Descrever a eficácia da quimioterapia nos cuidados paliativos em pacientes oncológicos. Trata-se de um estudo de revisão integrativa iniciado em abril de 2020, que utilizou como base de dados o Google Acadêmico, Medline, Scielo e PubMed. A estratégia PICO foi utilizada para a construção dos temas de pesquisa. De acordo com este método de busca, chegou-se a 255 artigos, e a definição por determinação dos critérios de exclusão foram selecionados 27 artigos originais utilizados nessa revisão. Os artigos selecionados foram analisados e organizados em quatro categorias temáticas, sendo: Cuidados Paliativos no Paciente Oncológico, Quimioterapia Paliativa em Tumores Sólidos, Quimioterapia Paliativa versus Qualidade de Vida e Competências e Cuidados da Enfermagem na Quimioterapia Paliativa. Verifica-se uma aceitação da quimioterapia paliativa em alguns casos e, em outros se identificam mais riscos do que benefícios, tornando imprópria a escolha desse tratamento. A escolha do tratamento deve ser feita seguindo avaliações individualizadas realizadas pela equipe responsável visando a melhor qualidade e expectativa de vida de cada paciente.

A high rate of hepatic, pancreatic and cardiac impairment by iron overload was demonstrated. Ferritin levels could not predict liver, heart or pancreas iron overload as measured by T2* magnetic resonance imaging. There was no correlation between liver, pancreas, liver and myocardial iron overload, neither between ferritin and fraction of labile plasma iron with liver, heart and pancreas T2* values.

Introduction KIT mutations, particularly the D816V mutation, are frequently found in patients with SM and play a central role in the pathogenesis of the disorder. A recent publication demonstrated pre-clinical evidence that inhibition of JAK-STAT signaling may inhibit KITD816V-mediated cell growth (Pardanani A et al, Leukemia 2010, 24:1378-1380), but there is no clinical data on the efficacy of JAK inhibitors in patients with MS. Objective To describe the case of a patient with KIT-mutated SM associated with myelofibrosis that was successfully treated with the JAK1/JAK2 inhibitor ruxolitinib Case Description A 67-years old male patient was referred to our center with an outside diagnosis of primary myelofibrosis (PMF). His main complaints included fatigue and pruritus. On physical examination, liver was enlarged 2 cm from right costal margin (RCM) and spleen was enlarged 8 cm from left costal margin (LCM). His complete blood count (CBC) showed Hb 13.9 g/dL, white blood cell count (WBC) was 22.41x109/L, and a platelet count of 702x109/L. His bone marrow (BM) biopsy was compatible with the diagnosis of PMF. He was found to be negative for the JAK2V617F-mutation. The patient was started on ruxolitinib at a dose of 20 mg twice daily. Four weeks from start of therapy, his spleen had decreased to 3 cm from LCM. The CBC at 4 weeks showed Hb 16 g/dL, WBC 12.8x109/L, platelets 459x109/L. After 16 weeks of therapy, the patient was feeling much better, and his spleen was down to <1 cm from LCM and liver was non-palpable. The CBC showed Hb 15.8 g/dL, WBC 23.44x109/L, platelet count 422x109/L. As of the time of this writing, the patient is still being treated with ruxolitinib and maintains his response. Since the patient was negative for the JAK2V617F-mutation and had presented with a clinical response to ruxolitinib, we proceeded with whole exome sequencing (WES) in order to detect mutations that might predict for response to ruxolitinib. Paired DNA (sorted CD66b-granulocytes/skin biopsy) was subjected to WES, sequence-aligned by Bowtie v2, and putative somatic variants detected via SomaticSniper (Washington University). Following in-house filters to decrease false-positive findings, a total of 124 putative somatic point mutations were detected in the CD66b-granulocytes sample. Two known oncogenic KIT mutations were found, D816V and K642E. The D816V mutation had a variant allele frequency (VAF) of 45%, indicating that it was present in the predominant clone, while the K642E mutation had a VAF of 28%, suggesting that it was subclonal and acquired later in the course of disease. No other tyrosine kinase or associated receptors (e.g. MPL) mutations were found. Since KIT mutations have not been previously reported in patients with PMF, we reviewed all clinical and laboratory data on the patient’s diagnosis. Tryptase staining of the BM biopsy slides showed aggregates of spindle-shaped mast cells that also stained positive for CD2 and CD25. A tryptase level was found to be elevated at 150 ng/ml. The KITD816V mutation was validated by Sanger sequencing. There were no lytic bone lesions, diarrhea, cytopenias or other “C” findings suggestive of aggressive SM. We changed the diagnosis from PMF to SM associated with myelofibrosis.  Even though the patients has features of myelofibrosis, no mutations commonly found in PMF were detected by WES, while the KITD816V mutation is probably the main driver of the disease due to its high allele frequency and known oncogenic role in SM. Currently, we are performing correlative studies to evaluate STAT3/5 phosphorylation in patient’s samples taken before and after therapy with ruxolitinib. Conclusion We believe this is the first case of a patient with KIT-mediated SM that was treated with a JAK inhibitor. The improvement in symptoms and other signs of myeloproliferation seen in this case suggest that JAK inhibition might be a therapeutic avenue in such patients, as expected from published pre-clinical data. A clinical trial evaluating JAK inhibitors in patients with SM should be conducted to further delineate the activity of this class of drugs in these patients. Disclosures: Santos: Novartis: Consultancy, Research Funding, Speakers Bureau. Off Label Use: Ruxolitinib for systemic mastocytosis.

Introduction: The development of next-generation sequencing has made it feasible to interrogate the entire genome or exome (coding genome) in a single experiment. Accordingly, our knowledge of the somatic mutations that cause cancer has increased exponentially in the last years. MPNs and MDS/MPD are chronic myeloid neoplasms characterized by an increased proliferation of one or more hematopoietic cell lineages, and an increased risk of transformation to acute myeloid leukemia (AML). MPNs and MDS/MPDs are heterogenous disorders, both in clinical presentation and in prognosis. We sought to determine the genetic landscape of Ph-negative MPNs and MDS/MPD through next-generation sequencing. Methods: Paired DNA (sorted CD66b-granulocytes/skin biopsy) from 102 patients with MPNs or MDS/MPD was subjected to whole exome sequencing on a Illumina HiSeq 2000 platform using Agilent SureSelect kit. Diagnosis included primary myelofibrosis (MF; N=42), essential thrombocythemia (ET; N=28), polycythemia vera (PV; N=12), chronic myelomonocytic leukemia (CMML; N=10), systemic mastocytosis (MS; N=6), MDS/MPD-Unclassified (N=2) and post-MPN AML (N=2). Tumor coverage was 150x and germline coverage was 60x. Somatic variants calls were generated by combining the output of Somatic Sniper (Washington University), Mutect (Broad Institute) and Pindel (Washington University). The combined output of these 3 tools was further filtered by in-house criteria in order to reduce false-positive calls (minimum coverage at both tumor/germline ≥8 reads; fraction of reads supporting alternate allele ≥10% in tumor and ≤10% in germline; ratio of allele fraction tumor:germline >2; excluding mutations seen in SNP databases). All JAK2 and CALR mutations were validated through Sanger sequencing. Validation of other somatic mutations is currently underway. Analysis of driver mutations was made with the Intogen web-based software, using the Oncodrive-FM and Oncodrive-cluster algorithms (www.intogen.org). Significantly mutated genes were considered as those with a q-value of <0.10. Results: We identified a total of 309 somatic mutations in all patients, with each patient having an average of 3 somatic abnormalities, fewer than most solid tumors that have been sequenced so far. Mutations occurred in 166 genes, and 40 of these were recurrently somatically mutated in Ph-negative MPNs. By the Oncodrive-FM algorithm, the following genes were identified as the most significantly mutated driver genes in Ph-negative MPNs and MDS/MPDs (in order of significance): CALR, ASXL1, JAK2, CBL, DNMT3A, U2AF1, TET2, TP53, RUNX1, EZH2, SH2B3 and KIT. By the Oncodrive-cluster algorithm, which considers clustering of mutations at a hotspot, the following genes were significantly mutated: KIT, JAK2, SRSF2 and U2AF1. Somatic mutations were seen in genes that are mutated at a low frequency in Ph-negative MPNs, including ATRX, BCL11A, BCORL1, BIRC5, BRCC3, CSF2RB, CUX1, IRF1, KDM2B, ROS1 and SUZ12. Consistent with the clinical phenotype, 96 patients (94%) had mutations that lead to increased cellular proliferation, either through activation of the JAK-STAT pathway (e.g. JAK2, CALR) or mutations that activated directly or indirectly signaling by receptor tyrosine kinases (e.g. FLT3, KIT, CBL). Besides biological pathways regulating cell proliferation, the most commonly implicated pathways included regulation of DNA methylation (e.g. DNMT3A, TET2), mRNA splicing (e.g. U2AF1, SRSF2) and histone modifications (e.g. ASXL1, EZH2), seen in 27%, 25% and 22% of patients, respectively. Abnormalities in these 3 pathways were more often seen in MF, MDS/MPD and CMML, as compared to PV and ET (65% vs. 20%; p<0.0001). Conclusions: Our study represents one of the largest series of patients with these neoplasms evaluated by whole exome sequencing, and together with the published data helps to delineate the genomic landscape of Ph-negative MPNs and MDS/MPDs. The majority of the most frequent mutations seen in Ph-negative MPNs have already been reported. Nevertheless, there are several low frequency mutations that need to be further studied and functionally validated in vitro and in vivo for a deeper knowledge of the pathophysiology of MPNs. Besides activation of cellular proliferation, abnormalities of DNA methylation, histone modification and mRNA splicing emerge as the most important biological pathways in these disorders. Disclosures No relevant conflicts of interest to declare.

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