (200mg / 100 g.p.c.) and 12.5% ethanol solution and Cremofor 12.5% in sterile water; Sorafenib group (SO) consisting of 9 Fischer 344 rats receiving maltodextrin (300 mg / 100 g, w / w), isocaloric control and sorafenib tosylate (3 mg / 100 g, w / w) in sterile water; The association group of tributyrin and sorafenib (AS) consisted of 9 Fischer 344 rats receiving TB (20 mg / 100 g p.o.) and sorafenib tosylate (3 mg / 100 g p.o.); treated intragastric (i.g) daily for 5 consecutive weeks. The concentrations of AB and SO were analyzed by gas chromatography associated with mass spectrometry and the neoplasms were characterized by immunohistochemistry. In relation to the evolution of the size of the neoplasias, the AS group presented smaller (p = 0.009) size of the same ones in relation to the CO group. However, these differences did not reach significant differences (p> 0.05) between the TB and CO groups, as well as between the SO and CO groups. However, when adjusted for size of the neoplasm by latency, significant changes (p <0.05) were observed in the different groups when compared to the CO group. The SO group increased the necrotic area of the neoplasias, although this difference did not reach a significant difference (p> 0.05), while the TB group reduced this necrotic area in relation to the CO group (p = 0.005). The TB and AS groups presented significantly higher (p <0.05) hepatic and neoplastic AB concentrations than the CO group. The SO and AS groups presented significantly higher (p <0.05) neoplastic concentrations of SO in relation to the CO group. The SO and AS groups reduced the PTEN expression when compared to the CO group, although this difference did not reach a significant difference (p> 0.05). The TB group in turn expressed higher levels of PTEN, although this difference did not increase statistical significance (p> 0.05). All groups expressed higher levels of caspase 3 cleaved when compared to the CO group (p> 0.05). The TB and SO groups reduced the expression of pERK ½ when compared to the CO group. although these differences did not reach statistical difference (p> 0.05). The AS group presented higher pERK ½ expression when compared to the CO group, although this difference did not reach a significant difference (p> 0.05). Characterization of the neoplasias of the CO group was standardized by immunohistochemistry, presenting positive for CK 7, CK8, CK19 and Arginase and negative for HepPar1 and CK18. Thus, the results suggest that the neoplasias obtained by implants with GP7TB cells present CPF characteristics originating from neoplastic stem cells. In addition, the experimental groups TB and AS presented promising anticarcinogenic activity in the model of syngeneic implants with GP7TB cells, which eventually involve mechanisms of action distinct from the chemotherapy activity presented by SO

Guía práctica para el manejo de efectos adversos por inhibidores multicinasas (sorafenib y vandetanib) en pacientes con cáncer de tiroides avanzado / Practice guidelines for the management of adverse effects due to multikinase inhibitors (sorafenib and vandetanib) in patients with advanced thyroid cancer

El advenimiento de la terapia con inhibidores multicinasas (IMK) representó un cambio radical en el tratamiento de pacientes con carcinoma avanzado de tiroides. Hasta la fecha, 2 fármacos se encuentran aprobados por la Asociación Nacional de Medicamentos, Alimentos y Tecnología Médica (ANMAT) en Argentina: sorafenib, para pacientes con carcinoma diferenciado de tiroides radiorresistente, y vandetanib, para aquellos con carcinoma medular de tiroides (enfermedad progresiva y/o sintomática). Los estudios de fase III han demostrado que estos fármacos aumentan significativamente la supervivencia libre de progresión en este grupo de pacientes. Si bien tienen una indicación precisa, su manejo requiere de un equipo multidisciplinario en contacto estrecho con un paciente involucrado en su tratamiento. Los efectos adversos de sorafenib y vandetanib son frecuentes, sin embargo, muchos de ellos disminuyen con el tiempo y la mayoría puede manejarse a menudo sin disminuir la dosis ni suspender el fármaco. El conocimiento del correcto manejo de los efectos adversos por parte del equipo tratante constituye una herramienta fundamental para poder educar al paciente y, consecuentemente, poder prevenirlos o minimizarlos, y de esta manera evitar complicaciones severas. El objetivo de esta publicación es brindar una guía para el diagnóstico y tratamiento de los efectos adversos de estos IMK y, por otro lado, presentar la iniciativa del Hospital de Clínicas de la Universidad de Buenos Aires en cuanto a la implementación de la misma.

The advent of multikinase inhibitors therapy has led to a radical change in the treatment of patients with advanced thyroid carcinoma. The ANMAT (the Argentinian regulatory health agency) has currently approved sorafenib for patients with radioiodine resistant differentiated thyroid carcinoma, and vandetanib for patients with medullary thyroid carcinoma (progressive and/or symptomatic disease). It has been demonstrated by phase III clinical trials that these drugs improve progression free survival in this group of patients. Although they have a precise indication, an interdisciplinary team in close contact with a committed patient, are required for their effective management. The adverse events of these drugs are common, but many of them may ameliorate over time, and most of them are manageable, even without the need for dose reduction or drug withdrawal. Knowledge of the correct management of the adverse events is a fundamental tool for the medical team and for the patient to prevent or minimise them, to avoid serious complications and to obtain better patient compliance. The primary objective of this article is to provide a guideline for the diagnosis and treatment of the adverse events produced by the multikinase inhibitors, and to present the initiative of the Hospital de Clinicas in order to implement these guidelines.

Interleukin-27 augments the inhibitory effects of sorafenib on bladder cancer cells

Both sorafenib and interleukin-27 (IL-27) are antineoplastic drugs. This study aimed to investigate the synergistic effect of these two drugs on bladder cancer cells. HTB-9 and T24 cells were stimulated with IL-27 (50 ng/mL), sorafenib (2 μM) or the synergistic action of these two drugs. The cells without treatment acted as control. Cell proliferation, apoptosis and invasion were measured by bromodeoxyuridine assay, flow cytometry and modified Boyden chamber, respectively. Simultaneously, both modified Boyden chamber and scratch assay were used to assess cell migration. Finally, the phosphorylation levels of key kinases in the Akt/mechanistic target of rapamycin (mTOR)/mitogen-activated protein kinase (MAPK) pathway, and expression levels of matrix metalloproteinase (MMP)-2 and MMP-9 were detected by western blot analysis. Stimulation with IL-27 or sorafenib repressed proliferation, migration and invasion but promoted apoptosis, and the effects were all enhanced by the combination of these two drugs in HTB-9 cells. The effect of the combined treatment on bladder cancer cells was verified in T24 cells. Additionally, the phosphorylation levels of AKT, mTOR and MAPK as well as the expression levels of MMP-2 and MMP-9 were all decreased by a single treatment of IL-27 or sorafenib, and further decreased by the combined treatment of these two drugs. The combination of IL-27 and sorafenib inhibited proliferation, migration and invasion and promoted apoptosis of bladder cancer cells compared with mono-drug treatment. Additionally, the AKT/mTOR/MAPK pathway might be implicated in the functional effects by down-regulations of MMP-2 and MMP-9.

Uso de inhibidores de tirosina quinasa en carcinoma medular de tiroides. Experiencia Institucional / Use of tyrosine kinase inhibitors in medullary thyroid carcinoma. Institutional Experience

El cáncer medular de tiroides (CMT) correspondeal 5% de los tumores de la glándula tiroides. El único tratamiento curativo es la cirugía. En pacientes con compromiso locorregional o a distancia, la enfermedad puede evolucionar en forma indolente o bien con una rápida progresión de síntomas, requiriendo tratamiento sistémico. Si bien el CMT se caracteriza por tener escasa respuesta a la quimioterapia (QT), la evidencia actual en estudios aleatorizados demostró que los inhibidores de tirosina quinasa (ITQ) han demostrado beneficio en supervivencia libre de progresión (SLP). Se analizaron 6 pacientes con un seguimiento mediano de 29 meses. Todos presentaron más de dos sitios metastásicos. Dos requirieron tratamientos locorregionales (quimioembolización y RT). Los ITQ más utilizados fueron: vandetanib (3), sorafenib (2) y sunitinib (1). Un 50% inició tratamiento con dosis plenas y 3 requirieron reducción de dosis debido a toxicidad G3-G4. El intervalo libre de progresión (ILP) mediano, luego del inicio con ITQ, fue de 4.1 meses (AU)

Medullary thyroid cancer (CMT) accounts for 5% of thyroid tumors. The only curative treatment is surgery. In patients with locally or distal involvement, the disease may evolve indolently or with rapid progression of symptoms, requiring systemic treatment. Although CMT is characterized by a poor response to chemotherapy, current evidence in randomized trials has shown that tyrosine kinase inhibitors (ITKs) have demonstrated benefit in progressionfree survival. Six patients with a median follow-up of 29 months were analyzed. All had more than two metastatic sites. Two patients required locoregional treatments (chemoembolization and radio therapy). The most commonly used ITKs were: vandetanib (3), sorafenib (2) and sunitinib (1). The 50% initiated treatment with full dose and 3 required reduction of the dose due to G3- G4 toxicity. The median progression-free interval after initiation with ITK was 4.1 months (AU)

Nuevas terapias target y vías moleculares clínicamente relevantes en carcinoma hepatocelular avanzado / New targeted therapies and molecular routes clinically relevant in advanced hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide. Most cases occur in patients with chronic liver disease who are diagnosed at an advanced stage, and their prognosis is poor. Because HCC is resistant to conventional systemic therapies, molecular therapies have emerged and been established as the standard for advanced forms of the disease. Since the publication of phase III clinical studies on sorafenib, research has searched for new molecular targets. Thus, multiple clinical studies that inhibit relevant molecular pathways have been performed with numerous patients. Many of these trials have had unexpectedly negative results, not only due to patient complexity and the difficulty in evaluating a therapeutic response, quality of life and the survival rate but also because phase II clinical studies, without the selection of molecular targets, have continued on to poor results in phase III studies. This review article aims to evaluate different phase II and phase III clinical studies to understand the clinically relevant molecular pathways and to improve the future management of HCC patients.

El carcinoma hepatocelular (CHC) es uno de los tumores más comunes a nivel mundial. La mayoría de los casos ocurre en pacientes con enfermedad hepática crónica, quienes son diagnosticados en un estado avanzado con muy pobre pronóstico. Terapias moleculares orientadas al tratamiento del CHC han sido destacadas; estas pueden afectar la proliferación celular del tumor, diferenciación celular, angiogénesis, invasión y metástasis, entre otros procesos críticos al desarrollo del tumor. El estándar para el CHC avanzado es la terapia target usando Sorafenib, sin embargo, nuevas moléculas han sido testeadas en estudios fase III de primera línea, tales como sunitinib, brivanib, erlotinib y linifanib, sin superioridad sobre sorafenib. La investigación de nuevos tratamientos es un desafío para investigadores, hepatólogos y oncólogos. Las principales vías moleculares de CHC con relevancia en estudios clínicos fase II y III son: MAP-kinase (MAPK), PI3K/AKT/mTOR, (HGF)/c-Met, cromatina y regulación epigenética, mantenimiento de telómeros, Notch, Hedgehog, Hippo y vía señalizante Jak/STAT. Las terapias futuras en CHC pueden ser orientadas rutinariamente usando sólo objetivos adecuados para terapias moleculares y seleccionando subgrupos de pacientes sobre la base de la expresión de targets moleculares o basados en nuevas clasificaciones definidas por estudios genómicos.

Partial response to sorafenib treatment associated with transient grade 3 thrombocytopenia in a patient with locally advanced thyroid cancer

Advanced radioactive refractory and progressive or symptomatic differentiated thyroid carcinoma (DTC) is a rare condition. Sorafenib was recently approved for the treatment of these patients. We present the case of a 67 year old woman diagnosed with DTC who underwent a total thyroidectomy with central, lateral-compartment neck dissection and shaving of the trachea and esophagus due to tumor infiltration. A local recurrence was detected 14 months later requiring, additionally, two tracheal rings resection. The patient received a cumulative 131I dose of 650 mCi and developed dysphagia and dyspnea 63 months after initial surgery. A 18FGD-PET/CT showed progression of the local mass associated to hypermetabolic pulmonary nodules. Sorafenib 800 mg/day was then prescribed. A dose reduction to 400 mg/day was necessary due to grade 3 thrombocytopenia that appeared four months after drug prescription. Platelet count went to normal after this dose reduction. Five months after initiation of sorafenib, a partial response of the local mass with significant intra-tumoral necrosis was observed. We conclude that sorafenib is a valid option for locally advanced DTC and that the platelet count should be evaluated regularly because it seems that thrombocytopenia might be more frequently observed in DTC than in other types of tumors.

Sorafenib prevents liver fibrosis in a non-alcoholic steatohepatitis (NASH) rodent model

Liver fibrosis occurring as an outcome of non-alcoholic steatohepatitis (NASH) can precede the development of cirrhosis. We investigated the effects of sorafenib in preventing liver fibrosis in a rodent model of NASH. Adult Sprague-Dawley rats were fed a choline-deficient high-fat diet and exposed to diethylnitrosamine for 6 weeks. The NASH group (n=10) received vehicle and the sorafenib group (n=10) received 2.5 mg·kg-1·day-1 by gavage. A control group (n=4) received only standard diet and vehicle. Following treatment, animals were sacrificed and liver tissue was collected for histologic examination, mRNA isolation, and analysis of mitochondrial function. Genes related to fibrosis (MMP9, TIMP1, TIMP2), oxidative stress (HSP60, HSP90, GST), and mitochondrial biogenesis (PGC1α) were evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Liver mitochondrial oxidation activity was measured by a polarographic method, and cytokines by enzyme-linked immunosorbent assay (ELISA). Sorafenib treatment restored mitochondrial function and reduced collagen deposition by nearly 63% compared to the NASH group. Sorafenib upregulated PGC1α and MMP9 and reduced TIMP1 and TIMP2 mRNA and IL-6 and IL-10 protein expression. There were no differences in HSP60, HSP90 and GST expression. Sorafenib modulated PGC1α expression, improved mitochondrial respiration and prevented collagen deposition. It may, therefore, be useful in the treatment of liver fibrosis in NASH.

More than 10 years survival with sequential therapy in a patient with advanced renal cell carcinoma: a case report

Although radical nephrectomy alone is widely accepted as the standard of care in localized treatment for renal cell carcinoma (RCC), it is not sufficient for the treatment of metastatic RCC (mRCC), which invariably leads to an unfavorable outcome despite the use of multiple therapies. Currently, sequential targeted agents are recommended for the management of mRCC, but the optimal drug sequence is still debated. This case was a 57-year-old man with clear-cell mRCC who received multiple therapies following his first operation in 2003 and has survived for over 10 years with a satisfactory quality of life. The treatments given included several surgeries, immunotherapy, and sequentially administered sorafenib, sunitinib, and everolimus regimens. In the course of mRCC treatment, well-planned surgeries, effective sequential targeted therapies and close follow-up are all of great importance for optimal management and a satisfactory outcome.