Rapamycin enhances the anti-tumor activity of cabozantinib in cMet inhibitor-resistant hepatocellular carcinoma / 医学前沿

Cabozantinib, mainly targeting cMet and vascular endothelial growth factor receptor 2, is the second-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, the lower response rate and resistance limit its enduring clinical benefit. In this study, we found that cMet-low HCC cells showed primary resistance to cMet inhibitors, and the combination of cabozantinib and mammalian target of rapamycin (mTOR) inhibitor, rapamycin, exhibited a synergistic inhibitory effect on the in vitro cell proliferation and in vivo tumor growth of these cells. Mechanically, the combination of rapamycin with cabozantinib resulted in the remarkable inhibition of AKT, extracellular signal-regulated protein kinases, mTOR, and common downstream signal molecules of receptor tyrosine kinases; decreased cyclin D1 expression; and induced cell cycle arrest. Meanwhile, rapamycin enhanced the inhibitory effects of cabozantinib on the migration and tubule formation of human umbilical vascular endothelial cells and human growth factor-induced invasion of cMet inhibitor-resistant HCC cells under hypoxia condition. These effects were further validated in xenograft models. In conclusion, our findings uncover a potential combination therapy of cabozantinib and rapamycin to combat cabozantinib-resistant HCC.

Nuevos retos en el tratamiento de la infección por helicobacter pylori / New challenges in the treatment of the infection for helicobacter pylori

RESUMEN La infección por helicobacter pylori afecta aproximadamente al 50% de la población mundial, es causante de gastritis crónica, úlcera péptica, cáncer gástrico y linfoma del tejido linfoide asociado a la mucosa. Desde su descubrimiento, la erradicación ha sido uno de los más importantes retos en Gastroenterología. En muchos países se desconoce la prevalencia de resistencia primaria del microorganismo a los diferentes antibióticos que empíricamente se utilizan, y por no realizar pruebas de rutina que verifican su erradicación en la práctica diaria, se ignora la efectividad de los esquemas prescritos. El incremento progresivo de la resistencia a la claritromicina y metronidazol, unido a una ausencia de antibioticoterapia alternativa, desafía la capacidad para eliminar de manera efectiva a ésta bacteria. El subcitrato de bismuto ha resurgido y su adición en la terapia ha permitido aumentar las tasas de curación por encima del 90%. Actualmente se invoca que para mejorar la eficacia en el tratamiento se debe combinar una supresión potente del ácido gástrico en tratamientos combinados cuádruples con una duración de 14 días, para la mayoría de los casos. La adherencia al tratamiento es crucial para obtener buenos resultados terapéuticos.

ABSTRACT The infection for helicobacter pylori affects approximately to the world population's 50%, it is causing of chronic gastritis, peptic ulcer, gastric cancer and linfoma associated to the mucous one. From their discovery, the eradication has been one of the most important challenges in Gastroenterología. In many countries the prevalencia of primary resistance is ignored from the microorganism to the different antibiotics that empirically they are used, and for not carrying out routine tests that verify its eradication in the daily practice, the effectiveness of the prescribed outlines it is ignored. The progressive increment of the resistance to the claritromicina and metronidazol, together to an absence of alternative antibioticotherapy, challenges the capacity to eliminate from an effective way to this bacteria. The bismuth subcitrato has resurged and its addition in the therapy has allowed to increase the cure rates above 90%. At the moment it is invoked that to improve the effectiveness in the treatment, that is should combine a potent suppression of the gastric acid in combined quadruple treatments with a duration of 14 days, for most of the cases. The adherence to the treatment is crucial to obtain therapeutic good results.

Molecular Mechanism and Progression of Primary Resistance to EGFR-TKI - Analysis of 2 Cases / 中国肺癌杂志

Tyrosine kinase inhibitor (TKI) have been proved to be effective in the treatment of advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) sensitive mutation, which is superior to chemotherapy. However, there are still some patients with sensitive mutations have primary drug resistance. It may be related to the coexistence of susceptible and resistant mutations of EGFR gene, downstream mutations of EGFR pathway, MET amplification and BIM deletion polymorphism. We present 2 cases of primary drug resistance and analyze the reasons.
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Prediction of prognostic nutritional index for the primary resistance to abiraterone and the prognosis in metastatic castration-resistant prostate cancer patients / 上海交通大学学报（医学版）

Objective • To determine whether pre-treatment prognostic nutritional index (PNI) level and its variation can predict the primary resistance to abiraterone (AA) and the prognosis in metastatic castration-resistant prostate cancer (mCRPC) patients treated with AA. Methods • A total of 112 mCRPC patients treated with AA were included in Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine. PNI levels were measured before and one month after AA treatment. PNI was calculated from preoperative laboratory parameters using the formula [10×serum albumin level (g/dL) + 0.005×lymphocyte count (per μL) in the peripheral blood]. Univariate and multivariate Logistic regression analyses were used to identify predictive factors of initial efficacy to AA treatment. Univariable and multivariable Cox regression analyses were performed to determine the prognostic factors that were associated with prostate-specific antigen (PSA) progression-free survival (PSA-PFS), radiographic PFS (rPFS) and overall survival (OS). Results • Eighty-one of all 112 (72.3%) patients showed initial response to AA treatment, and 15 patients experienced PSA flare during AA treatment. In multivariate Logistic regression analysis, the high baseline PNI level, the decrease of PSA level during the first month of AA treatment and the elevation of PNI level during the first month of AA treatment were significantly correlated with the initial response to AA treatment. In multivariate Cox regression analyses, the low baseline PNI level remained significant predictor of OS, rPFS and PSA-PFS.Conclusion • Independent of PSA level variation, the elevation of PNI level during the first month of AA treatment and high baseline PNI level are significantly correlated with the initial response to AA treatment. In addition, low baseline PNI level is a negative independent prognosticator of survival outcomes in mCRPC patients treated with AA.

Transmitted drug resistance in patients with acute/recent HIV infection in Brazil

Abstract Introduction: The widespread use of antiretroviral therapy increased the transmission of antiretroviral resistant HIV strains. Antiretroviral therapy initiation during acute/recent HIV infection limits HIV reservoirs and improves immune response in HIV infected individuals. Transmitted drug resistance may jeopardize the early goals of early antiretroviral treatment among acute/recent HIV infected patients. Methods: Patients with acute/recent HIV infection who underwent resistance test before antiretroviral treatment initiation were included in this analysis. HIV-1 sequences were obtained using an in house protease/reverse transcriptase genotyping assay. Transmitted drug resistance was identified according to the Stanford HIV Database for Transmitted Drug Resistance Mutations, based on WHO 2009 surveillance list, and HIV-1 subtyping according to Rega HIV-1 subtyping tool. Comparison between patients with and without transmitted drug resistance was made using Kruskal-Wallis and Chi-square tests. Results: Forty-three patients were included, 13 with acute HIV infection and 30 with recent HIV infection. The overall transmitted drug resistance prevalence was 16.3% (95% confidence interval [CI]: 8.1-30.0%). The highest prevalence of resistance (11.6%, 95% CI: 8.1-24.5) was against non-nucleoside reverse transcriptase inhibitors, and K103N was the most frequently identified mutation. Conclusions: The high prevalence of nonnucleoside reverse transcriptase inhibitors resistance indicates that efavirenz-based regimen without prior resistance testing is not ideal for acutely/recently HIV-infected individuals in our setting. In this context, the recent proposal of including integrase inhibitors as a first line regimen in Brazil could be an advantage for the treatment of newly HIV infected individuals. However, it also poses a new challenge, since integrase resistance test is not routinely performed for antiretroviral naive individuals. Further studies on transmitted drug resistance among acutely/recently HIV-infected are needed to inform the predictors of transmitted resistance and the antiretroviral therapy outcomes among these population.

Genetic diversity and primary resistance among HIV-1-positive patients from Maringá, Paraná, Brazil / Diversidade genética e resistência primária entre pacientes HIV-1-positivos de Maringá, Paraná, Brasil

The objective of this study is to identify subtypes of Human Immunodeficiency Virus type 1 (HIV-1) and to analyze the presence of mutations associated to antiretroviral resistance in the protease (PR) and reverse transcriptase (RT) regions from 48 HIV-1 positive treatment naïve patients from an outpatient clinic in Maringá, Paraná, Brazil. Sequencing was conducted using PR, partial RT and group-specific antigen gene (gag) nested PCR products from retrotranscribed RNA. Transmitted resistance was determined according to the Surveillance Drug Resistance Mutation List (SDRM) algorithm. Phylogenetic and SimPlot analysis of concatenated genetic segments classified sequences as subtype B 19/48 (39.6%), subtype C 12/48 (25%), subtype F 4/48 (8.3%), with 13/48 (27.1%) recombinant forms. Most recombinant forms were B mosaics (B/F 12.5%, B/C 10.4%), with one C/F (2.1%) and one complex B/C/F mosaic (2.1%). Low levels of transmitted resistance were found in this study, 2/48 (2.1% to NRTIs and 2.1% for PI). This preliminary data may subsidize the monitoring of the HIV evolution in the region.

O objetivo foi identificar subtipos do Vírus da Imunodeficiência Humana tipo-1 (HIV-1) e analisar a presença de mutações/polimorfismos nas regiões da protease (PR) e transcriptase reversa (TR) de 48 pacientes virgens de tratamento atendidos no município de Maringá, Paraná, Brasil. O sequenciamento foi conduzido usando produtos de nested PCR dos genes da PR, TR parcial e group-specific antigen gene (gag) de RNA retrotranscrito. A interpretação da resistência transmitida foi realizada segundo o algoritmo Surveillance Drug Resistance Mutation List (SDRM). As análises filogenética e SimPlot dos segmentos concatenados classificaram as sequências como subtipo B 19/48 (39,6%), subtipo C 12/48 (25%), subtipo F 4/48 (8,3%), com 13/48 (27,1%) formas recombinantes. A maioria das formas recombinantes era mosaicos B (B/F 12,5%, B/C 10,4%), com um C/F (2,1%) e um mosaico complexo B/C/F (2,1%). A prevalência de resistência transmitida foi de 4,2% (2,1% para ITRN e 2,1% para IP). Baixos níveis de resistência transmitida foram encontrados nesse estudo, 2/48 (2,1% para INTR e 2,1% para IP). Esses achados, embora preliminares, podem contribuir no monitoramento da epidemia de HIV na região.

Primary disseminated extrapulmonary multidrug resistant tuberculosis.

Disseminated tuberculosis is a common mode of presentation of tuberculosis in patients both with and without HIV/AIDS in India. However, primary multidrug resistance in disseminated tuberculosis involving only the extrapulmonary sites in an immunocompetent adult is rare. Here, we report a case of a 19-year-old man who had disseminated tuberculosis involving left pleura, pericardium, peritoneum and intraabdominal lymph nodes. He was initially taking WHO category I antituberculous drugs, but was not responding in spite of 5 months of chemotherapy. Culture of the pleural biopsy specimen grew Mycobacterium tuberculosis which was resistant to isoniazid and rifampicin. He was put on therapy for multidrug resistant tuberculosis,following 24 months of chemotherapyhe had an uneventful recovery.

Helicobacter pylori: Tratamiento actual. Un importante reto en gastroenterología / Helicobacter pylori: Current treatment An importanmt challenge for gastroenterology

Desde cuando se descubrió Helicobacter pylori, su erradicación ha constituido uno de los más importantes retos en gastroenterología. En muchas partes se desconocen las prevalencias de resistencia primaria del microorganismo a los diferentes antibióticos que empíricamente utilizan y por no realizar de rutina pruebas para verificar la erradicación, en la práctica diaria, se ignora la efectividad de los esquemas prescritos. Conocer estos dos factores, permite, no solo identificar los que aún persisten infectados, sino también elegir la próxima terapia de rescate de una manera más racional. El no disponer de la información sobre resistencia pretratamiento es un inconveniente que impide evaluar el impacto de la resistencia con el fracaso terapéutico. A nivel mundial, la triple terapia estándar ha perdido la eficacia que tenía en el pasado y la terapia secuencial no es igualmente eficaz en todos los sitios, en especial en regiones en donde existe alta resistencia a claritromicina y metronidazol. Los esquemas con levofloxacina han demostrado eficacia en triples terapias de primera línea o como terapia de rescate, pero es necesario que cada región adopte sus propios esquemas de tratamiento fundamentados en pruebas de susceptibilidad y en estudios farmacogenómicos.

Since when Helicobacter pylori was discovered, the eradication has been one of the most important challenges in gastroenterology. In many places, the prevalence of primary resistance of microorganism to the different antibiotics is not known, and these are used empirically. In daily practice, no routine test is used to verify the eradication, and therefore do not know the effectiveness of the schemes. Knowing these two factors is possible identify those still infected and choose the next rescue therapy in a rational form. The absence of information on pre-treatment resistance is a problem that cannot measure the impact of resistance to therapeutic failure. A global level, the standard triple therapy has lost the effectiveness that it had in the past and sequential therapy is not equally effective everywhere, especially in regions where there is high resistance to clarithromycin and metronidazole. The schemes have proved effective with levofloxacin triple therapies as first line therapy or rescue, but it is necessary that each region takes its own schemes of treatment based on susceptibility tests and pharmacogenomic studies.

Clinical Features and Management of Multidrug-Resistant Tuberculosis / 결핵

OBJECTIVES: Although outbreak of MDR Tb has been a recent problem in western countries, it has been a longstanding problem in Korea. The poor outcome of MDR Tb is mainly due to poor compliance, high rate of side reaction of secondary drugs, and limitation in number of available drugs. Thus, to improve the outcome of MDR Tb,, it is crucial to make individualized adequate prescription based on the knowledge of the patterns of resistance to each drugs in the community as well as the natural history. The purpose of present study is to evaluate the clinical features of Korean MDR Tb patients including patterns of drug resistance and success rate of treatment which was prescribed according to the sensitivity tests. METHODS: Retroscpective analysis of 71 Korean patients with MDR Tb was made. All strains isolated from patients showed resistence to at least two first line drugs. Patients profile, previous treatment history, patterns of drug resistance, outcome of treatment was analysed. Initial treatment regimen was selected according to the previous treatment history and was modified according to the sensitivity reports. The regimen was composed to include at least 4 sensitive drugs when possible. RESULTS: The patients showed resistance to 4.1 drugs on average. 90% of them were resistant to INH and RFP. Among 71 patients, 35 patients(49%) had cavitary lesions in CXR. Treatment outcome was analysed in 55 patients. 35 patients(67%) were improved after treatment and 18 patients(33%) showed treatment failure. 5 patients showed primary resistance. Treatment outcome could be evaluated in 4 of them and all showed improvement after treatment. 14 patients(20%) had to change their regimens due to drug side effects. The most frequent side effect was elevation of liver enzymes(6 patients). Others included dizziness, hyperuricemia, tinnitus, skin rash, GI troubles. More than 50% of side effects developed within 3 months. In repeated drug sensitivity test, the concordance rate of resistance to INH was 100% and RFP 98%. EMB,PZA showed 80% concordance rate. But in the other drugs, the concordances were less than 50%. Operation was done in 5 patients - 1 patients as a adjunctive means of chemotherapy In that case, negative conversion of sputum AFB was done. CONCLUSION: 2/3 patients of multidrug-resistant tuberculosis were improved by appropriate prescription and regular medication suggesting that more aggressive management and monitoring is indicated in multidrug-resistant tuberculosis.