Endoscopical and pathological dissociation in severe colitis induced by immune-checkpoint inhibitors

Checkpoint inhibitors have improved the survival of patients with advanced tumors and show a manageable toxicity profile. However, auto-immune colitis remains a relevant side effect, and combinations of anti-PD1/PDL1 and anti-CTLA-4 increase its incidence and severity. Here, we report the case of a 50-year-old patient diagnosed with stage IV cervical cancer that relapsed following radical surgery, external radiation/brachytherapy and standard chemotherapy. She was subsequently treated with Nivolumab and Ipilimumab combination and developed grade 2 colitis presenting a dissociation between endoscopic and pathological findings. At cycle 10 the patient reported grade 3 diarrhea and abdominal discomfort, without blood or mucus in the stools. Immunotherapy was withheld and a colonoscopy was performed, showing normal mucosa in the entire colon. Puzzlingly, histologic evaluation of randomly sampled mucosal biopsy of the distal colon showed an intense intraepithelial lymphocyte infiltration with crypt loss and some regenerating crypts with a few apoptotic bodies set in a chronically inflamed lamina propria, consistent with the microscopic diagnosis of colitis. Treatment with methylprednisolone 2 mg/kg was initiated which led to a decrease in the number of stools to grade 1. Additional investigations to exclude other causes of diarrhea rendered negative results. The patient experienced a major partial response and, following the resolution of diarrhea, she was re-challenged again with immunotherapy, with the reappearance of grade 2 diarrhea, leading to permanent immunotherapy interruption. We conclude and propose that performing random colonic biopsies should be considered in cases of immune checkpoint-associated unexplained diarrhea, even when colonoscopy shows macroscopically normal colonic mucosa inflammatory lesions

Identification of demand characteristics in the production of sires using a conceptual model of quality function deployment: a case study Determinação das características da demanda para produção de touros por meio de um modelo conceitual de desdobramento da função qualidade: um estudo de caso

The objective of this study is to identify demands of customers of a sire-producing company in Rio Grande do Sul, Brazil, by using a methodology adapted from quality function deployment tool. The adaptation consisted on the fact that matrices are treated in an unified manner among product and services due to the high perception of inter-relationship among these business components. The results evidenced that clients priorize traits related to the product, especially genetic value of the bulls. Service items were also highlighted, and they may be presented as an opportunity of differentiation among suppliers. Customer profile influenced priority order inasmuch as farmers with no technical services prioritized performance traits over genetic traits, opposing to those who were assisted and to technical consultants. Concerning to farm size, there were changes only in the tertiary level of the priority order of the demands. The adaptation of the methodology for joint analysis interfered in the results, especially in service prioritization. This study contributed to formatting a model for using quality function deployment in sire production, helping to identify quality demands and its priority levels for the population and researched company, and it may be used in further studies on the product beef sires.<br>Este trabalho foi realizado com o objetivo de identificar as demandas dos clientes de uma empresa produtora de touros de corte no Rio Grande do Sul por meio de uma metodologia adaptada da ferramenta desdobramento da função qualidade. A adaptação consistiu no fato de que as matrizes são tratadas de forma unificada entre o produto e os serviços, devido à percepção do elevado nível de inter-relacionamento entre esses componentes no negócio. Os resultados evidenciaram que os clientes priorizam as características relacionadas ao produto, especialmente o valor genético dos touros. Os itens de serviços também se destacaram, podendo configurar-se como uma oportunidade de diferenciação entre as empresas fornecedoras. O perfil dos clientes influenciou a ordem de priorização, uma vez que os produtores sem assistência técnica priorizaram as características de desempenho às genéticas, ao contrário dos assistidos e dos consultores técnicos. No tamanho da propriedade, só houve alterações na ordem de priorização no nível terciário das demandas. A adaptação da metodologia para a análise conjunta interferiu no resultado, principalmente na priorização dos serviços. O estudo contribuiu com a formatação de um modelo de uso do desdobramento da função qualidade na produção de touros, auxiliando na identificação da qualidade demandada e no seu nível de priorização para a população e empresa pesquisada, podendo ser utilizado em outros estudos para o produto touro

Custos da qualidade e da manufatura: um estudo de caso na indústria química Quality and manufacturing cost: a case study in the chemical industry

Este trabalho relata um estudo de caso envolvendo a otimização experimental de uma receita química. O estudo abrange as etapas de identificação do problema, planejamento do experimento, modelagem individual das variáveis de resposta, definição de uma função objetivo e otimização. Na identificação do problema e no planejamento do experimento foi utilizada uma estrutura matricial para reunir e organizar as informações. O experimento contemplou cinco fatores controláveis e dez variáveis de resposta. Na etapa de modelagem individual, foram construídos modelos para a média e a variabilidade de cada uma das variáveis de resposta. A função objetivo utilizada no estudo de otimização foi a Função de Perda Quadrática Multivariada, proposta por Ribeiro & Elsayed, acrescida dos custos de matéria prima e energia. Assim, a otimização foi conduzida levando em conta tanto os custos decorrentes da má qualidade (capturados pela função de perda) como os custos de matéria prima e energia. A otimização permitiu definir o melhor ajuste para os fatores controláveis. Ao final é feita uma análise de sensibilidade e é sugerido um envelope de operação para o controle do processo.<br>This paper presents a case study where the optimization of a chemical mixture was accomplished. The study included the following steps: problem identification, design of an experiment, model building for each individual response, choice of an objective function, and optimization. In the steps of problem identification and design of the experiment, a matrix was used to gather and to organize the information. Five control factors and ten response variables were included in the experiment. In the step of model building, models for mean and variability for each response variable were built. The objective function used for optimization was an extended version of the Multivariate Quadratic Loss Function proposed by Ribeiro & Elsayed (1995). The optimization was carried out taking into account the losses due to poor quality as well as the losses due to the costs of raw materials and energy. After the optimization it was possible to identify the best set for the control factors. A sensibility analysis was performed and an operational envelop for process control is suggested

Endoscopical and pathological dissociation in severe colitis induced by immune-checkpoint inhibitors

Checkpoint inhibitors have improved the survival of patients with advanced tumors and show a manageable toxicity profile. However, auto-immune colitis remains a relevant side effect, and combinations of anti-PD1/PDL1 and anti-CTLA-4 increase its incidence and severity. Here, we report the case of a 50-year-old patient diagnosed with stage IV cervical cancer that relapsed following radical surgery, external radiation/brachytherapy and standard chemotherapy. She was subsequently treated with Nivolumab and Ipilimumab combination and developed grade 2 colitis presenting a dissociation between endoscopic and pathological findings. At cycle 10 the patient reported grade 3 diarrhea and abdominal discomfort, without blood or mucus in the stools. Immunotherapy was withheld and a colonoscopy was performed, showing normal mucosa in the entire colon. Puzzlingly, histologic evaluation of randomly sampled mucosal biopsy of the distal colon showed an intense intraepithelial lymphocyte infiltration with crypt loss and some regenerating crypts with a few apoptotic bodies set in a chronically inflamed lamina propria, consistent with the microscopic diagnosis of colitis. Treatment with methylprednisolone 2 mg/kg was initiated which led to a decrease in the number of stools to grade 1. Additional investigations to exclude other causes of diarrhea rendered negative results. The patient experienced a major partial response and, following the resolution of diarrhea, she was re-challenged again with immunotherapy, with the reappearance of grade 2 diarrhea, leading to permanent immunotherapy interruption. We conclude and propose that performing random colonic biopsies should be considered in cases of immune checkpoint-associated unexplained diarrhea, even when colonoscopy shows macroscopically normal colonic mucosa inflammatory lesions

Identification of mutations associated with acquired resistance to sunitinib in renal cell cancer

Sunitinib is one of the most widely used targeted therapeutics for renal cell carcinoma (RCC), but acquired resistance against targeted therapies remains a major clinical challenge. To dissect mechanisms of acquired resistance and unravel reliable predictive biomarkers for sunitinib in RCC, we sequenced the exons of 409 tumor-suppressor genes and oncogenes in paired tumor samples from an RCC patient, obtained at baseline and after development of acquired resistance to sunitinib. From newly arising mutations, we selected, using in silico prediction models, six predicted to be deleterious, located in G6PD, LRP1B, SETD2, TET2, SYNE1, and DCC. Consistently, immunoblotting analysis of lysates derived from sunitinib-desensitized RCC cells and their parental counterparts showed marked differences in the levels and expression pattern of the proteins encoded by these genes. Our further analysis demonstrates essential roles for these proteins in mediating sunitinib cytotoxicity and shows that their loss of function renders tumor cells resistant to sunitinib in vitro and in vivo. Finally, sunitinib resistance induced by continuous exposure or by inhibition of the six proteins was overcome by treatment with cabozantinib or a low-dose combination of lenvatinib and everolimus. Collectively, our results unravel novel markers of acquired resistance to sunitinib and clinically relevant approaches for overcoming this resistance in RCC