Searching for targets that allow pharmacological inhibition of cell proliferation in over-proliferative states, such as cancer, leads us to finely understand the complex mechanisms orchestrating the perfect control of mitosis number, frequency and pace as well as the molecular arrangements that induce cells to enter functional quiescence and brings them back to cycling in specific conditions. Although the mechanisms regulating cell proliferation have been described several years ago, never before has so much light been shed over this machinery as during the last decade when therapy targets have been explored and molecules, either synthetic or in the form of antibodies with the potential of becoming cancer drugs were produced and adjusted for specific binding and function. Proteins containing tyrosine kinase domains, either membrane receptors or cytoplasmic molecules, plus the ones activated by those in downstream pathways, having tyrosine kinase domains or not, such as RAS which is a GTPase and serine/threonine kinases such as RAF, play crucial role in conducting proliferation information from cell surroundings to the nucleus where gene expression takes place. Tyrosine kinases phosphorylate tyrosine residues in an activating mode and are found in important growth factor receptors, such as for ligands from families collectively known as VEGF, PDGF and EGF, to name a few and in intracellular downstream molecules. They all play important roles in normal physiology and are commonly found mutated or overexpressed in neoplastic states. Our objective here is to present such kinases as druggable targets for cancer therapy, highlighting the ones for which the pharmacological arsenal is available, discussing specificity, resistance mechanisms and treatment alternatives in cases of resistance, plus listing potential targets that have not been successfully worked yet.

Somatic mutations in the telomerase reverse transcriptase (TERT) promoter regions are frequent events in urothelial cancer (UC) and their detection in urine (supernatant cell-free DNA or DNA from exfoliated cells) could serve as putative non-invasive biomarkers for UC detection and monitoring. However, detecting these tumor-borne mutations in urine requires highly sensitive methods, capable of measuring low-level mutations. In this study, we developed sensitive droplet digital PCR (ddPCR) assays for detecting TERT promoter mutations (C228T, C228A, CC242-243TT, and C250T). We tested the C228T and C250T ddPCR assays on all samples with sufficient quantity of urinary DNA (urine supernatant cell-free DNA (US cfDNA) or urine pellet cellular DNA (UP cellDNA)) from the DIAGURO (n = 89/93 cases and n = 92/94 controls) and from the IPO-PORTO (n = 49/50 cases and n = 50/50 controls) series that were previously screened with the UroMuTERT assay and compared the performance of the two approaches. In the DIAGURO series, the sensitivity and specificity of the ddPCR assays for detecting UC using either US cfDNA or UP cellDNA were 86.8% and 92.4%. The sensitivity was slightly higher than that of the UroMuTERT assay in the IPO-PORTO series (67.4% vs. 65.3%, respectively), but not in the DIAGURO series (86.8% vs. 90.7%). The specificity was 100% in the IPO-PORTO controls for both the UroMuTERT and ddPCR assays, whereas in the DIAGURO series, the specificity dropped for ddPCR (92.4% versus 95.6%). Overall, an almost perfect agreement between the two methods was observed for both US cfDNA (n = 164; kappa coefficient of 0.91) and UP cellDNA (n = 280; kappa coefficient of 0.94). In a large independent series of serial urine samples from DIAGURO follow-up BC cases (n = 394), the agreement between ddPCR and UroMuTERT was (i) strong (kappa coefficient of 0.87), regardless of urine DNA types (kappa coefficient 0.89 for US cfDNA and 0.85 for UP cellDNA), (ii) the highest for samples with mutant allelic fractions (MAFs) > 2% (kappa coefficient of 0.99) and (iii) only minimal for the samples with the lowest MAFs (< 0.5%; kappa coefficient 0.32). Altogether, our results indicate that the two methods (ddPCR and UroMuTERT) for detecting urinary TERT promoter mutations are comparable and that the discrepancies relate to the detection of low-allelic fraction mutations. The simplicity of the ddPCR assays makes them suitable for implementation in clinical settings.

A Young Patient With Undifferentiated And Advanced Medullary Thyroid Carcinoma With Negative RET – CASE REPORT INTRODUCTION: Medullary Thyroid Carcinoma (MTC) is a rare and aggressive form of thyroid cancer that arises from C cells, representing 5% of all thyroid malignancy. The biochemical characteristic of MTC is the elevation of serum calcitonin (CTN), which aids in the initial diagnosis and surveillance of this disease. Another important, but less specific marker in the follow-up is the carcinoembryogenic antigen (CEA). Although, it is observed in the Undifferentiated MTC that there is a disproportion between the expected values of CEA and CTN. Case Report A previously healthy 16 years old female patient was hospitalized for the investigation of cervical discomfort, involuntary weight loss and progressive back pain for 9 months. She had a BMI of 14.9kg/cm2, a palpable thyroid nodule measuring approximately 2. 0cm and painful cervical lymph node enlargement. Laboratory tests showed CTN 79.1pg/mL, CEA 4999.42ng/mL added with an independent PTH hypercalcemia. Thyroid US showed a solid nodule with lobulated contours, heterogeneous echotexture, predominantly hypoechogenic, with its longest axis parallel to the skin, measuring approximately 2.4×0.9×0.9 cm, located in the lower middle third of the right thyroid lobe (TI -RADS 4) added to multiple lymph nodes inthe anterior cervical area (in agreement with the neck CT). Regarding the staging Chest CT showed a metastasis suggestive nodulation; Cranial CT, bone scan and total spine MRI showed evidence of several infiltrative nodular formations with heterogeneous enhancement affecting the skullcap, sacrum, iliac bones and multiple vertebral bodies. Sacral bone biopsy was performed giving us the diagnose of a metastatic Medullary Thyroid Carcinoma (MTC). A FineNeedle Aspiration (FNA) of the thyroid nodule and cervical lymph node showed calcitonin levels of 31.1pg/mL added with positive immunohistochemistry for chromogranin,synaptophysin, CD56 and Calcitonin in a focal manner, confirming the hypothesis of Undifferentiated CMT. Genetic testing was performed by next-generation sequencing of the genes ATM, ATR, CDKN2A, EGLN1, FH, HRAS, KIF1B, KMT2D, MAX, MDH2, MERTK, MET, NF1, PIK3CA, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, TP53 (including promoter), VHL, which results were negative for all pathogenic variants, probably pathogenic or VUS therefore being considered a sporadic MTC. Patient was referred for cervical radiotherapy and started Vandetanib. Conclusion Serum CTN is the main diagnostic and surveillance marker of MTC. CEA is another marker that must be taken into account. We report the case of a young patient diagnosed with metastatic RET negative MTC with disproportionate values of CTN and CEA, which suggests its undifferentiated feature, revealing the importance of joint assessment of these two markers. Presentation: No date and time listed

Introduction: Choice of mode of childbirth by women has been addressed for some decades. In Brazil, cesarean delivery rates reached 55% in 2018 and, according to doctors, this is mainly due to women ́s request. Understanding how women perceive autonomy in choosing the mode of childbirth is, though, important. Bioethics allows us to reflect broadly on the issue. Objectives: There are many ways to view the autonomy, thus, this paperwork goal is to understand how women who had recently given birth viewed their empowerment over choosing their mode of delivery and also draw a possible path of autonomy construction or the lack of it that may contribute to giving women more empowerment over choosing their mode of delivery. Methodology: A questionnaire was applied to ten women who gave birth for the first time within 12 and 48 hours after labor in a specific hospital between July of 2019 and November of 2019. Then, the interviews were analyzed using Bardin’s content analysis method. Results: Financial expenditures and work: within the 10 interviewed women, 7 referred to work and/or split their home expenses which was a way to see whether they had financial autonomy or not. The women’s empowerment also reflects their reproductive planning and their anti-pregnancy chosen methods. Contraception: it was observed that some of our interviewees did not participate on the contraception choices, despite the existing concern on educative practice, because they were reduced to an informative moment showing off that the health professional is the knowledge owner and the woman does not actively participate of the contraception and pregnancy planning. But the questionnaire was not effectively implemented to assess further information on this issue. Preliminary information and Healthcare professionals: childbirth preliminary information is essential to women’s full autonomy on the pregnancy. However, in the current assistance system it is seen an asymmetric relationship between the physician and the pregnant woman by not prioritizing the women’s knowledge over their bodies and reproduction processes which were observed in most of the interviews. Decision and mode of delivery choosing participation: only one of the interviewed women referred that she did not participate in the mode of delivery choice. However, despite choosing their mode of delivery, 6 interviewed women had shown that they had no autonomy on other areas of life that the questionnaire came up - financial expenditures and work, contraception, information about labor and decision and participation on choosing the mode of delivery. Discussion: The obtained data allowed us to imply that there are flaws in the women’s autonomy construction mainly about the mode of delivery which affects directly on choosing it, even though sometimes the woman believes she has chosen, but she didn’t know her options and by not knowing it she did not have a complete autonomy over her choices, indicating that there’s a long path in order to women to conquer the right of choosing the mode of delivery of their children. Conclusion: Women’s autonomy construction is affected by many factors. Health professional information is essential to this process, and the lack of it may directly affect the choice of the mode of delivery by women.