Monitoring advanced gastrointestinal stromal tumor with circulating tumor DNA.

PURPOSE OF REVIEW: This review explores the role of circulating tumor (ct)DNA as a biomarker for clinical decision-making and monitoring purposes in metastatic gastrointestinal stromal tumor (GIST) patients. We discuss key insights from recent clinical trials and anticipate the future perspectives of ctDNA profiling within the clinical landscape of GIST. RECENT FINDINGS: The identification and molecular characterization of KIT/platelet-derived growth factor receptor alpha (PDGFRA) mutations from ctDNA in metastatic GIST is feasible and reliable. Such identification through ctDNA serves as a predictor of clinical outcomes to tyrosine-kinase inhibitors (TKIs) in metastatic patients. Additionally, conjoined ctDNA analysis from clinical trials reveal the evolving mutational landscapes and increase in intratumoral heterogeneity across treatment lines. Together, this data positions ctDNA determination as a valuable tool for monitoring disease progression and guiding therapy in metastatic patients. These collective efforts culminated in the initiation of a ctDNA-based randomized clinical trial in GIST, marking a significant milestone in integrating ctDNA testing into the clinical care of GIST patients. SUMMARY: The dynamic field of ctDNA technologies is rapidly evolving and holds significant promise for research. Several trials have successfully validated the clinical utility of ctDNA in metastatic GIST, laying the foundations for its prospective integration into the routine clinical management of GIST patients.

Hyperammonemic encephalopathy after tyrosine kinase inhibitors: A literature review and a case example.

OBJECTIVE: To review the evidence of uncommon but fatal adverse event of hyperammonemic encephalopathy by tyrosine kinase inhibitors (TKI) and the possible mechanisms underlying this condition and to describe the case of a patient that developed drug-induced hyperammonemic encephalopathy related to TKI. DATA SOURCES: Literature search of different databases was performed for studies published from 1 January 1992 to 7 May 2023. The search terms utilized were hyperammonemic encephalopathy, TKI, apatinib, pazopanib, sunitinib, imatinib, sorafenib, regorafenib, trametinib, urea cycle regulation, sorafenib, carbamoyl-phosphate synthetase 1, ornithine transcarbamylase, argininosuccinate synthetase, argininosuccinate lyase, arginase 1, Mitogen activated protein kinases (MAPK) pathway and mTOR pathway, were used individually search or combined. DATA SUMMARY: Thirty-seven articles were included. The articles primarily focused in hyperammonemic encephalopathy case reports, management of hyperammonemic encephalopathy, urea cycle regulation, autophagy, mTOR and MAPK pathways, and TKI. CONCLUSION: Eighteen cases of hyperammonemic encephalopathy were reported in the literature from various multitargeted TKI. The mechanism of this event is not well-understood but some authors have hypothesized vascular causes since some of TKI are antiangiogenic, however our literature review shows a possible relationship between the urea cycle and the molecular inhibition exerted by TKI. More preclinical evidence is required to unveil the biochemical mechanisms responsible involved in this process and clinical studies are necessary to shed light on the prevalence, risk factors, management and prevention of this adverse event. It is important to monitor neurological symptoms and to measure ammonia levels when manifestations are detected.

KIT/PDGFRA inhibitors for the treatment of gastrointestinal stromal tumors: getting to the gist of the problem.

INTRODUCTION: Approximately 90% of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in receptor tyrosine-kinases KIT or PDGFRA. Despite the outstanding results of first-line imatinib in advanced GIST, resistance ultimately occurs mainly through secondary mutations in KIT/PDGFRA. Other tyrosine-kinase inhibitors (TKIs) with a broader spectrum of activity against these mutations are approved after imatinib failure. However, response rates and progression-free survival are drastically lower compared to imatinib. Notably, imatinib also triggers early tolerance adaptation mechanisms, which precede the occurrence of secondary mutations. AREAS COVERED: In this review, we outline the current landscape of KIT inhibitors, discuss the novel agents, and present additional biological pathways that may be therapeutically exploitable. EXPERT OPINION: The development of broad-spectrum and highly selective TKIs able to induce a sustained KIT/PDGFRA inhibition is the pillar of preclinical and clinical investigation in GIST. However, it is now recognized that the situation is more intricate, with various factors interacting with KIT and PDGFRA, playing a crucial role in the response and resistance to treatments. Future strategies in the management of advanced GIST should integrate driver inhibition with the blockade of other molecules to enhance cell death and establish enduring responses in patients.

KIT ATP-Binding Pocket/Activation Loop Mutations in GI Stromal Tumor: Emerging Mechanisms of Kinase Inhibitor Escape.

PURPOSE: Imatinib resistance in GI stromal tumors (GISTs) is primarily caused by secondary KIT mutations, and clonal heterogeneity of these secondary mutations represents a major treatment obstacle. KIT inhibitors used after imatinib have clinical activity, albeit with limited benefit. Ripretinib is a potent inhibitor of secondary KIT mutations in the activation loop (AL). However, clinical benefit in fourth line remains limited and the molecular mechanisms of ripretinib resistance are largely unknown. PATIENTS AND METHODS: Progressing lesions of 25 patients with GISTs refractory to ripretinib were sequenced for KIT resistance mutations. Resistant genotypes were validated and characterized using novel cell line models and in silico modeling. RESULTS: GISTs progressing on ripretinib were enriched for secondary mutations in the ATP-binding pocket (AP), which frequently occur in cis with preexisting AL mutations, resulting in highly resistant AP/AL genotypes. AP/AL mutations were rarely observed in a cohort of progressing GIST samples from the preripretinib era but represented 50% of secondary KIT mutations in patients with tumors resistant to ripretinib. In GIST cell lines harboring secondary KIT AL mutations, the sole genomic escape mechanisms during ripretinib drug selection were AP/AL mutations. Ripretinib and sunitinib synergize against mixed clones with secondary AP or AL mutants but do not suppress clones with AP/AL genotypes. CONCLUSION: Our findings underscore that KIT remains the central oncogenic driver even in late lines of GIST therapy. KIT-inhibitor combinations may suppress resistance because of secondary KIT mutations. However, the emergence of KIT AP/AL mutations after ripretinib treatment calls for new strategies in the development of next-generation KIT inhibitors.

Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase 3 INTRIGUE trial.

INTRIGUE was an open-label, phase 3 study in adult patients with advanced gastrointestinal stromal tumor who had disease progression on or intolerance to imatinib and who were randomized to once-daily ripretinib 150 mg or sunitinib 50 mg. In the primary analysis, progression-free survival (PFS) with ripretinib was not superior to sunitinib. In clinical and nonclinical studies, ripretinib and sunitinib have demonstrated differential activity based on the exon location of KIT mutations. Therefore, we hypothesized that mutational analysis using circulating tumor DNA (ctDNA) might provide further insight. In this exploratory analysis (N = 362), baseline peripheral whole blood was analyzed by a 74-gene ctDNA next-generation sequencing-based assay. ctDNA was detected in 280/362 (77%) samples with KIT mutations in 213/362 patients (59%). Imatinib-resistant mutations were found in the KIT ATP-binding pocket (exons 13/14) and activation loop (exons 17/18). Mutational subgroup assessment showed 2 mutually exclusive populations with differential treatment effects. Patients with only KIT exon 11 + 13/14 mutations (ripretinib, n = 21; sunitinib, n = 20) had better PFS with sunitinib versus ripretinib (median, 15.0 versus 4.0 months). Patients with only KIT exon 11 + 17/18 mutations (ripretinib, n = 27; sunitinib, n = 25) had better PFS with ripretinib versus sunitinib (median, 14.2 versus 1.5 months). The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations. ClinicalTrials.gov identifier: NCT03673501.

Ibero-American Consensus for the Management of Peritoneal Sarcomatosis: Updated Review and Clinical Recommendations.

Peritoneal sarcomatosis is a rare malignant disease with a poor prognosis, secondary to peritoneal dissemination of abdominopelvic soft tissue sarcomas. Its rarity, together with the characteristic histological heterogeneity and the historically poor response to systemic treatments, has prevented the establishment of widely accepted treatment criteria with curative intent. In this sense, radical cytoreductive surgery (CRS) with peritonectomy procedures and hyperthermic intraperitoneal chemotherapy (HIPEC), widely used in peritoneal carcinomatosis with excellent results, have not had the same evolutionary development in patients with peritoneal sarcomatosis. A multidisciplinary working group of experts in sarcomas and peritoneal oncological surgery established a series of recommendations based on current scientific evidence for the management of peritoneal sarcomatosis, taking into account the different histological subgroups of abdominopelvic sarcomas that can cause it depending on their origin: retroperitoneal sarcomas, uterine sarcomas, and visceral/peritoneal sarcomas of GIST (gastrointestinal stromal tumor) and non-GIST origin. This article shows the results of sarcoma experts' voting on the recommendations presented during the I Ibero-American Consensus on the Management of Peritoneal Sarcomatosis, which took place during the recent celebration of the III Hispanic-Portuguese Meeting for Updates on the Treatment of Sarcomas.

Cancer Core Europe: Leveraging Institutional Synergies to Advance Oncology Research and Care Globally.

Cancer Core Europe brings together the expertise, resources, and interests of seven leading cancer institutes committed to leveraging collective innovation and collaboration in precision oncology. Through targeted efforts addressing key medical challenges in cancer and partnerships with multiple stakeholders, the consortium seeks to advance cancer research and enhance equitable patient care.

Prevalencia de tumor del estroma gastrointestinal en el hospital militar Dr. Carlos Arvelo durante los años 2000-2008

Objetivo: Determinar la prevalencia de pacientes con diagnostico de tumores del estroma gastrointestinal hospitalizados desde el año 2000-2008 en el Hospital Militar Dr. Carlos Arvelo. Materiales y métodos: Se realizó un estudio retrospectivo cuyos datos fueron obtenido de la revisión de historias clínicas del hospital, en pacientes con diagnostico de GIST, cuyas biopsias confirmaron el diagnóstico. Se revisaron 7 casos, de los cuales 4 (57%) fueron masculinos, y 3 (43%) femeninos, con edades comprendidas entre 49 y 76 años, de los cuales fallecieron 2, durante su hospitalización. Se clasificaron según edad, sexo, motivo de consulta, complicaciones, y tratamiento. Resultados: De un total de 7 pacientes registrados con diagnostico de tumor del estroma gastrointestinal, fueron estudiados, 4 masculinos y 3 femeninos, con una media de edad de 64 años. Los motivos de consulta de estos pacientes de los cuales fueron: dolor abdominal, masa palpable, pérdida de peso. Conclusiones: Los tumores del Estroma Gastrointestinal son un reto diagnóstico para el clínico, por lo que ante la presencia de tumoración Gastrointestinal con signos y síntomas inespecíficos, el apoyo anatomopatológico sustentado en el estudio inmunohistoquímico es determinante.

Objective: Determine the number of patients with diagnosis of gastrointestinal stromal tumor hospitalized from the year 2000-2008 in the Military Hospital Dr. Carlos Arvelo. Patients and Methods: retrospective study which information was obtained of the review of clinical histories from the file of the hospital,in patients with GISTÊs diagnosis, to which endoscopic studies were realized and which biopsies confirmed the diagnosis. There were checked 7 cases, of which 4 (57 %) were masculine, and 3 (43 %) were feminine, with ages included between 49 and 76 years, of which 2 died, during their hospitalization. They qualified according to age, sex, motive of consultation, complications, and treatment. Results: Of a whole of 7 patients registered in the file of the hospital, with diagnosis of gastrointestinal stromal tumor were studied, 4 masculine and 3 feminine, by an average of age of 64 years. The motives of consultation of these patients were: abdominal pain, palpable mass, loss of weight. Conclusions: Gastrointestinal stromal tumors are a diagnostic challenge for the clinician, thatÊs why when the diagnosis is made; the support in a pathological study based on immunohistochemistry is determinant.

Evaluación de métodos de corrección para efectos ambientales para peso al destete en corderos Suffolk / Evaluation of adjustment methods for environmental effects for weaning weight in Suffolk lambs

Data of weaning weights (WW) from 2 172 Suffolk lambs with complete genealogical information, obtained from a flock in central Mexico from 1992 to 2004, were analyzed using mixed linear models with direct and maternal effects, to generate correction factors and to compare different methods for the adjustment of sex, type of birth and age of the mother effects. The methods compared were: analysis of weaning weights with a complete mixed model (PDMOD), analysis of WW preadjusted to 68 days and for sex and age of the mother-type of birth with factors developed from this population (PD68PRE), analysis of WW adjusted to 68 days with a complete model (PD68MOD) and analysis of WW preadjusted to 68 days and for sex, age of the mother and type of birth with factors developed for the Suffolk population of the United States of America (PD68USA). The effects of year of birth, sex, type of birth, age of the mother, year of birth x age of the mother interaction and the linear and quadratic effects of weaning age were all significant (P < 0.01). The inclusion of all the effects in the model gave slightly smaller residual coefficients of variation with reductions < 0.51 %, compared to preadjusted data with correction factors generated either in the flock or adapted from those suggested for the Suffolk population of the United States of America. Small differences between methods in the ranking of the animals according to the genetic evaluations based on empirical BLUP's for direct and maternal genetic effects were found, with Spearman's correlation values > 0.96.

Datos de pesos al destete (PD) de 2 172 corderos Suffolk con información genealógica completa, obtenidos de 1992 a 2004 en un rebaño en el centro de México, fueron analizados usando modelos lineales mixtos con efectos directos y maternos, para generar factores de corrección y comparar diferentes métodos de ajuste para los efectos de sexo, tipo de nacimiento y edad de la madre. Los métodos comparados fueron: análisis de PD con un modelo completo (PDMOD), análisis de PD preajustados a 68 días y para sexo, edad de la madre-tipo de nacimiento con factores desarrollados a partir de esta población (PD68PRE), análisis de PD ajustados a 68 días con un modelo completo (PD68MOD) y análisis de PD preajustados a 68 días y para sexo, edad de la madre y tipo de nacimiento con factores desarrollados para la población Suffolk de los Estados Unidos de América (PD68USA). Los efectos de año de nacimiento, sexo, tipo de nacimiento, edad de la madre, interacción año de nacimiento x edad de la madre y edad al destete lineal y cuadrática fueron significativos (P < 0.01). La inclusión de todos los efectos en el modelo dio coeficientes de variación residual ligeramente menores, con reducciones < 0.51%, en comparación con el uso de datos preajustados con factores de corrección generados en el propio rebaño o adaptados de los recomendados para la población Suffolk de los Estados Unidos de América. Las diferencias entre los métodos en la jerarquización de los animales de acuerdo con las evaluaciones genéticas con los BLUP empíricos de los efectos directos y maternos fueron pequeñas, con valores de correlaciones de Spearman > 0.96.

Cirugia laparoscopica en Urologia: ­Es una realidad! / Laparoscopic surgery in Urology

Se hace una revisión de la historia de la cirugía laparoscópica en urología junto al desarrollo tecnológico que ha permitido que esta técnica quirúrgica se convierta en una realidad a nivel mundial

Técnica de Mitrofanoff modificada para la creación de conductos continentes / Modified mitrofanoff technique designed to create coninent ducts

Se presenta la experiencia de los autores con la técnica de Mitrofanoff aplicada en siete pacientes. De cuatro pacientes con estenosis de uretra postraumática, en tres se utilizó apéndice como conducto cateterizable continente con modificación en la técnica de anastomosis apendicovesical, esto es, sin efectuar un túnel submucoso, y en uréter residual subsecuente a nefrectomía simple. En tres pacientes, de los cuales uno tenía vejiga hipotónica y dos estenosis de uretra, se efectuó el procedimiento de Mitrofanoff con apéndice por acceso laproscópico en forma completa. Tras un promedio de seguimiento de 13.5 meses, los autores observaron continencia diurna y nocturna en todos los pacientes, y sólo en cuatro persiste la bacteriuria pero sin pruebas de deterioro de la función renal. Se concluye que con la modificación de la técnica de anastomosis de apéndice con vejiga realizada en forma directa se simplifica el tiempo quirúrgico, se minimizan las complicaciones y se tiene la oportunidad de efectuar la técnica por vía laparoscópica, con todas las ventajas que ofrece el acceso miniinvasivo, con conservación de la continencia urinaria como se demostró mediante estudios urodinámicos