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.

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.