Synergistic Antitumor Effect of Everolimus Combined with Gemcitabine on Diffuse Large B-Cell Lymphoma / 中国实验血液学杂志

OBJECTIVE@#To investigate the effects of mTOR inhibitors everolimus (EVE) and gemcitabine (GEM) on the proliferation, apoptosis and cell cycle of diffuse large B-cell lymphoma (DLBCL) cell line U2932, and further explore the molecular mechanisms, so as to provide new ideas and experimental basis for the clinical treatment of DLBCL.@*METHODS@#The effect of EVE and GEM on the proliferation of U2932 cells was detected by CCK-8 assay, the IC50 of the two drugs was calculated, and the combination index (CI=) of the two drugs was calculated by CompuSyn software. The effect of EVE and GEM on apoptosis of U2932 cells was detected by flow cytometry with AnnexinV-FITC/PI staining. Flow cytometry with propidium iodide (PI) staining was used to detect the effect of EVE and GEM on the cell cycle of U2932 cells. Western blot assay was used to detect the effects of EVE and GEM on the channel proteins p-mTOR and p-4EBP1, the anti-apoptotic proteins MCL-1 and Survivin, and the cell cycle protein Cyclin D1.@*RESULTS@#Both EVE and GEM could significantly inhitbit the proliferation of U2932 cells in a time- and dose-dependent manner (r=0.465, 0.848; 0.555, 0.796). According to the calculation of CompuSyn software, EVE combined with GEM inhibited the proliferation of U2932 cells at 24, 48 and 72 h with CI=<1, which had a synergistic effect. After treated U2932 cells with 10 nmol/L EVE, 250 nmol/L GEM alone and in combination for 48 h, both EVE and GEM induced apoptosis, and the difference was statistically significant compared with the control group (P<0.05). The apoptosis rate was significantly enhanced after EVE in combination with GEM compared with single-agent (P<0.05). Both EVE and GEM alone and in combination significantly increased the proportion of cells in G1 phase compared with the control group (P<0.05). The proportion of cells in G1 phase was significantly increased when the two drugs were combined (P<0.05). The expression of p-mTOR and effector protein p-4EBP1 was significantly downregulated in the EVE combined with GEM group, the expression of anti-apoptotic proteins MCL-1, Survivin and cell cycle protein cyclin D1 was downregulated too (P<0.05).@*CONCLUSION@#EVE combined with GEM can synergistically inhibit the proliferation of U2932 cells, and the mechanism may be that they can synergistically induce apoptosis by downregulating the expression of MCL-1 and Survivin proteins and block the cell cycle progression by downregulating the expression of Cyclin D1.

Análise de custo-efetividade do uso de inibidores da via de sinalização mTOR x micofenolato em receptores de transplante renal sem profilaxia para citomegalovírus s / Cost-effectiveness analysis of the use of mTOR signaling pathway inhibitors x mycophenolate in kidney transplantation recipients without cytomegalovirus prophylaxis

Objetivo: Avaliar a relação de custo-efetividade dos regimes imunossupressores utilizados em pacientes receptores de transplante renal, no Hospital Santa Casa de Misericórdia de Juiz de Fora, MG, basiliximabe, micofenolato de sódio, tacrolimo e prednisona (Grupo 1 = 93 pacientes), comparados com a associação de timoglobulina, everolimo, tacrolimo e prednisona (Grupo 2 = 91 pacientes). Métodos: Para a análise farmacoeconômica, foi utilizado o modelo de Árvore de Decisão, desenvolvido no software Treeage Suite 2011. Foi considerada uma coorte real de pacientes submetidos ao transplante renal entre janeiro de 2013 e março de 2017, os quais foram acompanhados por um período de um ano, sendo mensurados os benefícios clínicos, bem como os custos associados, na perspectiva do Sistema Único de Saúde. O método de custeio utilizado foi o botton-up. Foram adotados os limiares de custo-efetividade (LCEs) equivalentes a 1 PIB per capita e 1 a 3 PIB, considerando o ano de 2017. Resultados: No que diz respeito à sobrevida, a RCEI foi de cerca de R$ 214.234,12 para 1 ano de vida ganho. Em relação aos eventos adversos, a RCEI foi de cerca de R$ 43.682,98 para 1 ano sem incidência de eventos adversos. Conclusões: Ao avaliar a sobrevida e a incidência de eventos adversos, timoglobulina+everolimo não é considerado custo-efetivo em relação ao esquema contendo basiliximabe+micofenolato de sódio diante do LCE de 1 PIB per capita. No entanto, ao adotarmos o LCE até 3 PIB per capita, o regime contendo moglobulina+everolimo é custo-efetivo, ultrapassando cerca de 38% do PIB per capita.

Objective: Evaluate the cost-effectiveness of immunosuppressive regimens used in kidney transplant recipients at the Santa Casa de Misericórdia, Hospital in Juiz de Fora, MG, compared with basiliximab, mycophenolate sodium, tacrolimus and prednisone (Group 1 = 93 patients) with the association of thymoglobulin, everolimus, tacrolimus and prednisone (Group 2 = 91 patients). Methods: For the pharmacoeconomic analysis, the Decision Tree model was used, developed in the TreeAge Suite 2011 software. A real cohort of patients undergoing kidney transplantation between January 2013 and March 2017 was considered, they were followed up for a period of 1 year, where the clinical benefits were measured, as well as the associated costs, from the perspective

Expert consensus on the clinical application of PI3K/AKT/mTOR inhibitors in the treatment of advanced breast cancer / 中华肿瘤杂志

Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway (PAM pathway) plays an important role in the development of breast cancer and are closely associated with the resistance to endocrine therapy in advanced breast cancer. Therefore, anti-cancer treatment targeting key molecules in this signaling pathway has become research hot-spot in recent years. Randomized clinical trials have demonstrated that PI3K/AKT/mTOR inhibitors bring significant clinical benefit to patients with advanced breast cancer, especially to those with hormone receptor (HR)-positive, human epidermal growth factor receptor (HER) 2-negative advanced breast cancer. Alpelisib, a PI3K inhibitor, and everolimus, an mTOR inhibitor, have been approved by Food and Drug Administration. Based on their high efficacy and relatively good safety profile, expanded indication of everolimus in breast cancer have been approved by National Medical Products Administration. Alpelisib is expected to be approved in China in the near future. The members of the consensus expert panel reached this consensus to comprehensively define the role of PI3K/AKT/mTOR signaling pathway in breast cancer, efficacy and clinical applications of PI3K/AKT/mTOR inhibitors, management of adverse reactions, and PIK3CA mutation detection, in order to promote the understanding of PI3K/AKT/mTOR inhibitors for Chinese oncologists, improve clinical decision-making, and prolong the survival of target patient population.

An open-label randomized clinical trial to evaluate the efficacy of everolimus versus tacrolimus in triple maintenance immunosuppressive therapy for kidney transplant patients

Tacrolimus (TAC), a calcineurin inhibitor, and everolimus (EVL), an mTOR inhibitor, have been used as immunosuppressive (ISS) drugs in post-kidney transplantation therapy. The objective of this study was to compare the efficacy of EVL vs TAC in the ISS maintenance triple therapy. Ninety-seven kidney transplant patients, who received triple maintenance therapy with TAC, mycophenolate mofetil (MMF), and methyl prednisone (PRED), were evaluated. After four months of post-kidney transplant therapy, 30 patients enrolled in a randomized controlled clinical trial, in which 16 patients received TAC+MMF+PRED (cohort 1), and 14 patients switched to EVL+MMF+PRED (cohort 2). The patients were followed-up for 36 months. Two patients from cohort 1 lost their grafts after one year due to non-adherence. Two patients from cohort 2 had intolerance to mTOR inhibitors and were switched back to TAC from EVL. One case (6.25%) in cohort 1 and three cases (21.43%) in cohort 2 of acute T-cell-mediated rejection was observed. Antibody-mediated acute rejection (ABMAR) was observed in four patients (25.0%) in cohort 1, and antibody-mediated chronic rejection (ABMCR) was observed in two patients (12.50%). One patient from cohort 2 lost the graft after 15 months due to polyomavirus infection. The graft survival rate was 87.50% in cohort 1 and 92.86% in cohort 2. This clinical trial showed that the EVL+MMF+PRED triple maintenance therapy was efficacious compared with TAC during 32 months of follow-up. However, further studies are needed to confirm the efficacy of this regimen for long-term graft survival.

Rabdomioma intracardiaco: presentación clínica y opciones terapéuticas actuales a propósito de tres casos / Cardiac rhabdomyoma: Clinical presentation of three cases and current therapeutic options

Resumen Hasta hace algunas décadas los tumores cardiacos tenían solo un interés académico dada su baja tasa de presentación; sin embargo, con el advenimiento del baipás cardiopulmonar, el manejo quirúrgico comienza a ser posible y, más recientemente, junto con la investigación farmacológica, contribuyen al desarrollo de nuevas estrategias de tratamiento para estos pacientes. La incidencia estimada de los tumores cardiacos es baja y tiene un comportamiento generalmente benigno y manifestaciones clínicas inespecíficas. Estos tumores en la edad pediátrica se asocian a esclerosis tuberosa, una enfermedad de patrón de herencia autosómica dominante que se caracteriza por una alteración en la diferenciación y multiplicación celular (hamartomas) en diferentes sistemas. Desde el punto de vista cardiaco, el grado de morbilidad está condicionado por el tamaño y la localización tumoral dentro de la cavidad, y tiene riesgo de obstruir los tractos de salida ventriculares, alterar la función valvular o producir trastornos de conducción. Algunos pacientes solo requieren seguimiento clínico durante el transcurso de su vida, pero existe la posibilidad de regresión tumoral; otros se benefician de una resección quirúrgica por su impacto hemodinámico o alteraciones del ritmo cardiaco. Sin embargo, no todos son candidatos quirúrgicos, en cuyo caso el manejo con inhibidores m-TOR ha surgido como una alternativa terapéutica. Se presenta el caso de tres neonatos con esclerosis tuberosa y rabdomioma cardiaco, diagnosticados en etapa prenatal, a quienes se les realizó un abordaje terapéutico individualizado, basado en las opciones actuales disponibles para este grupo de pacientes.

Abstract Up to a few decades ago, cardiac tumours were only of academic interest given their low presentation rate. However, with the advances in cardiopulmonary, surgical management began to be possible, and more recently, they contribute to the development of new treatment strategies for these patients. The estimated incidence of cardiac tumours is low and are generally benign with non-specific clinical signs and symptoms. In paediatrics, these tumours are associated with tuberous sclerosis, a disease with a dominant autosomal inheritance pattern, which is characterised by an alteration in cell differentiation and multiplication (hamartomas) in different systems. From a cardiac point of view, the morbidity level is determined by the size and location of the tumour within the cavity, the risk of obstructing ventricular outflow tracts, alterations in valvular function, and conduction disorders. Some patients only require clinical follow-up all their lives, as there is the risk of tumour regression. Others may benefit from surgical resection due to its haemodynamic impact or changes in cardiac rhythm. However, not everyone is a candidate for surgery, in which case, management with m-TOR inhibitors has emerged as a therapeutic alternative. The case is presented on three neonates with tuberous sclerosis and a cardiac rhabdomyoma, diagnosed in the prenatal stage. An individualised therapeutic approach was made based on the current options available for this group of patients.

The Systematic Review of the Efficacy and Safety of Immune Checkpoint Inhibitor in Urological Cancers

To systematically review relevant literature on efficacy and safety of immune checkpoint inhibitors (ICIs) in patients with advanced and metastatic urothelial cell cancer (UCC), renal cell cancer (RCC), and prostate cancer. In platinum pretreated UCC, efficacy of pembrolizumab was superior to chemotherapy, with longer median overall survival (OS; 10.3 months vs. 7.4 months), a higher objective response rate (ORR; 21.1% vs. 11.4%, p=0.001), and a lower adverse event rate (60.9% vs. 90.2%). Three randomized controlled trials (RCTs) assessed the safety and efficacy of nivolumab in advanced RCC. The median OS (25.0 months vs. 19.6 months) and the ORR (25% vs. 5%) were higher in patients treated with nivolumab compared with second-line everolimus. In patients with metastatic castration-resistant prostate cancer, 2 RCTs were identified, which did not show significant benefits for ipilimumab over placebo. In UCC and RCC, there was no conclusive association between programmed cell death receptor ligand 1 (PD-L1) expression in tumor tissue and clinical outcome during pembrolizumab and nivolumab treatment, respectively. Therefore, in metastatic UCC and RCC, pembrolizumab and nivolumab have superior efficacy and safety to second-line chemotherapy and everolimus, respectively. No beneficial effect of ipilimumab was observed in prostate cancer patients. PD-L1 expression status is currently not suitable as a predictive marker for treatment outcome.

Clinical outcomes after switch to mTOR inhibitors in kidney transplant recipients / Resultados clínicos en receptores de trasplante renal posterior a la conversión a ImTOR

Abstract Introduction: mTOR inhibitors Sirolimus and Everolimus are an alternative for inmunosuppression in renal transplant recipients. The aim of the study was to describe the experience of patients with switch to mTOR inhibitors, followed up for more than five years. Materials and methods: Patients with renal transplantation from 1995 to 2013, who had indication of calcineurin inhibitor (CNI) withdrawl after the third month post-transplant were included. All patients underwent renal biopsy prior to conversion. No patient had a diagnosis of chronic nephtopathy, IFTA>40 % or proteinuria >350mg/24h. A descriptive analysis for all variables was devoloped. Kaplan-Meier method was used for the patient's and graft survival and graft rejection incidence. Results: From 1273 renal transplants, the switch from CNI to mTOR inhibitors was performed in 166 (13 %), 78 % (n=129) were switched to Sirolimus. 12,6 % of the patients lost graft function and 4,2 % (n=7) died. 37% had mTOR inhibitors withdrawal, and the major cause was pathologic proteinuria. The incidence of graft rejection after switching to mTOR inhibitors was 9,6 %. The one and five year graf survival was 96,6 % and 83,5 %. The patient survival at one and five years was 98 % and 97 %. Conclusions: The use of mTOR inhibitors drugs appears to be safe in the managgement of specific renal transplant recipients, with a low rejection rate and good survival.

Resumen Introducción: los ImTOR, sirolimus y everolimus son una alternativa de inmunosupresión en personas que han recibido transplantes renales. En este artículo, se describe la experiencia de pacientes que han experimentado una conversión a ImTOR, y a los que se les ha hecho un seguimiento por más de cinco años. Materiales y métodos: se incluyeron pacientes con transplantes renales desde 1995 hasta 2013, quienes tuvieron indicación de suspensión del inhibidor de calcineurina (ICN) después del tercer mes posterior al trasplante. Todos los pacientes fueron sometidos a biopsia renal antes de la administración de ImTOR. Ningún paciente tuvo diagnóstico de nefropatía crónica, IFTA >40 % o proteinuria >350 mg/24h. Se elaboró un análisis descriptivo para todas las variables. Para estudiar la supervivencia del paciente y del injerto, y la incidencia de rechazo agudo, se usó el método de Kaplan-Meier. Resultados: de 1273 trasplantes renales, la conversión de ICN a ImTOR se realizó en 166 casos (13 %). Al 78 % (n=129) se le administró sirolimus. El 13 % de los pacientes perdió la función del injerto y 7 pacientes (4,2 %) fallecieron. En el 37 % de los casos, se retiró el ImTOR. La principal causa de retiro fue el hallazgo de proteinuria patológica. La incidencia de rechazo agudo después del cambio a ImTOR fue de 9,6 %. La supervivencia del injerto tras uno y cinco años fue de 96,6 % y 83,5 %, respectivamente; y la supervivencia del paciente a uno y cinco años fue de 98 % y 97 %, respectivamente. Conclusiones: el uso de inhibidores ImTOR parece ser seguro en este grupo de pacientes trasplantados, pues hubo una baja tasa de rechazo y buena supervivencia del injerto.

Effect of conversion from calcineurin inhibitors to everolimus on hepatitis C viremia in adult kidney transplant recipients / Efeitos da conversão de inibidores da calcineurina para Everolimo na viremia por hepatite C em receptores adultos de transplantes renais

ABSTRACT Introduction: Currently, there is no specific immunosuppressive protocol for hepatitis C (HCV)-positive renal transplants recipients. Thus, the aim of this study was to evaluate the conversion effect to everolimus (EVR) on HCV in adult kidney recipients. Method: This is an exploratory single-center, prospective, randomized, open label controlled trial with renal allograft recipients with HCV-positive serology. Participants were randomized for conversion to EVR or maintenance of calcineurin inhibitors. Results: Thirty patients were randomized and 28 were followed-up for 12 months (conversion group, Group 1 =15 and control group, Group 2 =13). RT-PCR HCV levels reported in log values were comparable in both groups and among patients in the same group. The statistical analysis showed no interaction effect between time and group (p value G*M= 0.852), overtime intra-groups (p-value M=0.889) and between group (p-value G=0.286). Group 1 showed a higher incidence of dyslipidemia (p=0.03) and proteinuria events (p=0.01), while no difference was observed in the incidence of anemia (p=0.17), new onset of post-transplant diabetes mellitus (p=1.00) or urinary tract infection (p=0.60). The mean eGFR was similar in both groups. Conclusion: Our study did not show viral load decrease after conversion to EVR with maintenance of antiproliferative therapy.

RESUMO Introdução: Atualmente não há um protocolo imunossupressor específico para os receptores de transplantes renais portadores de hepatite C (HCV). Assim, o objetivo deste estudo foi avaliar o efeito da conversão a Everolimo (EVR) na HCV em receptores adultos de transplantes renais. Método: Trata-se de um estudo unicêntrico, prospectivo, randomizado, exploratório, controlado, aberto em receptores de aloenxertos renais com sorologia positiva para HCV. Os participantes foram randomizados para conversão a EVR ou manutenção dos inibidores da calcineurina. Resultados: Trinta pacientes foram randomizados e 28 foram acompanhados por um período de 12 meses (grupo de conversão, Grupo 1 = 15 e grupo controle, Grupo 2 =13). Níveis de RT-PCR HCV descritos em valores logarítmicos foram comparáveis entre os grupos e entre pacientes em um mesmo grupo. A análise estatística não mostrou efeitos de interação entre tempo e grupo (valor p G*M= 0,852), ao longo do tempo em cada grupo (valor p M=0,889) e entre grupos (valor p G=0,286). O Grupo 1 apresentou uma maior incidência de eventos de dislipidemia (p=0,03) e proteinúria (p=0,01); não houve diferença na incidência de anemia (p=0,17), diabetes mellitus de início pós-transplante (p=1,00) ou infecção do trato urinário (p=0,60). A TFGe média foi semelhante nos dois grupos. Conclusão: Nosso estudo não mostrou redução da carga viral após conversão a EVR com manutenção do tratamento antiproliferativo.

Stents farmacológicos: estado atual / Drug-eluting stents: state-of-the-art

Stents farmacológicos foram desenvolvidos para reduzir a resposta proliferativa neointimal e consequentemente a reestenose, mais frequente limitação da intervenção coronária percutânea com balão e stents não faramcológicos. O desenvolvimento destes dispositivos baseia-se no maior entendimento da biologia da reestenose, na seleção de fármacos anti-proliferativos adequados para os diversos mecanismos envolvidos nesta complicação e no uso de plataformas/polímeros adequados para entrega do fármaco. Consequentemente o desempenho destes dispositivos depende da perfeita interação de todos estes elementos. As abordagens atuais para minimizar a reestenose são revisados neste capítulo. Embora a primeira geração dos stents farmacológicos tenha sido focada na eficácia em reduzir a reestenose, questões relacionadas à sua segurança surgiram, comprometendo seu uso mais disseminado. As novas gerações de stents farmacológicos com polímeros duráveis ou bioabsorvíveis conseguiu reduzir as taxas de nova intervenção e de trombose. Embora o modelo ideal de stent farmacológico ainda esteja em investigação, é certo que esta tecnologia já se estabeleceu como primeira linha na intervenção coronária percutânea contemporânea

Revascularização cirúrgica do miocárdio - análise crítica da evolução e estado atual / Surgical mocardial revascularization - critical analysis of its evolution and current state

O desenvolvimento da cinecoronariografia por Sones, no início da década de 1960, abriu caminho para a moderna cirurgia de revascularização do miocárdio. Em 1967, Favarolo realizou as primeiras pontes de veia safena e a técnica se expandiu mundialmente. Apesar de seu começo empolgante, no início da década de 1970, estudos angiográficos mostraram taxas de oclusão dos enxertos venosos, no primeiro ano, entre 10 a 15%. Em 1986, Loop e colaboradores mostraram o aumento da sobrevida dos pacientes em 10 anos, quando utilizava-se a artéria torácica interna esquerda anastomosada na artéria descendente anterior. Lytle, em 1999, indicou que esse benefício era melhorado quando utilizava-se ambas as artérias torácicas internas. Paralelamente, novas técnicas também foram surgindo, como a cirurgia sem o uso da circulação extracorpórea e, também, a partir de 1995, a utilização de mini acesso. Durante todos esses anos, inúmeros estudos foram realizados, dentre eles podemos destacar: o estudo SYNTAX e sua grande contribuição com o desenvolvimento do syntax score ; o estudo Freedom, mostrando que pacientes diabéticos apresentam maior benefício com a cirurgia de revascularização do miocárdio em comparação ao tratamento percutâneo. Em relação às lesões de tronco de coronária esquerda, dois grandes estudos (NOBLE e EXCEL) mostraram que o tratamento percutâneo, em pacientes com syntax score baixo, é uma boa opção terapêutica. Nas síndromes coronarianas agudas sem elevação do segmento ST no eletrocardiograma, a opinião do Heart Team é de extrema importância para decisão de qual tratamento realizar, seja ele clínico, percutâneo ou cirúrgico. Já nas SCA com elevação do segmento ST no eletrocardiograma, o tratamento por cateter, com a colocação de stent, é o preferencial, reservando o tratamento cirúrgico apenas para casos de falha no tratamento percutâneo ou quando há aparecimento de complicações mecânicas

The development of coronary angiography by Sones, in the early 1960s, opened the way for modern myocardial revascularization surgery. In 1967, Favarolo performed the first saphenous vein coronary artery bypass grafting (CABG) surgery, and the technique expanded worldwide. Despite its exciting start, at the beginning of the 1970s, angiographic studies showed vein graft occlusion rates, in the first year, of between 10% and 15%. In 1986, Loop and colleagues showed increased 10-year patient survival when the left anastomosed internal thoracic artery was used in the left anterior descending artery. Lytle, in 1999, indicated that this benefit was improved when both internal thoracic arteries were used. Meanwhile, new techniques were also emerging, such as off-pump CABG and since 1995, the use of minimally invasive surgery. During these years, numerous studies were carried out, including: the SYNTAX Trial, with its major contribution with the development of the syntax score; and the Freedom Trial, which showed that diabetic patients still benefit most from myocardial revascularization surgery compared to percutaneous treatment. In relation to lesions of the left coronary trunk, two large studies (NOBLE and EXCEL) showed that percutaneous treatment in patients with a low syntax score is a good therapeutic option. In acute coronary syndromes without ST segment elevation in the electrocardiogram, the opinion of the Heart Team is extremely important for deciding on the best treatment, be it clinical, percutaneous, or surgical. In ACS with ST segment elevation in the electrocardiogram, catheter treatment with stent placement is the preferred choice, reserving surgical treatment only for cases of percutaneous treatment failure, or where there are mechanical complications.

Fibrous Plaque of the Eyelid in a Patient with Tuberous Sclerosis Responding to Everolimus

No abstract available.

Living donor liver transplantation prior to multiple myeloma treatment in a patient with hepatitis B-associated hepatocellular carcinoma and liver cirrhosis: a case report

Clinical outcomes of living donor liver transplantation (LDLT) for hepatocellular carcinoma (HCC) in patients with multiple myeloma (MM) have not been established in terms of HCC recurrence and MM deterioration after LDLT. A 51-year-old man with chronic hepatitis B was diagnosed with HCC and MM. Since the patient also had decompensated liver cirrhosis (LC), he underwent LDLT prior to autologous peripheral blood stem cell transplantation (PBSCT) to prevent fulminant hepatitis due to HBV reactivation. The patient received Epstein-Barr virus prophylaxis and a triple immunosuppressive regimen of tacrolimus, everolimus, and steroid after LDLT. Autologous PBSCT was performed 7 months after LDLT. He showed a complete response to treatment of MM without post-LT complications or HCC recurrence. In conclusion, LDLT could be adapted for treatment of MM patients with combined HCC and decompensated LC because it is an effective strategy of preventing HBV reactivation and HCC recurrence after induction therapy of MM.

Crizotinib in Combination with Everolimus Synergistically Inhibits Proliferation of Anaplastic Lymphoma Kinase‒Positive Anaplastic Large Cell Lymphoma / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Anaplastic large cell lymphoma (ALCL) is a rare aggresive non-Hodgkin lymphoma, of which over 50% of cases have an aberrant nucleophosmin (NPM)‒anaplastic lymphoma kinase (ALK) fusion protein. Both mechanistic target of rapamycin (mTOR) inhibitor everolimus and ALK inhibitor crizotinib have shown promising antitumor activity in ALK-positive cancer cell lines. However, their combined effect has not yet been investigated. MATERIALS AND METHODS: We evaluated the anti-proliferative effects of everolimus and/or crizotinib in ALK-positive ALCL cell lines, Karpas 299 and SU-DHL-1, and lung adenocarcinoma cell line, NCI-H2228. RESULTS: We found that individually, both everolimus and crizotinib potently inhibited cell growth in a dose-dependent manner in both Karpas 299 and SU-DHL-1 cells. A combination of these agents synergistically inhibited proliferation in the two cell lines. Crizotinib down-regulated aberrant AKT and ERK phosphorylation induced by everolimus. Combination treatment also significantly increased G0/G1 cell-cycle arrest, DNA damage, and apoptosis compared with everolimus or crizotinib alone in ALK-positive ALCL cells. In the Karpas 299 xenograft model, the combination treatment exerted a stronger antitumor effect than monotherapies, without significant change in body weight. The synergistic effect of everolimus and crizotinib was also reproduced in the ALK-positive lung adenocarcinoma cell line NCI-H2228. The combination treatment abrogated phosphoinositide 3-kinase/AKT and mTOR signaling pathways with little effect on the Ras/ERK pathway in NCI-H2228 cells. CONCLUSION: Crizotinib combinedwith everolimus synergistically inhibits proliferation of ALK-positive ALCL cells. Our results suggest that this novel combination is worthy of further clinical development in patients with ALK-positive ALCL.

Tuberous Sclerosis Complex with Crohn's Disease / 대한소아신경학회지

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutation of one of two genes, TSC1 (encoding hamartin, 9q34) and TSC2 (encoding tuberin, 16p13). It invades the central nervous system and various parts of the body, causing various symptoms. Crohn's disease (CD) is a chronic immune-mediated disease that has not been clearly elucidated. It is thought to be caused by an excessive immune response of the body to bacteria that normally exist in the digestive tract with genetic factors. No cases have been reported in which both of the above-mentioned diseases occurred simultaneously. We report a case of CD in a patient with TSC. A 12-year-old boy was brought to our hospital because of abdominal pain. Skin lesions were observed in the TSC. Fundus examination revealed a hamartoma in the right retina. Brain magnetic resonance imaging revealed a subendothelial giant cell astrocytoma (SEGA). On the basis of these findings, he was diagnosed as having TSC. Blood test results showed increased levels of inflammatory markers. On abdominal ultrasonography, his colon walls were observed to be thickened with increased vascularity of the proximal ascending colon, ileocecal valve, and terminal ileum. Colonoscopy revealed discontinuous ulcerations and inflammations of the ileum, IC valve, and cecum, similar to those found in CD. Everolimus was administered orally for the SEGA but was discontinued frequently owing to the exacerbation of CD. The possibility of CD should be kept in mind in patients with TSC considering to undergo treatment for SEGA.

Impact of ⁶⁸Ga-DOTA-Peptide PET/CT on the Management of Gastrointestinal Neuroendocrine Tumour (GI-NET): Malaysian National Referral Centre Experience / 대한핵의학회잡지

PURPOSE: The National Cancer Institute is the only referral centre in Malaysia that provides ⁶⁸Ga-DOTA-peptide imaging. The purpose of this study is to determine the impact of ⁶⁸Ga-DOTA-peptide PET/CT on the management of gastrointestinal neuroendocrine tumours (GI-NET).MATERIALS AND METHODS: A cross-sectional study was performed to review the impact of ⁶⁸Ga-DOTA-peptide (⁶⁸Ga-DOTATATE or ⁶⁸Ga-DOTATOC) PET/CT on patients with biopsy-proven GI-NET between January 2011 and December 2015. Suspected NET was excluded. Demographic data, tumoral characteristics, change of disease stage, pre-PET intended management and post-PET management were evaluated.RESULTS: Over a 5-year period, 82 studies of ⁶⁸Ga-DOTA-peptide PET/CT were performed on 44 GI-NET patients. The most common primary site was the rectum (50.0%) followed by the small bowel, stomach and colon. Using WHO 2010 grading, 40.9%of patients had low-grade (G1) tumour, 22.7% intermediate (G2) and 4.5% high (G3). Of ten patients scheduled for pre-operative staging, ⁶⁸Ga-DOTA-peptide PET/CT only led to therapeutic change in three patients. Furthermore, false-negative results of ⁶⁸Ga-DOTA-peptide PET/CT were reported in one patient after surgical confirmation. However, therapeutic changes were seen in 20/36 patients (55.6%) scheduled for post-surgical restaging or assessment of somatostatin analogue (SSA) eligibility. When ⁶⁸Ga-DOTApeptide PET/CT was used for monitoring disease progress during systemic treatment (sandostatin, chemotherapy, everolimus and PRRT) in metastatic disease, impact on management modification was seen in 19/36 patients (52.8%), of which 84.2% had inter-modality change (switch to everolimus, chemotherapy or PRRT) and 15.8% had intra-modality change (increased SSA dosage).CONCLUSIONS: ⁶⁸Ga-DOTA-peptide PET/CT has a significant impact on management decisions in GI-NET patients as it can provide additional information on occult metastasis/equivocal lesions and supply the clinician an opportunity to select patients for targeted therapy.

Everolimus Plus Ku0063794 Regimen Promotes Anticancer Effects against Hepatocellular Carcinoma Cells through the Paradoxical Inhibition of Autophagy / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Everolimus only inhibits mammalian target of rapamycin complex 1 (mTORC1), whereas Ku0063794 inhibits both mTORC1 and mTORC2. Although they have similar anticancer effects, their combination has a synergistic effect against hepatocellular carcinoma (HCC) cells. We aimed to determine the mechanism underlying the synergistic effects of everolimus and Ku0063794 associated with autophagy in HCC cells. MATERIALS AND METHODS: We compared the effects of everolimus and Ku0063794, individually or in combination, on both the in vitro and in vivo models of HCCs. RESULTS: HepG2 cells treated with both agents had significantly lower rates of cell proliferation and higher apoptosis than the individual monotherapies (p < 0.05). Autophagic studies consistently indicated that, unlike the monotherapies, the combination therapy significantly reduced autophagy (p < 0.05). Autophagic blockage directly promoted the pro-apoptotic effects of combination therapy, suggesting autophagy as the survival mechanism of HCC cells. Unlike the monotherapies, combination therapy showed the potential to inhibit sirtuin 1 (SIRT1), the positive regulator of autophagy. SIRT1 overexpression abrogated the autophagy-inhibiting and pro-apoptotic effects of combination therapy. In a nude mouse xenograft model, the shrinkage of tumors was more prominent in mice treated with combination therapy than in mice treated with the respective monotherapies (p < 0.05). The immunohistochemical and immunofluorescence stains of the tumor obtained from the xenograft model showed that combination therapy had the potential of reducing autophagy and promoting apoptosis. CONCLUSION: The combination of everolimus and Ku0063794 potentiates anticancer effects on HCCs through a decrease in autophagy, which is prompted by SIRT1 downregulation.