Establishment of patient-derived tumor organoids to functionally inform treatment decisions in metastatic colorectal cancer.

BACKGROUND: Metastatic colorectal cancer (mCRC) patients tend to have modest benefits from molecularly driven therapeutics. Patient-derived tumor organoids (PDTOs) represent an unmatched model to elucidate tumor resistance to therapy, due to their high capacity to resemble tumor characteristics. MATERIALS AND METHODS: We used viable tumor tissue from two cohorts of patients with mCRC, naïve or refractory to treatment, respectively, for generating PDTOs. The derived models were subjected to a 6-day drug screening assay (DSA) with a comprehensive pipeline of chemotherapy and targeted drugs against almost all the actionable mCRC molecular drivers. For the second cohort DSA data were matched with those from PDTO genotyping. RESULTS: A total of 40 PDTOs included in the two cohorts were derived from mCRC primary tumors or metastases. The first cohort included 31 PDTOs derived from patients treated in front line. For this cohort, DSA results were matched with patient responses. Moreover, RAS/BRAF mutational status was matched with DSA cetuximab response. Ten out of 12 (83.3%) RAS wild-type PDTOs responded to cetuximab, while all the mutant PDTOs, 8 out of 8 (100%), were resistant. For the second cohort (chemorefractory patients), we used part of tumor tissue for genotyping. Four out of nine DSA/genotyping data resulted applicable in the clinic. Two RAS-mutant mCRC patients have been treated with FOLFOX-bevacizumab and mitomycin-capecitabine in third line, respectively, based on DSA results, obtaining disease control. One patient was treated with nivolumab-second mitochondrial-derived activator of caspases mimetic (phase I trial) due to high tumor mutational burden at genotyping, experiencing stable disease. In one case, the presence of BRCA2 mutation correlated with DSA sensitivity to olaparib; however, the patient could not receive the therapy. CONCLUSIONS: Using CRC as a model, we have designed and validated a clinically applicable methodology to potentially inform clinical decisions with functional data. Undoubtedly, further larger analyses are needed to improve methodology success rates and propose suitable treatment strategies for mCRC patients.

Diagnóstico por imagen de la hipertensión portal / Imaging diagnosis of portal hypertension

La hipertensión portal (HTP) es una condición clínica definida por una presión hidrostática >5mmHg en el territorio venoso portal, siendo clínicamente significativa cuando es ≥10mmHg. A partir de este umbral pueden desarrollarse complicaciones, como sangrado de varices esofágicas, aparición de ascitis o encefalopatía hepática. Las técnicas de imagen tienen un papel importante como método no invasivo para determinar la presencia de HTP. En este artículo se analizan varios hallazgos radiológicos que pueden sugerir HTP y contribuir a definir su etiología, gravedad y posibles complicaciones

Portal hypertension is a clinical entity defined by a hydrostatic pressure greater than 5mm Hg in the portal territory, being clinically significant when it is greater than or equal to 10mm Hg. Starting from this threshold, complications can develop, such as the bleeding of esophageal varices, the appearance of ascites, or hepatic encephalopathy. Imaging techniques play an important role as a noninvasive method for determining whether portal hypertension is present. This article analyzes various imaging findings that can suggest the presence of portal hypertension and can help to define its etiology, severity, and possible complications

Imaging diagnosis of portal hypertension. / Diagnóstico por imagen de la hipertensión portal.

Portal hypertension is a clinical entity defined by a hydrostatic pressure greater than 5mm Hg in the portal territory, being clinically significant when it is greater than or equal to 10mm Hg. Starting from this threshold, complications can develop, such as the bleeding of esophageal varices, the appearance of ascites, or hepatic encephalopathy. Imaging techniques play an important role as a noninvasive method for determining whether portal hypertension is present. This article analyzes various imaging findings that can suggest the presence of portal hypertension and can help to define its etiology, severity, and possible complications.

Radiofrecuencia percutánea guiada por ecografía en el tratamiento de masas renales pequeñas / Ultrasound-guided percutaneous radiofrequency ablation for treating small renal masses

Introducción: El objetivo del presente estudio ha sido analizar y evaluar la experiencia en ablación por radiofrecuencia de masas renales pequeñas mediante abordaje percutáneo guiado por ecografía con contraste en pacientes no aptos para la resección quirúrgica, y/o que no aceptaron vigilancia u observación. Material y método: Desde enero de 2007 hasta agosto de 2015 se han realizado 164 tratamientos en un total de 148 pacientes. Se presentan las características clínico-radiológicas de los pacientes, los resultados oncológicos y funcionales a corto y medio plazo. Resultados: La tasa de éxito técnico global fue del 97,5%, con éxito final en una sesión en el 100% de lesiones ≤ 3 cm y el 92% en lesiones entre 3-5 cm. El diámetro medio de los tumores en los que el tratamiento fue finalmente exitoso fue de 2,7 cm, mientras que el diámetro medio de estos fallos fue de 3,9 cm (p < 0,05). No se observaron diferencias estadísticamente significativas en la creatinina sérica y en el filtrado glomerular estimado. Conclusiones: A pesar de la baja tasa de biopsia renal positiva en la serie, la aplicación de radiofrecuencia percutánea ecoguiada en el tratamiento de lesiones renales pequeñas parece un procedimiento eficaz y seguro, con un mínimo impacto sobre la función renal, un aceptable control oncológico a corto y medio plazo, con una baja tasa de complicaciones

Introduction: The objective of this study was to analyse and assess the experience with radiofrequency ablation of small renal masses using a contrast-enhanced, ultrasound-guided percutaneous approach for patients who are not suitable for surgical resection and/or who refused surveillance or observation. Material and method: From January 2007 to August 2015, 164 treatments were performed on a total of 148 patients. We present the patients’ clinical-radiological characteristics, oncological and functional results in the short and medium term. Results: The overall technical success rate was 97.5%, with a successful outcome in 1 session in 100% of the lesions ≤ 3cm and 92% in lesions measuring 3-5cm. The mean tumour diameter in the patients for whom the treatment was ultimately successful was 2.7 cm, while the mean diameter of these in the unsuccessful operations was 3.9 cm (P < .05). There were no statistically significant differences in the serum creatinine levels and estimated glomerular filtration rates. Conclusions: Despite the low rate of positive renal biopsies in the series, ultrasound-guided percutaneous radiofrequency ablation for treating small renal lesions appears to be an effective and safe procedure with a minimum impact on renal function, an acceptable oncologic control in the short and medium term and a low rate of complications

Pancreatic cancer heterogeneity and response to Mek inhibition.

Our increasing knowledge of the mechanisms behind the progression of pancreatic cancer (PC) has not yet translated into effective treatments. Many promising drugs have failed in the clinic, highlighting the need for better preclinical models to assess drug efficacy and characterize mechanisms of resistance. Using different experimental models, including patient-derived xenografts (PDXs), we gauged the efficacy of therapies aimed at two hallmark lesions of PCs: activation of signaling pathways by oncogenic KRAS and inactivation of tumor-suppressor genes. Although the drug targeting inactivation of tumor suppressors by DNA methylation had little effect, the inhibition of Mek, a K-Ras effector, in combination with the standard of care (chemotherapy consisting of gemcitabine/Nab-paclitaxel), reduced the growth of three out of five PC-PDXs and impaired metastasis. The two least responding PC-PDXs were composed of genetically diverse cells, which displayed sensitivities to the Mek inhibitor differing by >10-fold. Unexpectedly, our analysis of this genetic diversity unveiled different KRAS mutations. As mutation in KRAS occurs early during progression, this heterogeneity may reflect the simultaneous appearance of different malignant cellular clones or, alternatively, that cells containing two mutations of KRAS are selected during tumor evolution. In vitro and in vivo analyses indicated that the intratumoral heterogeneity, along with the selective pressure imposed by the Mek inhibitor, resulted in rapid selection of resistant cells. Together with the gemcitabine/Nab-paclitaxel backbone, Mek inhibition could be effective in treatment of PC. However, resistance because of intratumoral heterogeneity is likely to develop frequently, pointing to the necessity of identifying the factors and mechanisms of resistance to further develop this therapy.

Ultrasound-guided percutaneous radiofrequency ablation for treating small renal masses. / Radiofrecuencia percutánea guiada por ecografía en el tratamiento de masas renales pequeñas.

INTRODUCTION: The objective of this study was to analyse and assess the experience with radiofrequency ablation of small renal masses using a contrast-enhanced, ultrasound-guided percutaneous approach for patients who are not suitable for surgical resection and/or who refused surveillance or observation. MATERIAL AND METHOD: From January 2007 to August 2015, 164 treatments were performed on a total of 148 patients. We present the patients' clinical-radiological characteristics, oncological and functional results in the short and medium term. RESULTS: The overall technical success rate was 97.5%, with a successful outcome in 1 session in 100% of the lesions≤3cm and 92% in lesions measuring 3-5cm. The mean tumour diameter in the patients for whom the treatment was ultimately successful was 2.7cm, while the mean diameter of these in the unsuccessful operations was 3.9cm (P<.05). There were no statistically significant differences in the serum creatinine levels and estimated glomerular filtration rates. CONCLUSIONS: Despite the low rate of positive renal biopsies in the series, ultrasound-guided percutaneous radiofrequency ablation for treating small renal lesions appears to be an effective and safe procedure with a minimum impact on renal function, an acceptable oncologic control in the short and medium term and a low rate of complications.

A New Surgical Model of Skeletal Muscle Injuries in Rats Reproduces Human Sports Lesions.

Skeletal muscle injuries are the most common sports-related injuries in sports medicine. In this work, we have generated a new surgically-induced skeletal muscle injury in rats, by using a biopsy needle, which could be easily reproduced and highly mimics skeletal muscle lesions detected in human athletes. By means of histology, immunofluorescence and MRI imaging, we corroborated that our model reproduced the necrosis, inflammation and regeneration processes observed in dystrophic mdx-mice, a model of spontaneous muscle injury, and realistically mimicked the muscle lesions observed in professional athletes. Surgically-injured rat skeletal muscles demonstrated the longitudinal process of muscle regeneration and fibrogenesis as stated by Myosin Heavy Chain developmental (MHCd) and collagen-I protein expression. MRI imaging analysis demonstrated that our muscle injury model reproduces the grade I-II type lesions detected in professional soccer players, including edema around the central tendon and the typically high signal feather shape along muscle fibers. A significant reduction of 30% in maximum tetanus force was also registered after 2 weeks of muscle injury. This new model represents an excellent approach to the study of the mechanisms of muscle injury and repair, and could open new avenues for developing innovative therapeutic approaches to skeletal muscle regeneration in sports medicine.

[Transobturator subvesical mesh. Tolerance and short-term results of a 103 case continuous series]. / La prothèse sous-vésicale transobturatrice. Tolérance et résultats à court terme d'une série continue de 103 cas.

OBJECTIVE: Native tissue plasty for surgical repair of anterior prolapse segment is associated with high level of recurrent defects. MATERIAL AND METHODS: We used a transvaginal polypropylen tension-free mesh fixed through the obturator hole with Emmet needle. We report the results of a total of 103 consecutive transobturator mesh fixations between January 1, 2000 and June 30, 2002. RESULTS: Vaginal erosion ratio is 5% and recurrence ratio is 3% at 18 months post operative follow-up. CONCLUSION: Transobturator mesh is a safe and efficient method for anterior segment prolapse repair.

Antrochoanal polyps in children: CT findings and differential diagnosis.

Antrochoanal polyp (Killian polyp) is an infrequent, usually solitary, benign, slowly growing lesion that arises from the maxillary antrum and reaches the choana. These polyps have a discrete male predominance and are diagnosed usually between the third and the fifth decades of life. This report is based on three cases of antrochoanal polyp, occurring in the pediatric group, and the objective is to demonstrate their different CT characteristics, principal differential diagnoses, and potential complications. We emphasize that in all three cases of our series the growth of the polyp to the choana is through the accessory ostium.

Antrochoanal autopolypectomy: CT findings.

Antrochoanal polyp (Killian polyp) is an infrequent, benign lesion of maxillary origin. We describe the basic characteristics of this lesion and a rare case of autopolypectomy. Coronal and axial CT images are presented before and after autoexpulsion of an antrochoanal polyp in a patient with long-standing nasal obstruction. The initial CT examination revealed a typical left antrochoanal polyp filling all the maxillary sinus and passing through the ethmoid infundibulum until the choana. The CT after autopolypectomy showed the secondary mass effect at surrounding structures and residual inflammatory changes.

Congenital intrahepatic portosystemic venous shunt: sonographic and magnetic resonance imaging.

We report an intrahepatic portosystemic venous shunt (IPVS) detected by ultrasound in an asymptomatic newborn. The lesion, which was further documented using color Doppler ultrasound and magnetic resonance imaging (MRI), had almost totally disappeared 6 months later without any treatment. Intrahepatic portosystemic venous shunts (IPVS) are uncommon and their etiology is controversial. Some cases of IPVS have been reported in the literature, most of them in adult patients with portal hypertension and cirrhosis of the liver. However, only scattered reports describe IPVS in the absence of liver pathology. A revision of the proposed etiologies of IPVS is made and the usefulness of gray-scale and color Doppler sonography and MRI in diagnosing IPVS is discussed.

Tuberculous Addison's disease. Utility of CT in diagnosis and follow-up.

The computed tomographic (CT) findings in five patients with tuberculous Addison's disease were evaluated. All patients had extra-adrenal tuberculosis. Two patients had enlarged adrenal glands with calcifications at the times of diagnosis. Follow-up CT from 4 to 30 months showed a progressive decrease in the size of adrenal glands from bilateral enlargement to small calcified glands and provides a clue to the etiology of Addison's disease and proper therapy.