Impact of a guaranteed access program to imatinib on the survival of patients with chronic myeloid leukemia.

PURPOSE: This work aimed to evaluate the impact of a guaranteed access program to imatinib on the survival of patients with Chronic Myeloid Leukemia. METHODS: We carried out a retrospective, observational, and analytical study of the database of patients diagnosed with Chronic Myeloid Leukemia of the Instituto Nacional de Cancerología and the Hospital General de México Dr. Eduardo to assess overall survival based on guaranteed access or not to imatinib. RESULTS: With an average follow-up of 99 months, all patients' estimated 20-year overall survival was 72% (95% CI, 76-67). A significant difference was found in the 20-year survival probability in favor of patients with guaranteed access 76% (95% CI, 81-71) vs. 61% (95% CI, 69-52) (p < 0.001), in addition to those in which they had better attachment 81.2% (95% CI, 85-76) vs. 44.9% (95% CI, 52-37) (p < 0.001). CONCLUSION: CML is the most frequent chronic leukemia in Mexico. It mainly affects the economically active population (mean age 40), and the prognosis in our country has improved, emulating developed countries; however, the results depend on access to treatment and proper monitoring.

Neoadjuvant Imatinib in Gastrointestinal Stromal Tumors (GIST): The First Analysis of a Mexican Population.

Introduction Gastrointestinal stromal tumors (GISTs) are neoplasms originating from the interstitial cells of Cajal, pacemaker cells responsible for intestinal motility. Patients with locally advanced GISTs and those with borderline resections due to the proximity of vital anatomical structures, which could result in unacceptable post-surgical morbidity, require special therapeutic consideration. Imatinib, a tyrosine kinase inhibitor, has demonstrated significant success in the non-surgical management of metastatic GIST, and its favorable impact on overall survival in the adjuvant setting makes it logical to speculate on the benefit it could provide as a neoadjuvant medication in patients with locally advanced disease. Methods Patients aged 18-90 years with a diagnosis of GIST confirmed by immunohistochemistry (CD117 positivity) who were treated at the Oncology Hospital of Centro Médico Nacional Siglo XXI in Mexico City from January 2012 to December 2016 were included in the study. It is a retrospective study with a duration of four years. Clinical data were collected from the medical records, which included sex, age, tumor location, initial resectability, reason for unresectability, initial tumor size, and mitotic rate. In the case of unresectable disease, patients who were evaluated by medical oncology and who had received treatment with 400 mg of imatinib daily were evaluated. Results A total of 312 patients diagnosed with GIST were analyzed. One hundred thirty-one were men (42%) with a mean age of 57 years, and 181 were women (58%) with a mean age of 59 years. The most frequent anatomical location was the stomach (n=185, 59.2%). At the time of diagnosis, 210 patients (67.3%) presented with resectable disease, while n=102 patients (32.7%) had unresectable disease. A total of 102 patients with unresectable disease received therapy with 400 mg of imatinib per day. Sixteen patients (15.7%) presented a reduction in tumor dimensions and underwent surgery. Conclusion The study highlights the importance of complete surgical resection and the potential benefit of neoadjuvant imatinib therapy in converting unresectable to resectable disease. The results suggest that imatinib can be effective in converting unresectable GISTs to resectable ones, allowing for a complete resection to be performed and obtaining an R0 resection in 93.7% of these cases.

Alterations in pharmacogenetic genes and their implications for imatinib resistance in Chronic Myeloid Leukemia patients from an admixed population.

Imatinib is the tyrosine kinase inhibitor used as the gold standard for the treatment of Chronic Myeloid Leukemia. However, about 30% of patients do not respond well to this therapy. Variants in drug administration, distribution, metabolism and excretion (ADME) genes play an important role in drug resistance especially in admixed populations. We investigated 129 patients diagnosed with Chronic Myeloid Leukemia treated with imatinib as first choice therapy. The participants of the study are highly admixed, populations that exhibit genetic diversity and complexity due to the contributions of multiple ancestral groups. Thus, the aim of this work was to investigate the association of 30 SNVs in genes related to response to treatment with Imatinibe in CML. Our results indicated that for the rs2290573 of the ULK3 gene, patients with the recessive AA genotype are three times more likely to develop resistance over time (secondary resistance) (p = 0.019, OR = 3.19, IC 95%= 1.21-8.36). Finally, we performed interaction analysis between the investigated variants and found several associations between SNVs and secondary resistance. We concluded that the variant rs2290573 of the ULK3 gene may be relevant for predicting treatment response of CML with imatinib, as well as possible treatment resistance. The use of predictive biomarkers is an important tool for therapeutic choice of patients, improving their quality of life and treatment efficacy.

Spirooxadiazoline-oxindoles derived from imatinib show antimyeloproliferative potential in K562 cells.

Imatinib mesylate was the first representative BCR-ABL1 tyrosine kinase inhibitor (TKI) class for the treatment of chronic myeloid leukemia. Despite the revolution promoted by TKIs in the treatment of this pathology, a resistance mechanism occurs against all BCR-ABL1 inhibitors, necessitating a constant search for new therapeutic options. To develop new antimyeloproliferative substances, we applied a medicinal chemistry tool known as molecular hybridization to design 25 new substances. These compounds were synthesized and biologically evaluated against K562 cells, which express BCR-ABL1, a constitutively active tyrosine kinase enzyme, as well as in WSS-1 cells (healthy cells). The new compounds are conjugated hybrids that contain phenylamino-pyrimidine-pyridine (PAPP) and an isatin backbone, which are the main pharmacophoric fragments of imatinib and sunitinib, respectively. A spiro-oxindole nucleus was used as a linker because it occurs in many compounds with antimyeloproliferative activity. Compounds 2a, 2b, 3c, 4c, and 4e showed promise, as they inhibited cell viability by between 45% and 61% at a concentration of 10 µM. The CC50 of the most active substances was determined to be within 0.8-9.8 µM.

The Screening of microRNAs in Chronic Myeloid Leukemia: A Clinical Evaluation.

Chronic myeloid leukemia (CML) is a type of leukemia whose main genetic marker is the reciprocal translocation that leads to the production of the BCR::ABL1 oncoprotein. The expression of some genes may interfere with the progression and development of leukemias. MicroRNAs are small non-coding RNAs that have the potential to alter the expression of some genes and may be correlated with some types of leukemia and could be used as biomarkers in the diagnosis and prognosis of patients. Therefore, this project carried out an analysis of microRNA-type plasma biomarkers in patients with chronic myeloid leukemia at unique points, including follow-up analysis of patients from the Erasto Gaertner Hospital. 35 microRNAs were analyzed in different cohorts. Inside those groups, 70 samples were analyzed at unique points and 11 patients in a follow-up analysis. Statistically different results were found for microRNA-7-5p, which was found to be upregulated in patients with high expression of the BCR::ABL1 transcript when compared to healthy controls. This microRNA also had evidence of behavior related to BCR::ABL1 when analyzed in follow-up, but strong evidence was not found. In this way, this work obtained results that may lead to manifestations of a relationship between miR-7-5p and chronic myeloid leukemia, and evaluations of possible microRNAs that are not related to this pathology.

Bayesian analysis of the effect of exosomes in a mouse xenograft model of chronic myeloid leukemia.

The aim of this work is to estimate the effect of Imatinib, exosomes, and Imatinib-exosomes mixture in chronic myeloid leukemia (CML). For this purpose, mathematical models based on Gompertzian and logistic growth differential equations were proposed. The models contained parameters representing the effects of the three components on CML proliferation. Parameters estimation was performed under the Bayesian statistical approach. Experimental data reported in the literature were used, corresponding to four trials of a human leukemia xenograft in BALB/c female rats over a period of forty days. The models were fitted to the following growth dynamics: normal tumor growth, growth with exosomes, growth with Imatinib, and growth with exosomes-Imatinib mixture. For the proposed logistic growth model, it was determined that when using Imatinib treatment the growth rate is 0.93 (95% CrI: 84.33-99.64) slower and reduces the tumor volume to approximately 10% (95% CrI : 8.67-10.81). In the presence of exosome treatment, the growth rate is 0.83 (95% CrI: 1.52-16.59) faster and the tumor volume is expanded by 40% (95% CrI: 25.36-57.28). Finally, in the presence of Imatinib-exosomes mixture treatment, the growth rate is 0.82 (95% CrI: 76.87-88.51) slower and the tumor volume is reduced by 95% (95% CrI: 86.76-99.85). It is concluded that the presence of exosomes partially inactivates the effect of the Imatinib drug on tumor growth in a mouse xenograft model.

Impact of Imatinib on reducing the painful crisis in patients with sickle cell disease.

INTRODUCTION: Sickle cell disease (SCD) is a common hemoglobinopathy worldwide that causes painful crises and hospitalization of patients. These attacks decrease survival and cause chronic end-organ damage in these patients. HYPOTHESIS: For this reason, finding new treatment approaches could be helpful. METHOD: In this study, Imatinib was applied as a mast cell inhibitor to reduce pain crises in these patients. Seven patients resistant to hydroxyurea and folic acid treatment and who had at least four painful crises per year with hospitalization were enrolled in this study with treatment with Imatinib (100 mg, twice daily). Subsequently, the number and duration of hospitalizations, analgesic requirement, the severity of chronic pain, and changes in the hematological parameters of these patients were evaluated before and after the treatment. RESULTS: The data showed that the total number of hospitalizations and the entire duration of hospitalizations were reduced 16 times after treatment with Imatinib, without apparent changes in hematological parameters. Also, the demand for pethidine, tramadol, and nonsteroidal anti-inflammatory drugs (NSAIDs) was reduced in all patients. The average reduction in chronic pain was over 70%. CONCLUSION: This study demonstrates that treatment with Imatinib in patients with SCD or sickle cell anemia (SCA) may be a suitable therapeutic option for reducing painful crises.

Peripheral lymphocyte subsets as predicting factors for molecular recurrence after imatinib discontinuation in a phase 2 imatinib discontinuation trial in patients with chronic myeloid leukemia.

INTRODUCTION: Treatment-free remission (TFR) is successful in half of the patients with chronic myeloid leukemia who discontinue Imatinib (IM) after sustained molecular response. METHODS: In a prospective trial, we used pioglitazone for 3 months before stopping IM in 30 patients. Percentages of peripheral blood lymphocyte subsets were assessed before and after treatment. The relation of these data with duration of IM treatment and TRF were examined. RESULTS: The median time of IM treatment was 117.6 months. After discontinuation, 11 patients had molecular recurrence after 5.2 months (2.4 - 30). The observation time for those remaining in TFR was 46 (26 - 56) months. The independent factors for the maintenance of TFR were the duration of IM treatment and the percentage of double-positive T cells at IM stop. CONCLUSION: A longer treatment with imatinib was associated with a longer TFR after discontinuation. Pioglitazone could act as an immunomodulator, increasing DP T cells which may contribute to prevent relapse.

Genetic alterations in the BCR-ABL1 fusion gene related to imatinib resistance in chronic myeloid leukemia.

Use of the potent tyrosine kinase inhibitor imatinib as the first-line treatment in chronic myeloid leukemia (CML) has decreased mortality from 20% to 2%. Approximately 30% of CML patients experience imatinib resistance, however, largely because of point mutations in the kinase domain of the BCR-ABL1 fusion gene. The aim of this study was to use next-generation sequencing (NGS) to identify mutations related to imatinib resistance. The study included 22 patients diagnosed with CML and experiencing no clinical response to imatinib. Total RNA was used for cDNA synthesis, with amplification of a fragment encompassing the BCR-ABL1 kinase domain using a nested-PCR approach. Sanger and NGS were applied to detect genetic alterations. HaplotypeCaller was used for variant calling, and STAR-Fusion software was applied for fusion breakpoint identification. After sequencing analysis, F311I, F317L, and E450K mutations were detected respectively in three different participants, and in another two patients, single nucleotide variants in BCR (rs9608100, rs140506, rs16802) and ABL1 (rs35011138) were detected. Eleven patients carried e14a2 transcripts, nine had e13a2 transcripts, and both transcripts were identified in one patient. One patient had co-expression of e14a2 and e14a8 transcripts. The results identify candidate single nucleotide variants and co-expressed BCR-ABL1 transcripts in cellular resistance to imatinib.

SEOM-GEIS clinical guideline for gastrointestinal stromal tumors (2022).

Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin, and a paradigmatic model for a successful rational development of targeted therapies in cancer. The introduction of tyrosine kinase inhibitors with activity against KIT/PDGFRA in both localized and advanced stages has remarkably improved the survival in a disease formerly deemed resistant to all systemic therapies. These guidelines are elaborated by the conjoint effort of the Spanish Society of Medical Oncology (SEOM) and the Spanish Sarcoma Research Group (GEIS) and provide a multidisciplinary and updated consensus for the diagnosis and treatment of GIST patients. We strongly encourage that the managing of these patients should be performed within multidisciplinary teams in reference centers.

Betulinic Acid-Brosimine B Hybrid Compound Has a Synergistic Effect with Imatinib in Chronic Myeloid Leukemia Cell Line, Modulating Apoptosis and Autophagy.

Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by the formation of the BCR-ABL (breakpoint cluster region-Abelson) oncoprotein. As many patients display therapeutic resistance, the development of new drugs based on semisynthetic products represents a new potential therapeutic approach for treating the disease. In this study, we investigated the cytotoxic activity, possible mechanism of action of a hybrid compound of betulinic acid (BA) and brosimine B in CML cell lines that are sensitive (K-562) and resistant (K-562R) to imatinib, in addition to evaluating lower doses of imatinib in combination with the hybrid compound. The effects of the compound, and its combination with imatinib, on apoptosis, cell cycle, autophagy and oxidative stress were determined. The compound was cytotoxic in K-562 (23.57 ± 2.87 µM) and K-562R (25.80 ± 3.21 µM) cells, and a synergistic effect was observed when it was associated with imatinib. Apoptosis was mediated by the caspase 3 and 9 intrinsic pathway, and cell cycle evaluation showed arrest at G0/G1. In addition, the hybrid compound increased the production of reactive oxygen species and induced autophagy by increasing LC3II and Beclin-1 mRNA levels. Results suggest that this hybrid compound causes the death of both imatinib-sensitive and -resistant cell lines and may hold potential as a new anticancer treatment against CML.

Real-world Imatinib Mesylate Treatment in Patients with Chronic Myeloid Leukemia: The Importance of Molecular Monitoring and the Early Molecular Response.

INTRODUCTION: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the Philadelphia (Ph) chromosome. After the introduction of imatinib mesylate (IM) in 2000, the natural history of the disease changed. Data on the treatment of CML with IM are from randomized clinical trials. Establishing whether these results can be reproduced or if caution is needed when extrapolating data to the general population with CML is essential. OBJECTIVES: To evaluate the molecular response (MR) in patients with chronic-phase CML (CML-CP) not included in clinical studies and correlate them with the responses obtained in clinical trials. METHODS: Between January 2007 and January 2017, 227 patients newly diagnosed with CML-CP treated with IM as first-line treatment were included. This study is an observational, retrospective, and single-center study. RESULTS: At a median follow-up time of 7.3 years, 60.3% of the 227 patients who started IM were still on IM. Early molecular response (EMR) at 3 and 6 months was achieved by 74.2% and 65%, respectively. The median time to a MMR was nine months. The MR4.0 and MR4.5 were 67.2% and 51.1%, respectively. The overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) of the patients who exclusively used IM were 91%, 91%, and 85.1%, respectively. CONCLUSION: The results presented are similar to those described in prospective and randomized trials, demonstrating that the outcomes are reproducible in the real world. EMR at 3 and 6 months reflects better long-term responses, including higher rates of deeper molecular responses. Considering treatment costs, the absence of literature evidence of an impact on overall survival demonstrated by first-line second-generation tyrosine kinase inhibitors (TKIs), and the global OS of 85.8%, imatinib mesylate (IM) is still an excellent therapeutic option.

Pro-adherence complementary audiovisual educational intervention model for chronic myeloid leukemia patients treated with imatinib mesylate.

BACKGROUND: Imatinib mesylate (IM) treatment adherence is a challenge, especially in an economic-social population neglected from developing countries. OBJECTIVE: To create a new complementary audiovisual educational intervention model to improve IM treatment adherence of CML patients. METHODS: Two adherence verification methods were applied before and after intervention: modified Morisky-Green test and molecular responses (BCR-ABL transcripts quantification). Adherence estimates were calculated using univariate and multivariate component analysis (MCA) for the socio-demographic and clinical characteristics of patients. RESULTS: Modified Morisky-Green test results demonstrated a substantial increase of CML patient adherence from 23% (pre-film) to 65% (post-film). Greater improvement was obtained for patients presenting major molecular response (MMR) from 38% (pre-film) to 60% (post-film). Although slight gain for complete molecular response (CMR) from 23% (pre-film) to 26% (post-film) was achieved, it represents a total tumour regression. MCA identified that females <50 years-old, using less than two medications (no disease associated) and CMR condition were the most benefited with intervention. CONCLUSION: Audiovisual educational intervention was an effective complementary pro-adherence model, activating patient memory and improving IM treatment adherence. Although this intervention shows effective, not all patients responded as expected, being necessary a combination of educational and clinical interventions to improve IM adherence.

Volumetric dried blood microsampling for monitoring imatinib mesylate therapy: Method development and clinical application in patients with chronic myeloid leukemia.

Chronic Myeloid Leukemia (CML) is a hematologic neoplasia, characterized as a proliferative disease of the hematopoietic system. Imatinib mesylate (IM), a selective tyrosine kinase inhibitor, is considered a first-line therapy for CML, indicated for both adult and pediatric patients presenting the Philadelphia chromosome (Ph+). However, patients in treatment with IM may show different responses due to interindividual pharmacokinetic variability. Therapeutic drug monitoring should be routinely performed to identify treatment response profile, adherence to treatment, or possible drug interactions, thus supporting better treatment management. Volumetric absorptive microsampling (VAMS) are innovative devices for blood collection whose advantages include the possibility of home collection by the patient or at the physician's office. The assay was fully validated according to bioanalytical validation guidelines. Estimated plasma concentrations of IM were not statistically different between groups according to adherence (p = 0.15), with median of 789 ng ml-1 in the group with some level of non-adherence versus 1141.9 ng ml-1 in the group with adherence, classified with the Morisky-Green questionnaire. This study included 33 patients with CML in treatment with IM. These patients answered socioeconomic, sociodemographic, and adherence profile (Morisky-Green) questionnaires. Patients also received instructions for home blood collection with VAMS devices. Afterwards, the samples were analyzed by LC-MS/MS. The mean age of the patients was 52 years, 84.8% were ingesting doses of 400 mg/day and the majority were male (69.7%). IM and its metabolite NIM were extracted from VAMS with an aqueous solution with 0.1% formic acid, followed by protein precipitation with acetonitrile. The methodology developed in this study was satisfactory for the determination of IM and NIM in VAMS and can be used in hospital and office routines for the therapeutic monitoring of patients with CML.

Imatinib en el tratamiento de pacientes con tumor del estroma gastrointestinal / Imatinib in the Treatment of Patients With Gastrointestinal Stromal Tumor

Introducción. Los tumores del estroma gastrointestinal (GIST) son neoplasias de tejido blando (sarcomas) originados en el sistema gastrointestinal (células intersticiales de Cajal). Se presentan mayormente en el estómago y el intestino delgado. La introducción del imatinib en el tratamiento ha cambiado el pronóstico de esta enfermedad. Objetivo. Describir las características clínicas, biológicas y la respuesta al tratamiento con imatinib de pacientes bolivianos con GIST. Material y métodos. Estudio descriptivo transversal de tipo retrospectivo de pacientes con diagnóstico de GIST (n=9) remitidos entre marzo de 2012 a julio de 2022. Se recopiló y analizó datos demográficos, clínicos y laboratoriales de pacientes con estudio imnunohistoquímica positivos para GIST (CD117, CD34, mutación PDGFRA) que posterior a cirugía recibieron tratamiento con imatinib dentro del programa asistencial GIPAP. Se consideró criterios SWOG y signos de desaparición del tumor para evaluar la respuesta y remisión completa. Resultados. La media de edad de los pacientes (4 mujeres, 5 varones) fue 56 años. Los sitios primarios del GIST fueron el estómago e intestino, 56 % de pacientes presentó tumor >10 cm de diámetro, y 78 % metástasis (peritoneo e hígado). Todos los pacientes alcanzaron remisión completa tras el primer año de tratamiento. Dos pacientes presentaron recaída después de abandonar el tratamiento tras 4 y 8 años respectivamente; uno de ellos reflejó una segunda remisión tras reiniciar tratamiento. Conclusiones. Los datos epidemiológicos son similares a los reportados en otros trabajos,empero un diagnóstico en estadios avanzados y abandono del tratamiento aun tratándose de un programa de tratamiento gratuito constituyen variables diferenciales. Más allá del desconocimiento, la negligencia e irresponsabilidad de los pacientes resulta preocupante.

Introduction. Gastrointestinal stromal tumor (GIST) are mesenchymal neoplasms (sarcomas) in the gastrointestinal tract (interstitial cells of Cajal). It occurs mostly in the stomach and small intestine. The introduction of imatinib for GIST treatment has changed the prognosis of this disease. Objective. To describe the clinical and biological characteristics, and the treatment response to imatinib in Bolivian patients with GIST. Material and methods. Retrospective descriptive cross-sectional study of patients with GIST(n=9) referred between March 2012 and July2022. It was collected demographic, clinical, and laboratory data of patients with immunohistochemical study positive for GIST (CD117, CD34, PDGFRA mutation) who after surgery received treatment with imatinib within the GIPAP program. SWOG criteria and signs of tumor vanishing were considered to assess treatment response and complete remission. Results. The mean age of patients (4 women, 5 men) was 56 years. Primary sites of GIST were the stomach and intestine, 56% of patients presented tumor >10 cm in diameter, and 78% metastasis (peritoneum and liver). All patients achieved complete remission after the first year of treatment. Two patients presented relapse after discontinuing treatment, with a follow-up 4 and 8 years respectively; one of them reflected a second remission after restarting treatment. Conclusions. These epidemiological data are similar to those reported in other studies, however a late-stages diagnosis and treatment dropout, even when trying a free treatment program, constitute differential variables. Beyond misinformation, patients' neglect and irresponsibility is worrying.

Ketoconazole Reverses Imatinib Resistance in Human Chronic Myelogenous Leukemia K562 Cells.

Chronic myeloid leukemia (CML) is a hematologic disorder characterized by the oncogene BCR-ABL1, which encodes an oncoprotein with tyrosine kinase activity. Imatinib, a BCR-ABL1 tyrosine kinase inhibitor, performs exceptionally well with minimal toxicity in CML chemotherapy. According to clinical trials, however, 20-30% of CML patients develop resistance to imatinib. Although the best studied resistance mechanisms are BCR-ABL1-dependent, P-glycoprotein (P-gp, a drug efflux transporter) may also contribute significantly. This study aimed to establish an imatinib-resistant human CML cell line, evaluate the role of P-gp in drug resistance, and assess the capacity of ketoconazole to reverse resistance by inhibiting P-gp. The following parameters were determined in both cell lines: cell viability (as the IC50) after exposure to imatinib and imatinib + ketoconazole, P-gp expression (by Western blot and immunofluorescence), the intracellular accumulation of a P-gp substrate (doxorubicin) by flow cytometry, and the percentage of apoptosis (by the Annexin method). In the highly resistant CML cell line obtained, P-gp was overexpressed, and the level of intracellular doxorubicin was low, representing high P-gp activity. Imatinib plus a non-toxic concentration of ketoconazole (10 µM) overcame drug resistance, inhibited P-gp overexpression and its efflux function, increased the intracellular accumulation of doxorubicin, and favored greater apoptosis of CML cells. P-gp contributes substantially to imatinib resistance in CML cells. Ketoconazole reversed CML cell resistance to imatinib by targeting P-gp-related pathways. The repurposing of ketoconazole for CML treatment will likely help patients resistant to imatinib.

Modelo de negocios en la salud e investigación clínica: la cuestión de las patentes en la ciencia

Propósito/Contexto. En este artículo se exponen las tendencias y las características de un modelo de negocio que la industria farmacéutica ha venido imponiendo con la ayuda del desarrollo de nuevos medicamentos a los que se les cuestiona su "altura inventiva" y que, a pesar de ello, les son otorgadas las patentes de segunda generación, considerándose esta una práctica abusiva y que favorece el incremento de los precios de estas innovaciones en el mercado. Metodología/Enfoque. Mediante la presentación de un caso: "la declaración de interés público del medicamento imatinib en Colombia" se identifican las estrategias y las maniobras anticompetitivas que dejan pocas oportunidades a los Estados para distribuir de manera equitativa los beneficios de las invenciones de medicamentos. En el análisis bioético del caso se caracteriza el dilema como tipo práctico, esto es, aquel en el que persisten requerimientos morales en tensión con un interés privado, en esta ocasión, entre la salud pública, por un lado, y la propiedad intelectual como política internacional, por el otro. Resultados/Hallazgos. La tesis es que este es un problema transfronterizo sintomático de la falta de justicia global en razón a la suplantación del sentido de "bien común" que ha acallado los vínculos sociales, solidarios y colaborativos. Discusión/Conclusiones/Contribuciones. Se insta a un consenso sobre las bases sociales y el respeto de la dignidad de las personas, un mandato de solidaridad superior en beneficio del bien común y el "florecimiento de la humanidad".

Objetivo/Contexto. Este artigo expõe as tendências e características de um modelo de negócio que a indústria farmacêutica tem vindo a impor com a ajuda do desenvolvimento de novos medicamentos cujo nível de inventividade é questionado. Como resultado, é-lhes concedidas patentes de segunda geração, o que é considerado uma prática abusiva e favorece o aumento dos preços destes inovações no mercado. Metodologia/Abordagem. Através da apresentação de um caso "A Declaração de Interesse Público da droga Imatinib na Colômbia", são identificadas estratégias e manobras anticompetitivas, que deixam poucas oportunidades para os Estados distribuírem os benefícios das invenções de drogas de forma equitativa. Na análise bioética do caso, o dilema é especificado como sendo prático, ou seja, um dilema em que os requisitos morais persistem em tensão com um interesse privado, neste caso, entre a saúde pública, por um lado, e a propriedade intelectual como uma política internacional, por outro. Resultados/Descobertas. A tese é que se trata de um problema transfronteiriço sintomático de falta de justiça global devido à suplência de um senso o bem comum que silenciou os laços sociais de solidariedade e colaboração. Discussão/Conclusões/Contribuições. Apela a um consenso sobre os fundamentos sociais e o respeito pela dignidade das pessoas, um mandato de maior solidariedade em benefício do bem comum, o florescimento da humanidade.

Purpose/Background. This article exposes the tendencies and characteristics of a business model that the pharmaceutical industry has been imposing with the help of the development of new drugs whose degree of inventiveness is questioned. As a result, they are granted second generation patents, which is considered an abusive practice that favors the increase of the prices of these innovations in the market. Methodology/Approach. Through the presentation of a case "The Declaration of Public Interest of the Drug Imatinib in Colombia", anti-competitive stra-tegies and maneuvers are identified, which leave few opportunities for the States to distribute the benefits of drug inventions in an equitable manner. In the bioethical analysis of the case, the dilemma is specified as a practical one, that is, one in which moral requirements persist in tension with a private interest, in this case, between public health on the one hand, and intellectual property as an international policy, on the other. Results/Findings. The thesis is that this is a cross-border problem symptomatic of a lack of global justice due to the supplanting of the sense of the common good that has silenced social bonds of solidarity and collaboration. Discussion/Conclusions/Contributions. It calls for a consensus on social foundations and respect for the dignity of persons, a higher mandate of solidarity for the benefit of the common good, and the flourishing of humanity.

Reacción adversa a medicamento con signos cutáneos (erupción liquenoide) atribuibles a imatinib, y respuesta favorable al tratamiento con fototerapia UVB de banda angosta / Adverse drug reaction with skin signs (lichenoid rash) attributable to imatinib, and favorable response to treatment with narrowband UVB phototherapy

Resumen El imatinib es un agente antineoplásico que actúa como inhibidor de la tirosina-cinasa. Los efectos adversos cutáneos son, en general, leves y autolimitados. Dentro de estos, la erupción liquenoide es infrecuente y suele mejorar sólo con tratamiento tópico. Presentamos el caso de una paciente con erupción liquenoide por imatinib refractaria al tratamiento con corticoides tópicos, con respuesta favorable a terapia de luz ultravioleta B de banda estrecha. No existen casos publicados a la fecha en la literatura de erupción liquenoide por imatinib tratada con fototerapia.

Abstract Imatinib is an antineoplastic agent that acts as a tyrosine kinase inhibitor. Cutaneous adverse effects are generally mild and self-limited. The lichenoid eruption due to imatinib is rare. It usually improves just with topical treatment. We present the case of a patient with a lichenoid reaction due to imatinib, refractory to treatment with topical corticosteroids, with a favorable response to narrow-band ultraviolet B phototherapy. There are no published cases to date in the literature of lichenoid eruption due to imatinib treated with phototherapy.

Avances en tumores del estroma gastrointestinal: ¿hacia dónde vamos?

Gastrointestinal Stromal Sarcomas (GIST) are mesenchymal neoplasms whose incidence accounts for 1-2% of digestive tumors, being located in the stomach (55-60%) and small intestine (30%). The advances in its knowledge and management succeeded in the last years have being spectacular. This review aims to summarize the most important of them for surgeons. We identified four areas of interest: molecular oncology, laparoscopic approach, management of GIST located at unusual locations, and management of advanced GIST. Advances in the field of molecular oncology lead to the discovery of new oncogenic mutations making the term Wil Type GIST obsolete. Moreover, these advances allow for the development of 2 new drugs: Avapritinib and Ripretinib, that added to the previous 3 commercially available drugs (imatinib, sunitinib and regorafenib) make possible the management of GIST with resistant mutations. The principles of the surgical management of primary GIST are well stablished which laparoscopic approach must accomplish. This approach is limited by 2 main factors: location and size. The diagnosis of GIST in unusual locations as esophagus, duodenum, rectum of out of the gastrointestinal tract (EGIST), implies an extraordinary therapeutic challenge, being imperative to manage them by surgeons and oncologist among others in the setting of a multidisciplinary team. The management of advanced/metastatic GIST has changed in a revolutionary fashion because surgery is now part of its treatment as adjuvant to tyrosine kinase inhibitors.

Los tumores del estroma gastrointestinal (GIST) suponen el 1-2% de los tumores digestivos, siendo su localización más frecuente el estómago (55-60%) y el intestino delgado (30%). Los avances más importantes sucedidos en los últimos años se centran en cuatro áreas: biología molecular, abordaje quirúrgico laparoscópico, manejo técnico del GIST en localizaciones inusuales y tratamiento e integración de la cirugía en el manejo del GIST avanzado. Los avances en el conocimiento de la biología molecular del GIST han dado lugar a la progresiva identificación de nueva mutaciones oncogénicas que hacen del concepto wild type obsoleto. Estos avances han permitido el desarrollo de dos nuevos fármacos, avapritinib y ripretinib, lo que permite el tratamiento de pacientes con mutaciones resistentes a las tres líneas terapéuticas clásicas. El tratamiento quirúrgico del GIST se rige por unos principios técnicos bien establecidos que el abordaje laparoscópico debe cumplir, abordaje que queda limitado por dos factores clave: localización y tamaño. El GIST de localización infrecuente (esófago, duodeno o recto, o extradigestivo) supone un reto terapéutico. Estos pacientes deben ser manejados en un contexto multidisciplinario. La cirugía queda integrada en el manejo del GIST avanzado, considerándose como adyuvante a los inhibidores de la tirosina cinasa.

Hybrids of Imatinib with Quinoline: Synthesis, Antimyeloproliferative Activity Evaluation, and Molecular Docking.

Imatinib (IMT) is the first-in-class BCR-ABL commercial tyrosine kinase inhibitor (TKI). However, the resistance and toxicity associated with the use of IMT highlight the importance of the search for new TKIs. In this context, heterocyclic systems, such as quinoline, which is present as a pharmacophore in the structure of the TKI inhibitor bosutinib (BST), have been widely applied. Thus, this work aimed to obtain new hybrids of imatinib containing quinoline moieties and evaluate them against K562 cells. The compounds were synthesized with a high purity degree. Among the produced molecules, the inhibitor 4-methyl-N3-(4-(pyridin-3-yl)pyrimidin-2-yl)-N1-(quinolin-4-yl)benzene-1,3-diamine (2g) showed a suitable reduction in cell viability, with a CC50 value of 0.9 µM (IMT, CC50 = 0.08 µM). Molecular docking results suggest that the interaction between the most active inhibitor 2g and the BCR-ABL1 enzyme occurs at the bosutinib binding site through a competitive inhibition mechanism. Despite being less potent and selective than IMT, 2g is a suitable prototype for use in the search for new drugs against chronic myeloid leukemia (CML), especially in patients with acquired resistance to IMT.