Research status and prospect of immunotherapy in gastrointestinal stromal tumors / 中华胃肠外科杂志

Tyrosine kinase inhibitors (TKI) significantly reduce the risk of recurrence and metastasis and prolong survival in patients with gastrointestinal stromal tumors (GIST), but drug resistance is often inevitable. Immunotherapy has been proven effective in multiple solid tumors, but the efficacy in GIST is unclear. The efficacy of immunotherapy depends on the tumor microenvironment (TME). Tumor-infiltrating immune cells and immune checkpoints are important components of TME, which not only participate in the regulation of tumor immune response but are also the key target of immunotherapy. A comprehensive analysis of them can clarify the mechanism of tumor immune escape. This review found that there are abundant tumor-infiltrating immune cells in GIST, which play an important role in tumor immune surveillance and escape. Although early clinical studies have shown that patients with GIST have a good tolerance to immunotherapy, the curative effect is not satisfactory. Therefore, how to select the responders of immunotherapy and coordinate the relationship between immunotherapy and TKIs is the key issue to be explored. At the same time, the gradual deepening of basic research and large sample prospective clinical trials will certainly provide more strategies for the application of immunotherapy in GIST.

Adherence to adjuvant with therapy imatinib in patients with gastrointestinal stromal tumor: a national multi-center cross-sectional study / 中华胃肠外科杂志

Objective: To analyze the current adherence to imatinib in patients with gastrointestinal stromal tumors (GIST) in China and its influencing factors. Methods: A cross-sectional survey was conducted. Study period: from October 1, 2020 to November 31, 2020. Study subjects: GIST patients taking imatinib who were diagnosed and treated in public tertiary level A general hospitals or oncology hospitals; those who had not been pathologically diagnosed, those who never received imatinib, or those who had taken imatinib in the past but stopped afterwards were excluded. The Questionnaire Star online surgery platform was used to design a questionnaire about the adherence to adjuvant imatinib therapy of Chinese GIST patients. The link of questionnaire was sent through WeChat. The questionnaire contained basic information of patients, medication status and Morisky Medication Adherence Scale. Results: A total of 2162 questionnaires from 31 provinces, autonomous regions, and municipalities were collected, of which 2005 were valid questionnaires, with an effective rate of 92.7%. The survey subjects included 1104 males and 901 females, with a median age of 56 (22-91) years old. Working status: 609 cases (30.4%) in the work unit, 729 cases (36.4%) of retirement, 667 cases of flexible employment or unemployment (33.3%). Education level: 477 cases (23.8%) with bachelor degree or above, 658 cases (32.8%) of high school, 782 cases (39.0%) of elementary or junior high school, 88 cases (4.4%) without education. Marital status: 1789 cases (89.2%) were married, 179 cases (8.9%) divorced or widowed, 37 cases (1.8%) unmarried. Two hundred and ninety-four patients (14.7%) had metastasis when they were first diagnosed, including 203 liver metastases, 52 peritoneal metastases, and 39 other metastases. One thousand eight hundred and sixty-nine patients underwent surgical treatment, of whom 1642 (81.9%) achieved complete resection. The median time of taking imatinib was 25 (1-200) months. Common adverse reactions of imatinib included 1701 cases (84.8%) of periorbital edema, 1031 cases (51.4%) of leukopenia, 948 cases (47.3%) of fatigue, 781 cases (39.0%) of nausea and vomiting, 709 cases (35.4%) of rash, and 670 cases (33.4%) of lower extremity edema. The score of the Morisky Medication Adherence Scale showed that 392 cases (19.6%) had poor adherence, 1023 cases (51.0%) had moderate adherence, and 590 cases (29.4%) had good adherence. Univariate analysis showed that gender, age, work status, economic income, residence, education level, marriage, the duration of taking medication and adverse reactions were associated with adherence to adjuvant imatinib therapy (all P<0.05). Multivariate analysis showed that female (OR=1.264, P=0.009), non-retirement (OR=1.454, P=0.001), monthly income ≤4000 yuan (OR=1.280, P=0.036), township residents (OR=1.332, P=0.005), unmarried or divorced or widowed (OR=1.362, P=0.026), the duration of imatinib medication >36 months (OR=1.478, P<0.001) and adverse reactions (OR=1.719, P=0.048) were independent risk factors for poor adherence to adjuvant imatinib. Among patients undergoing complete resection, 324 (19.7%) had poor adherence, 836 (50.9%) had moderate adherence, and 482 (29.4%) had good adherence. Meanwhile, 55 patients with good adherence (11.4%) developed recurrence after surgery, 121 patients with moderate adherence (14.5%) developed recurrence, 61 patients with poor adherence (18.8%) developed recurrence, and the difference was statistically significant (P=0.017). Conclusions: The adherence to adjuvant therapy with imatinib in Chinese GIST patients is relatively poor. Females, non-retirement, monthly income ≤4000 yuan, township residents, unmarried or divorced or widowed, the duration of imatinib medication >36 months, and adverse reactions are independently associated with poor adherence of GIST patients. Those with poor adherence have a higher risk of recurrence after surgery. Positive interventions based on the above risk factors are advocated to improve the prognosis of patients with GIST.

Definition of tumor rupture in gastrointestinal stromal tumor / 中华胃肠外科杂志

Tumor rupture is a common clinical event in the process of tumorigenesis, progression, diagnosis and treatment of gastrointestinal stromal tumor, which is closely associated with tumor recurrence, metastasis and poor prognosis. Tumor rupture may be associated with some intrinsic biological aggressiveness qualities, such as large tumor size, high mitotic count, and KIT exon 11 deletion mutations involving codons 557 and 558, and may be relatively more frequent with small intestine GIST and excellent response to imatinib neoadjuvant therapy resulting in tumor tissue rapid liquefacient and necrosis. The triggering factors involve sudden increase in abdominal pressure, external pressure, collision and improper surgical operation, etc. Tumor rupture is considered as an important risk factor of recurrence after macroscopically complete resection of tumor, and an indication for determining interval or even lifelong adjuvant therapy with imatinib according to guidelines. However, there is no consensus or universally accepted definition of tumor rupture, and, consequently, its incidence varies greatly across reported series and lacks detailed epidemiological data. Without pre-defined criteria, it is difficult to assess the clinical significance of rupture. We reviewed the relevant literature and international guidelines, and generally divided tumor rupture into spontaneous rupture and iatrogenic rupture. Based on the Oslo criteria, we proposed the following six definitions for tumor rupture: (1) tumor fracture or spillage; (2) blood-stained ascites; (3) gastrointestinal perforation at the tumor site; (4) microscopic infiltration of an adjacent organ; (5) intralesional dissection or piecemeal resection; (6) incisional biopsy. The following types of minor defects of tumor integrity should not be defined as rupture: (1) mucosal defects or spillage contained within the gastrointestinal lumen; (2) microscopic tumor penetration of the peritoneum or iatrogenic damage only to the serosa; (3) uncomplicated transperitoneal needle biopsy; (4) R1 resection. In addition, we further emphasize the importance of identifying risk factors of tumor rupture, prevention and positive intervention.

Modificación del abordaje quirúrgico en tumores estromales gástricos posterior a neoadyuvancia con Imatinib / Change of surgical approach in gastrointestinal stromal tumors after neoadyuvant therapy with Imatinib

Resumen Introducción: El tratamiento de los tumores estromales gastrointestinales (GIST) de alto riesgo es quirúrgico. Su resultado podría variar al usarse neoadyuvancia. Objetivo: Evaluar si el uso de la terapia neoadyuvante con imatinib puede cambiar el abordaje quirúrgico en los tumores estromales gastrointestinales de alto riesgo. Materiales y Métodos: Se realizó un análisis retrospectivo en el Hospital Clínic de Barcelona entre enero de 2002 y mayo de 2016. Resultados: Se obtuvo un total de 8 pacientes. La edad media fue 66,1 ± 13,3 años. La ubicación del tumor fue de 37,5% (3) en el tercio superior, el 50% (4) en el tercio medio y el 12,5% (1) en el tercio inferior. Debido a la clasificación de riesgo alto, la ubicación y/o la necesidad de resecciones multiviscerales, se indicó, previa evaluación comité oncológico, realizar terapia neoadyuvante. La mediana de tiempo de neoadyuvancia fue de 30 semanas. En el 100% (8) de los casos se logró un cambio de enfoque quirúrgico después de la utilización de imatinib. En todos los casos se realizó un resección local (7 laparoscópica y 1 endolaparoscópica) con márgenes negativos La biopsia posoperatoria mostró un promedio de 51,2% de reducción del tamaño tumoral inicial, lo que resultó en una diferencia estadística (p < 0,01) con el tamaño inicial de las lesiones. Durante el seguimiento, tanto la sobrevida relacionada al tumor como la global, fue de un 100%. Conclusión: La terapia neoadyuvante podría cambiar el abordaje quirúrgico de los pacientes con GIST gástrico de riesgo intermedio o alto mediante la reducción del tamaño tumoral, permitiendo realizar cirugías más económicas y logrando resultados oncológicos adecuados.

Introduction: The treatment of high-risk gastrointestinal stromal tumors (GIST) is surgical. Results may change when using neoadjuvant. Objetive: To evaluated if the use of neoadjuvant therapy with imatinib can change the surgical approach in high risk gastrointestinal stromal tumors (GIST). Materials and Methods: A retrospective analysis was performed from a prospective collected database in Hospital Clinic of Barcelona between January 2002 and May 2016. Results: A total of 8 patients were analyzed with a mean age of 66.1 ± 13.3 years. The tumor location was upper third 37.5% (3) cases, 50% (4) in the middle third and 12.5% (1) in lower third. Because of high risk classification, location and the need of multivisceral resections, neoadjuvant therapy was indicated. The median time of neoadjuvant therapy was 30 weeks. In 87.5% (7) cases a change of surgical approach was achieved after the use of imatinib. In 100% of our series laparoscopic wedge resection was performed achieving negative margins of resection. The postoperative biopsy showed 51.2% of reduction of initial tumor size, resulting in statistical difference (p < 0.01). All patients are alive and 100% of tumor related survival was achieved. Conclusion: Neoadjuvant therapy maybe can change the surgical approach of patients with high-intermediate risk gastric GIST by reducing tumor size. This response also eventually can achieve optimal oncological outcome.

Tumores del estroma gastrointestinal: Análisis de 40 casos / Gastrointestinal stromal tumors. Analysis of 40 cases

Los tumores del estroma gastrointestinal representan menos del 3% de los tumores digestivos. Se localizan principalmente en el estómago y el intestino delgado. El tratamiento radical es la resección quirúrgica. Cuando son inoperables o diseminados la administración de imatinib es el tratamiento de elección. La finalidad de este estudio retrospectivo fue describir las características de los pacientes con tumores del estroma gastrointestinal atendidos en nuestra institución en el período 2000-2015. Fueron analizados los casos de 40 pacientes consecutivos con diagnóstico de tumor del estroma gastrointestinal (edad media 58 años, rango 33-84). La supervivencia media a 5 años del total de pacientes fue 30.5%. Al diagnóstico, 30 (75%) tenían enfermedad localizada; de estos, 14 recibieron imatinib adyuvante y 15 seguimiento en observación. En este grupo, el intervalo libre de enfermedad fue 55 meses. En aquellos con enfermedad diseminada, el intervalo libre de progresión fue 30 meses.

Gastrointestinal stromal tumors represent less than 3% of all digestive tumors. They are primarily located in the stomach and the small intestine. The curative treatment is surgical resection. In the case of unresectable tumor or advanced disease, imatinib is the treatment of choice. The purpose of this retrospective study was to describe the characteristics of patients with gastrointestinal stromal tumors treated at our institution in the period 2000-2015. We analyzed 40 consecutive patients diagnosed with gastrointestinal stromal tumor (mean age 58-year old, range 33-84). The mean 5-year survival was 30.5%. At diagnosis, 30 patients had localized disease (75%); 14 of them received adjuvant imatinib and 15 follow-up on observation. In this group the disease-free interval was 55 months. In patients with advanced disease, the progression-free interval was 30 months.

Tumor del estroma gastrointestinal y trasplante renal / Gastrointestinal stromal tumor and renal transplant

El tumor estromal gastrointestinal (GIST) representa alrededor del 1% de todos los tumores digestivos y su aparición en pacientes trasplantados renales es infrecuente. Aproximadamente el 95% muestra tinción positiva para c-kit/CD117. DOG1 es un anticuerpo recientemente descrito que se sobre-expresa en los GIST, incluso en c-kit/ CD117 negativos. El diagnóstico preciso de GIST resulta imperativo, debido a la disponibilidad y la creciente eficacia de los inhibidores de la tirosina quinasa en estos tumores, incluso en el subgrupo c-kit/ CD117 negativo. Se presenta el caso de una mujer trasplantada renal inicialmente con GIST en intestino delgado y débil positividad para CD117 tratada con cirugía y recidiva tumoral a los tres años, pérdida de la expresión CD117 y tinción positiva para DOG1. Recibió tratamiento exitoso con imatimib sin presentar recaída tumoral durante un seguimiento de cinco años.

Gastrointestinal stromal tumor (GIST) accounts for nearly 1% of all gastrointestinal tumors. Its association with renal transplantation is not frequent. Approximately 95% of GIST show staining for CD177. DOG1 is a recently described monoclonal antibody that shows positivity even in the absence of CD177 staining. The diagnosis of GIST should be pursued because of the availability of very effective treatments with tyrosine-kinase inhibitors. Herein, we describe the case of a woman with renal transplant who presented a small bowel GIST and weak positivity for CD177, treated initially with surgery. Tumor recurrence was documented 3 years later and histopatology showed loss of CD177 staining and positivity for DOG1. She was treated with imatimib without further recurrence after five years of follow up.

Informe de evaluación científica basada en la evidencia disponible: tumor de estroma gastrointestina / Scientific evaluation report based on available evidence: gastrointestinal stromal tumor

INTRODUCCIÓN: Los tumores mesenquimatosos del tracto gastrointestinal más frecuentes son los del estroma gastrointestinal (GIST). Se localizan preferentemente en el estómago y el intestino delgado, aunque pueden desarrollarse en cualquier lugar del aparato digestivo e incluso fuera de él. Son originarios de células mesenquimales del tracto gastrointestinal que actúan como marcapasos del tubo digestivo, o de un precursor común de células a lo largo del intestino; desde el punto de vista molecular presentan mutaciones características y recurrentes en los genes KIT (75-80%), PDGFRA (5-8%). Son tumores raros, con una incidencia estimada de 1,5/100.000 habitantes /año. Existe mayor incidencia en hombres con localizaciones de estómago e intestino delgado, estimándose que la incidencia puede llegar a 2/100. TECNOLOGÍAS SANITARIAS ANALIZADAS: Imatinib, Sunitinib, Regorafenib. EFICACIA DE LOS TRATAMIENTOS: La evidencia encontrada indica que: -Imatinib probablemente no disminuye la mortalidad en tumores del estroma gastrointestinal operados. -Imatinib aumenta los efectos adversos grado 3 o 4. -Sunitinib probablemente disminuye la mortalidad en GIST avanzado que progresa tras tratamiento de primera línea con imatinib. -Sunitinib podría no asociarse a efectos adversos severos, pero la certeza de la evidencia es baja. -Regorafenib no disminuye la mortalidad. La certeza de la evidencia es moderada. -Regorafenib aumenta los efectos adversos grado 3 o 4. EVALUACIÓN ECONÓMICA: Existe gran incertidumbre alrededor de los resultados de las evaluaciones económicas del tratamiento con Imatinib en 1ra línea. En general, de los estudios encontrados se puede afirmar que no fueron todos concluyentes con respecto a su perfil de costo efectividad relacionándola directamente con el precio al que se pueda obtener el medicamento. En Chile, existen varias alternativas en el mercado de Imatinib por lo que se podrían lograr mejores precios que los mencionados en los estudios encontrados. Los estudios encontrados para Sunitinib en segunda línea al compararlo con Imatinib en segunda línea concluyen que Sunitinib es más caro y de menor eficacia que Imatinib. Cuando se compara Sunitinib en 2da línea contra tratamiento habitual, los estudios no son concluyentes entre sí, llegando a recomendarlos en algunos países por su relación de costo-efectividad o como en el caso de Canadá, recomendarlo a pesar de no ser costo-efectivo por convertirse en la única alternativa disponible de tratamiento para los que no responden a imatinib. Un solo estudio evaluó la costo-efectividad de Regorafenib en tercera línea luego del fracaso a Imatinib y Sunitinib, concluyendo que se recomienda el tratamiento, siempre y cuando la costoefectividad mejore, principalmente por el costo del medicamento. El impacto presupuestario esperado para el primer año es de $ 4.496 millones para Imatinib, $ 2.256 millones para Sunitinib y $ 4.101 millones para Regorafenib. CONCLUSIÓN: Para dar cumplimiento al artículo 28° del Reglamento que establece el proceso destinado a determinar los diagnósticos y tratamientos de alto costo con Sistema de Protección Financiera, según lo establecido en los artículos 7°y 8° de la ley N°20.850, aprobado por el decreto N°13 del Ministerio de Salud, se concluye que el presente informe de evaluación se considera favorable, de acuerdo a lo establecido en el Título III. de las Evaluaciones Favorables de la Norma Técnica N° 0192 de este mismo ministerio.

Tumores del estroma gastrointestinal: revisión de nuestra experiencia / Surgery of gastrointestinal stromal tumors: review of our experience in the last five years

Objective: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Surgical resection is the standard treatment for localized primary GISTs. The aim of the study is to present our 5-year surgical experience, as well as the results obtained in terms of survival and disease progression. Material and Method: We conducted a descriptive, retrospective study of primary GISTs treated in our center between 2009-2013. We analyze the most relevant variables, criteria of risk of progression according Fletcher's classification from National Institutes of Health and the Miettinem's classification from the Armed Forces Institute of Pathology, as well as analysis of relapse-free survival (RFS) with Kaplan-Meier survival curves. Results: We present a series of 30 patients. Mean age 65 years (40-84 years). The most common location was the stomach (n = 14, 46.6 percent). The surgery was R0 in 23 cases of 30. The mean tumor diameter was 5.3 cm (0.5-18). 14 patients received adjuvant treatment with Imatinib. After an average follow-up of 31.2 months (6-62 months), it was found relapse in 4 patients, progression and exitus in 1, exitus in 3 and exitus in the immediate postoperative period in 1. RFS at one year was 96.7 percent, and 89.2 percent at 4 years. Mean survival time was 56.2 months (95 percent CI 51.8-60.6). Conclusion: The recommended attitude after radical surgery is follow-up. In selected patients with risk of relapse, adjuvant treatment with Imatinib delays the progression of the disease and increases the survival.

Objetivo: Los tumores del estroma gastrointestinal son las neoplasias mesenquimales más frecuentes del tubo digestivo. La resección quirúrgica es el tratamiento estándar en los GISTs primarios localizados. El objetivo del estudio es presentar nuestra experiencia quirúrgica en 5 años, así como los resultados obtenidos en cuanto supervivencia y progresión de la enfermedad. Material y Método: Serie de casos, estudio observacional descriptivo retrospectivo, que analiza los resultados obtenidos en cuanto al tratamiento quirúrgico de GIST primarios sometidos a resección quirúrgica en nuestro centro entre 2009-2013. Todas las intervenciones fueron realizadas por personal del Staff y dentro de los protocolos de las unidades de cirugía hepato-biliar y esófago-gástrica. Se analizan las variables de mayor relevancia, criterios de riesgo de progresión según la clasificación de Fletcher del National Institutes of Health y la clasificación de Miettinem del Armed Forces Institute of Pathology, así como análisis de la supervivencia libre de recaída (SLR) con curvas de Kaplan-Meier. Resultados: Presentamos una serie de 30 pacientes. Edad media de 65 años (40-84 años). La localización más frecuente fue estómago (n = 14, 46,6 por ciento). La cirugía fue R0 en 23 de los 30 pacientes. El diámetro tumoral medio fue de 5,3 cm (0,5-18, con una mediana de 4 cm. Catorce pacientes recibieron tratamiento adyuvante con Imatinib. Tras un seguimiento medio 31,2 meses (6-62 meses), se detectó recaída en 4 pacientes, progresión y exitus en 1, exitus en 3 y exitus en el postoperatorio inmediato en 1. La SLR al año fue del 96,7 por ciento, siendo del 89,2 por ciento a los 4 años. El tiempo medio de supervivencia fue de 56,2 meses (IC 95 por ciento 51,8-60,6). Conclusiones: La actitud recomendada tras una cirugía radical es el seguimiento. En pacientes seleccionados con riesgo de recaída el tratamiento adyuvante con Imatinib retrasa la progresión de la enfermedad y aumenta la supervivencia.

Subdural hematoma during therapy of gastro-intestinal stromal tumor [GIST] with Imatinib mesylate

Imatinib mesylate is a widely used tyrosine-kinase inhibitor [TKI] in chronic myeloid leukemia [CML] treatment. Imatinib has contributed to complete and prolong cytogenetic responses so that it is now the standard treatment of CML. Recently, Imatinib mesylate has shown a significantly prolonged progression-free survival and overall survival in metastatic and locally advanced c-Kit positive gastro-intestinal stromal tumors [GISTs] and more recently a prolonged disease-free survival in operated high risk GIST. Imatinib is a welltolerated treatment with few side effects mainly gastro-intestinal symptoms [nausea, vomiting and diarrhea], headaches, rash and periorbital edema. Hemorrhage incidents are rare in patients treated with Imatinib. They are more frequently seen in CML patients. Hemorrhage incidents in CML include in many cases upper gastro-intestinal [GI] tract bleeding and central nervous system bleeding in rare ones. In GIST patients treated with Imatinib, hemorrhage incidents are exclusively made of upper GI tract bleeding consecutive to tumor perforation or necrosis. In our observation, we present the case of a subdural hematoma occurring in a patient treated with adjuvant Imatinib for a high risk localized gastric GIST. No other case of subdural hematoma in GIST treated with Imatinib has been reported in literature

Imatinib mesylate-induced interstitial lung disease in a patient with prior history of Mycobacterium tuberculosis infection

No abstract available.

Fluid Retention Associated with Imatinib Treatment in Patients with Gastrointestinal Stromal Tumor: Quantitative Radiologic Assessment and Implications for Management

OBJECTIVE: We aimed to describe radiologic signs and time-course of imatinib-associated fluid retention (FR) in patients with gastrointestinal stromal tumor (GIST), and its implications for management. MATERIALS AND METHODS: In this Institutional Review Board-approved, retrospective study of 403 patients with GIST treated with imatinib, 15 patients with imaging findings of FR were identified by screening radiology reports, followed by manual confirmation. Subcutaneous edema, ascites, pleural effusion, and pericardial effusion were graded on a four-point scale on CT scans; total score was the sum of these four scores. RESULTS: The most common radiologic sign of FR was subcutaneous edema (15/15, 100%), followed by ascites (12/15, 80%), pleural effusion (11/15, 73%), and pericardial effusion (6/15, 40%) at the time of maximum FR. Two distinct types of FR were observed: 1) acute/progressive FR, characterized by acute aggravation of FR and rapid improvement after management, 2) intermittent/steady FR, characterized by occasional or persistent mild FR. Acute/progressive FR always occurred early after drug initiation/dose escalation (median 1.9 month, range 0.3-4.0 months), while intermittent/steady FR occurred at any time. Compared to intermittent/steady FR, acute/progressive FR was severe (median score, 5 vs. 2.5, p = 0.002), and often required drug-cessation/dose-reduction. CONCLUSION: Two distinct types (acute/progressive and intermittent/steady FR) of imatinib-associated FR are observed and each type requires different management.

Preoperative imatinib for patients with primary unresectable or metastatic/recurrent gastrointestinal stromal tumor

OBJECTIVES: Despite its rising popularity, reports on the use of preoperative imatinib mesylate (IM) in patients with advanced gastrointestinal stromal tumor (GIST) are limited. This study aims to explore the clinical efficacy of preoperative IM in patients with primarily unresectable or metastatic/recurrent GIST. METHODS: Between September 2009 and February 2014, patients with primarily unresectable or metastatic/recurrent GIST treated by a single medical team were recruited and considered for preoperative IM therapy. Re-examination was conducted regularly and abdominal enhanced CT data, blood biochemistry and responses to IM were recorded. RESULTS: A total of 18 patients were enrolled, including 13 with a primary tumor (7 stomach, 3 small bowel, 2 rectal and 1 pelvic tumor) and 5 with recurrent or metastatic GIST (2 with liver metastasis, 2 with anastomotic recurrence and 1 with pelvic GIST). The median follow-up time was 9.5 months (range of 3-63). The median tumor sizes before and after initiation of IM treatment were 9.1 cm and 6.0 cm (p = 0.003) based on the CT findings, respectively. All patients showed a decrease in tumor burden and the median tumor size reduction was 35%. Sixteen of the 18 patients showed a partial response to IM and two possessed stable disease. Nine of the 18 patients (50%) underwent surgical resection of primary or metastatic/recurrent tumors, with a median of 7 months of IM therapy. One case each of multivisceral resection and tumor recurrence were noted. CONCLUSIONS: IM as a preoperative therapy is feasible and safe for unresectable or metastatic/recurrent GIST that can effectively decrease tumor size, facilitating resection. .

Neoadyuvancia cnn imatinib en el manejo de gist gigante del tabique rectovaginal / Neo-adjuvant treatment with imatinib for a rectal gastrointestinal stromal tumor

Introducción: Los tumores estromales gastrointestinales (GIST) del recto son muy raros. En la última década se ha planteado la neoadyuvancia con imatinib en los casos de tumores localmente avanzados o inicialmente irresecables. Caso clínico: Se presenta una paciente portadora de un GIST maligno del tabique rectovaginal inicialmente considerado irresecable que fue sometido a neoadyuvancia con Imatinib como terapia de inducción durante 3 meses, logrando una respuesta clínica notable que permitió realizar una resección local exitosa por vía endoanal. La presencia de factores pronósticos deletéreos (tamaño tumoral mayor de 5 cm y 13 mitosis por 50 campos de aumento mayor) determinó la mantención del tratamiento con Imatinib por 15 meses luego de la cirugía con el fin de reducir el riesgo de recidiva local. Luego de 20 meses de seguimiento la paciente está libre de enfermedad, con continencia fecal plena, ha recuperado la actividad sexual, aunque persisten algunos efectos residuales de la droga que están en franca disminución. Conclusión: La neoadyuvancia con imatinib se considera actualmente la terapia estándar en el manejo de los GIST localmente avanzados y/o irresecables.

Background: Rectal gastrointestinal stromal tumors (GIST) are rare. Neo-adjuvant therapy with imatinib is recommended for locally advanced or non-resectable tumors. Case report: We report a 63 years old woman with a malignant GIST located in the recto-vaginal septum which was initially considered non-resectable. The patient was treated with imatinib as induction therapy for three months. After this lapse the tumor was successfully excised using an endo-anal approach. Due to a tumor size over 5 cm and the presence of 13 mitoses per 50 high power fields, two bad prognostic factors, treatment with imatinib was maintained for 15 months after surgery. After 20 months of follow up, the patient is free of disease with complete fecal continence and with an adequate sexual life. Secondary effects of imatinib are gradually subsiding.

Management of gastrointestinal stromal tumor: The lmatinib era and beyond.

The availability of imatinib followed by other tyrosine kinase inhibitors (TKIs) has dramatically altered the outcome of gastrointestinal stromal tumor (GIST). Patients with advanced or poor risk disease can now expect survival measured in years instead of months. An experienced multi disciplinary team (MDT) will be able to personalize therapy to ensure maximum benefit. This review will provide the updated information and finer points regarding state of the art management of GIST with the use of imatinib and other TKIs.

Mesilato de imatinibe para quimioterapia adjuvante do tumor do estroma gastrointestinal / Imatinib mesylate for gastrointestinal stromal tumor adjuvant chemotherapy

INTRODUÇÃO: Os tumores do estroma gastrointestinal ("gastrointestinal stromal tumors" ­ GIST) são neoplasias raras, tipicamente subepiteliais. Compreendem vários subtipos molecularmente distintos de sarcomas que coletivamente representam os tumores mesenquimais mais comuns do trato gastrointestinal. Afetam, em 75% dos casos, o estômago e o intestino delgado proximal, mas podem ocorrer em qualquer parte do trato digestivo, como cólon e reto e apêndice. Os GIST extra-gastrointestinais são raros e podem se originar no omento, mesentério ou retroperitôneo. Os GIST ocorrem em ambos os sexos e em qualquer faixa etária; entretanto, mais comumente afetam pessoas acima de 40-50 anos, com média de idade ao diagnóstico de 58-63 anos. Esses tumores correspondem a aproximadamente 1% das neoplasias primárias do trato digestivo, e se estima que a incidência anual seja de 7 a 20 casos por milhão de pessoas. Em faixas etárias mais jovens, estima-se que a incidência seja de 0,06 a cada 100.000 pessoas entre 20-29 anos e 0,02 por milhão de crianças menores de 14 anos. TRATAMENTO: O GIST é raro em crianças e adultos jovens (1,4%). Na falta de estudos prospectivos e, portanto, de um consenso quanto ao tratamento padrão, a conduta em caso GIST pediátrico deve ser feita por uma equipe multidisciplinar em serviços especializados em oncologia pediátrica. As opções terapêuticas descritas para o GIST no adulto envolvem a ressecção cirúrgica, a radioterapia e a utilização de inibidor da tirosinoquinase, o mesilato de imatinibe. As opções de tratamento variam de acordo com o estadiamento da doença ao diagnóstico e os grupos prognósticos. METODOLOGIA DE BUSCA E AVALIAÇÃO DE LITERATURA: Para revisão da literatura foram utilizadas as bases de dados Medline/Pubmed e Embase em 02/04/213. No Medline/Pubmed foi utilizada a seguinte estratégia: termos "Gastrointestinal Stromal Tumors"[Mesh]; Limites Humans, Meta-Analysis, Randomized Controlled Trial, Clinical Trial, Phase III, Systematic Reviews resultando em 110 artigos. No Embase foi utilizada a seguinte estratégia: termos 'gastrointestinal stromal tumors'/exp AND 'therapy'/exp AND [meta analysis]/lim OR [randomized controlled trial]/lim OR [systematic review]/lim) AND ([english]/lim OR [portuguese]/lim OR [spanish]/lim) AND [humans]/lim AND [embase]/lim, resultando em 159 artigos. Primeiramente foram selecionadas meta-análises e revisões sistemáticas relativas a opções de tratamento do tumor do estroma gastrointestinal, excluindo artigos não relacionados ao assunto e estudos cujos desfechos não tivessem relevância clínica. Após, foram selecionados os estudos de fase III publicados após as meta-análises e revisões sistemáticas selecionadas. Foi utilizada ainda a base de dados UpToDate 2013, com o termo GIST, e diretrizes clínicas de sociedades internacionais de especialistas. RECOMENDAÇÃO DA CONITEC: Os membros da CONITEC presentes na 22ª reunião ordinária do plenário do dia 06/02/2014 recomendaram a incorporação do mesilato de imatinibe para a quimioterapia adjuvante do tumor do estroma gastrointestinal (GIST). DECISÃO: PORTARIA Nº 27, de 4 de julho de 2014 - Torna pública a decisão de incorporar o mesilato de imatinibe para quimioterapia adjuvante do tumor do estroma gastrointestinal no Sistema Único de Saúde - SUS.

Imatinib Plasma Monitoring-Guided Dose Modification for Managing Imatinib-Related Toxicities in Gastrointestinal Stromal Tumor Patients

Imatinib, the first-line treatment in patients with advanced gastrointestinal stromal tumors (GIST), is generally well tolerated, although some patients have difficulty tolerating the standard dose of 400 mg/day. Adjusting imatinib dosage by plasma level monitoring may facilitate management of patients who experience intolerable toxicities due to overexposure to the drug. We present two cases of advanced GIST patients in whom we managed imatinib-related toxicities through dose modifications guided by imatinib plasma level monitoring. Imatinib blood level testing may be a promising approach for fine-tuning imatinib dosage for better tolerability and optimal clinical outcomes in patients with advanced GIST.

Características genético-moleculares de los tumores estromales gastrointestinales (GIST) / Molecular and genetic features of gastrointestinal stromal tumors (GIST)

Los tumores estromales gastrointestinales (GIST) son neoplasias mesenquimales que típicamente surgen a nivel del estómago, intestino delgado, colon, y otros sitios en la cavidad abdominal y su identificación se ha incrementado por mejoras en los criterios de detección. La mayor parte de los tumores GIST son causados por mutaciones activadoras en los genes de receptores transmembranares tirosina quinasa c-KIT y receptor alpha del factor de crecimiento derivado de plaquetas (PDGFRA). Las mutaciones causales de GIST se restringen solo a ciertas regiones del gen que corresponden a importantes zonas funcionales de c-KIT o PDGFRA. Se reporta que hasta 70% de casos de GIST se debe a mutaciones en el exón 11 del gen c-Kit que corresponde a la región yuxtamembrana del receptor. La región y el tipo de mutación determinan diferencialmente cómo se desarrolla la neoplasia, el pronóstico y su respuesta a inhibidores de las tirosina quinasas como el Imanatib. Por tal motivo, el genotipado de KIT y PDGFRA es importante para el diagnóstico y establecimiento de la sensibilidad a los inhibidores tirosina quinasa.

Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms typically arising in the stomach, small intestine, colon, and other sites in the abdominal cavity and its identification has improved dramatically mainly due to better criteria in its detection. Most GISTs tumors harbor activating mutations in the tyrosine kinase receptor c-KIT or platelet derived growth factor receptor-alpha (PDGFRA). Those mutations are restricted to a few regions corresponding to important functional domains of c-KIT or PDGFRA. Upto 70% of cases are due to mutations in exon 11 of c-KIT corresponding to its juxtamembrane region of the receptor. The location and type of mutation will differentially determine the development of the disease, its prognosis and the response to inhibitors of tyrosine kinases as Imanatib. For this reason, genotyping c-KIT and PDGFRA is important for GIST diagnosis and assessment of sensitivity to tyrosine kinase inhibitors.

Desarrollo de resistencia secundaria a imatinib y tratamiento quirúrgico de un GIST gástrico maligno / Secondary imatinib resistance and surgical treatment of a malignant gastric GIST

Introduction. Gastrointestinal stromal tumors (GIST) constitute a pathological condition whose treatment require the interaction of surgical and pharmacological procedures in primary, recurrent, and metastatic disease. Herein, we discuss the case of a patient operated for malignant primary GIST who suffered recurrence of his disease secondary to the development of imatinib resistance. Case report: A male patient was operated on March 2007 because of a malignant gastric GIST, with wedge resection of the tumor. In June 2008, a computerized abdominal tomography scan (CT) showed the presence of nodules over the porta hepatis, mesocolon, greater omentum and gastric antrum; at this moment imatinib 400 mg/day was initiated. A new CT in June 2010, showed a cystic tumor in the right lower abdominal quadrant besides the previously described peritoneal implants, and surgical treatment was proposed. The surgical findings consisted on a big cystic GIST implanted over the greater omentum, and multiple epiploic nodules over the gallbladder and gastric antrum. All visible tumors were resected including the gallbladder and gastric antrum. A positron emission tomography taken on December 2010, described 2 small hypermetabolic peritoneal nodules. The imatinib dose was increased to 800 mg/day, and at the last control, one year after the last surgery, the CT did not show disease progression. Discussion: This case report illustrates the GIST’s malignant potential. The tumor developed imatinib resistance after an initial period of good response to the drug. To control the disease, a new surgical intervention and an increase in the dose of imatinib was required.

Introducción. Los tumores del estroma gastrointestinal (GIST) constituyen una condición patológica cuyo tratamiento requiere la interacción de procedimientos terapéuticos y farmacológicos en los tumores primarios, recurrencias y metástasis. Reportamos el caso de un paciente operado por un GIST primario que sufrió recurrencia secundaria a desarrollo de resistencia al imatinib. Caso clínico: Paciente que se operó en marzo de 2007 por un GIST gástrico maligno, realizándose resección en cuña del tumor. En junio de 2008, como parte del seguimiento, se tomó una tomografía abdominal que informó la presencia de nódulos en el hilio porta, mesocolon, epiplón mayor y antro gástrico, iniciándose tratamiento con imatinib 400 mg diarios. La tomografía realizada en junio de 2010 demostró en el hemiabdomen derecho un tumor quístico, además de los implantes previamente descritos. Con estos antecedentes se decidió el tratamiento quirúrgico. Los hallazgos consistieron en un GIST del epiplón mayor, múltiples lesiones epiploicas, vesiculares y del antro gástrico. Se decidió resecar todas las lesiones visibles, la vesícula biliar y el antro gástrico. Una tomografía por emisión de positrones de diciembre de 2010 describe 2 pequeños nódulos hipermetabólicos peritoneales. Se aumentó la dosis de imatinib a 800 mg diarios y en el último control a 1 año de la última cirugía, la tomografía no demostró progresión de la enfermedad. Discusión: El presente caso ilustra el potencial maligno de los GIST. El tumor desarrolló resistencia al imatinib después de un período inicial con buena respuesta. Para controlar la enfermedad se requirió una nueva intervención quirúrgica y aumento de la dosis de imatinib.

Avaliação de potenciais biomarcadores preditores de benefício clínico ao mesilato de imatinibe em portadores de GIST metastático / [Evaluation of potential biomarkers predictive of clinical benefit to imatinib mesylate in patients with metastatic GIST]

Contexto: Apesar dos benefícios do uso do mesilato de imatinibe no tratamento do GIST metastático, observa-se que um número considerável de pacientes (em torno de 75%) evoluem com progressão de doença no curso do tratamento, sendo o desenvolvimento de resistência à droga um problema cada vez mais relevante na prática clínica. Embora alguns preditores de resposta ao mesilato de imatinibe tenham sido identificados, a busca por biomarcadores mais validados tem sido a tônica, pois possibilitará a otimização do tratamento e a busca de novas ferramentas para superar a resistência à droga. objetivo: o presente estudo busca investigar o papel de potenciais biomarcadores (Expressão imuno-histoquimica de IGF-1R, PKC theta total e fosforilada e RKIP; perda de heterozigose do gene KIT; status mutacional dos genes KIT, PDGFRA e BRAF) como preditores de beneficio clinico ao mesilato de imatinibe em portadores de GIST metastático. Pacientes e métodos: Analisamos retrospectivamente 76 portadores de GIST metastático tratados com imatinibe entre 2002 e 2007. Após a exclusão de 13 casos, a análise final foi realizada com 63 pacientes. A expressão imuno-histoquimica de IGF-1R, PKCθ (total e fosforilada) e RKIP e o status mutacional dos genes KIT, PDGFRA e BRAF foram correlacionados com a resposta objetiva ao imatinibe, sobrevida livre de progressão (SLP) e sobrevida global (SG). Resultados: O seguimento mediano foi de 31,2 meses (IC 95%, 26,3-36,1). Houve associação estatisticamente significante entre a expressão de IGF-1R e a resposta objetiva ao imatinibe (p=0,05), ou seja, maior expressão de IGF-1R se relacionou à menor taxa de resposta objetiva ao imatinibe. Curiosamente, essa associação ocorreu apenas no grupo feminino (p=0,015) e não no masculino (p=0,5). Porém, a expressão de IGF-1R não teve impacto na SLP nem na SG. Não houve correlação entre a expressão das proteínas PKCθ (total e fosforilada) e RKIP e os desfechos estudados. Portadores de GIST com mutação no éxon 9 do gene KIT apresentaram pior SLP quando comparado aos outros tipos de mutação (p=0,027). A análise da perda de heterozigose do gene KIT não pôde ser correlacionada com as medidas de desfecho. Não foi identificada mutação no gene BRAF nos casos estudados Conclusões: A expressão imuno- histoquimica de IGF-1R parece ser um biomarcador preditor de resposta ao imatinibe em portadores de GIST metastático, especialmente no sexo feminino. A presença da mutação no éxon 9 do gene KIT pode ser considerado fator prognóstico e preditor de resposta ao imatinibe.

Background: Despite the benefits derived from the use of imatinib mesylate in the treatment of metastatic GIST, it is observed that a considerable number of patients (around 75%) will have disease progression during treatment. Therefore, the development of drug resistance has become a relevant problem in the clinical practice. Although some predictors of response to imatinib have been identified, the recognition of more reliable markers is warranted, as will enable treatment optimization and the search for new tools to overcome drug resistance. Objective: The aim of this study is: to investigate the role of potential biomarkers (IGF-1R, total PKCθ, phosphorylated PKCθ and RKIP imunohistochemical expression; Loss of heterozygosity of KIT gene; KIT, PDGFRA and BRAF genes mutational status) as predictors of clinical benefit to imatinib treatment in metastatic GIST. Patients and methods: We retrospectively reviewed 76 patients with metastatic GIST submitted to imatinib treatment from 2002 to 2007. Over the course of the study, 13 patients initially intended for the study were excluded from further analysis, resulting in a cohort of 63 patients for the final study population. IGF-1R, total PKCθ, phosphorylated PKCθ at Thr538 and RKIP immunohistochemical expression and KIT and PDGFRA genes mutational status were correlated with objective response to imatinib treatment, progression-free survival (PFS) and overall survival (OS). Results: Median follow-up was 31.2 months (95% CI, 26.3-36.1). There was a statistically significant association between IGF-1R expression and the objective response to imatinib treatment (p=0.05), i.e, higher IGF-1R expression was related to lower objective response rate to imatinib therapy. Interestingly, this association was true in females (p=0.015) but not in males (p=0.5). However IGF-1R higher expression did not impact on PFS and OS. There was no association between total PKCθ, phosphorylated PKCθ and RKIP imunohistochemical expression and the endpoints analyzed. Patients with KIT Exon 9 mutation tumors had worse PFS than other mutation (p=0.027). Loss of heterozygosity of KIT gene could not be correlated with the endpoints variables. No BRAF mutations were found. Conclusion: IGF-1R immunohistochemical expression seems to be a biomarker for prediction of response to imatinib treatment in metastatic GIST, specially in the female group. KIT exon 9 mutation is a prognostic and predictive factor in GIST tumors.

Resultados del tratamiento quirúrgico de los tumores del estroma gastrointestinal (GIST) en la IV Región de Chile / Surgical outcomes of gastrointestinal stromal tumors (GIST)

Background: Despite that current knowledge regarding the pathology and treatment of Gastrointestinal Stromal Tumors (GIST) is widely available; most patients in the developing world and mainly in rural areas of developing countries have limited access to diagnostic technology and modern specific therapy such as imatinib. Objective: To review the management and outcomes of GISTs treated at the hospitals of the IV Region of Chile. Patients and Methods: This retrospective, observational and descriptive study was performed with data obtained from the medical records of 3 community hospitals were all surgical practice of the IV Region is performed. During the study period, 24 consecutive patients with GISTs at different localizations of the gastrointestinal tract were treated. Results: Five patients were operated on with the preoperative diagnostic of GIST, in 19 patients the diagnostic of GIST was suspected during the operation and confirmed by histology and immunohistochemistry. Most patients were operated on emergency grounds. Of 10 patients requiring imatinib therapy, only 2 are currently receiving the medication sponsored by an international foundation. Conclusions: There were no disparities in the standard surgical care of our patients. The main differences with published series from Chile and developed countries are the available technology to perform a preoperative diagnosis and the availability of imatinib for the treatment of metastatic and recurrent disease.

Introducción: A pesar de que el conocimiento actual sobre la patología y tratamiento de los tumores del estroma gastrointestinal (GIST) se encuentra ampliamente disponible, la mayoría de los pacientes en los países en desarrollo, principalmente en las áreas rurales, tienen un limitado acceso a la tecnología diagnóstica moderna y a tratamientos específicos como el imatinib. Objetivo: Revisión del manejo y resultados de los GIST tratados en los hospitales de la IV Región de Chile. Pacientes y Métodos: Estudio retrospectivo, observacional y descriptivo de la información obtenida de las fichas clínicas de 3 hospitales tipo 2 en los cuales se realiza toda la práctica quirúrgica de la IV Región. Durante el período estudiado, 24 pacientes consecutivos con GISTs en diferentes localizaciones fueron tratados quirúrgicamente. Resultados: Cinco pacientes fueron operados con el diagnóstico preoperatorio de GIST, en los otros 19 pacientes el diagnóstico se sospechó durante la cirugía y fue confirmado por histología e inmunohistoquímica. La mayoría de los pacientes fueron operados de urgencia. Diez pacientes fueron candidatos a tratamiento con imatinib, sólo 2 pacientes se encuentran actualmente en tratamiento gracias a una fundación internacional. Conclusiones: El tratamiento quirúrgico de nuestros pacientes es similar a las publicaciones nacionales e internacionales. Las diferencias se presentan en la disponibilidad de estudios de imagen para el diagnóstico preoperatorio y en la disponibilidad de imatinib para el tratamiento de las recurrencias y metástasis.