Preoperative prognostic nomogram for prophylactic steroid treatment of patients with subclinical Cushing’s syndrome

BackgroundSubclinical Cushing’s syndrome (SCS) is incidentally detected in a growing number of patients by advanced imaging technology. However, there is no consensus on the clinical management of SCS, especially in terms of whether prophylactic steroid treatment is necessary following adrenalectomy. In this study we developed a model based on preoperative indices for predicting postoperative adrenal insufficiency (AI) that can guide therapeutic decision-making.MethodsA total of 27 patients with SCS who underwent adrenalectomy between August 2016 and August 2019 were enrolled and divided into AI and non-AI groups. Cox proportional hazards regression and least absolute shrinkage and selection operator analyses were performed to select relevant clinical parameters. The predictive performance of our model was evaluated by time-dependent receiver operating characteristic (ROC) curve and calibration curve analyses.ResultsFive clinical parameters (apolipoprotein A1, neutrophil–lymphocyte ratio, total cholesterol, platelet count, and homocysteine) were identified as the best predictors of replacement therapy (RT). The areas under the ROC curve for our prognostic model were 0.833, 0.945, and 0.967 for 3-, 4-, and 5-day non-(N)RT, respectively. The calibration curve of the 5 independent RT-related markers showed a good fit between nomogram-predicted probability of NRT and actual NRT, suggesting that our model has good predictive value.ConclusionsOur prognostic nomogram can help clinicians identify patients with AI who would benefit from RT so that timely treatment can be initiated.KeywordsSubclinical Cushing’s syndrome (SCS); Replacement therapy (RT); Adrenal insufficiency (AI); Nomogram; Receiver operating characteristic (ROC)     

Chemotherapy-associated clonal hematopoiesis mutations should be taken seriously in plasma cell-free DNA KRAS/NRAS/BRAF genotyping for metastatic colorectal cancer

BackgroundGenotyping of plasma cell-free DNA (cfDNA) is an increasingly important method to assess the tumor mutation status in colorectal cancer (CRC) patients. Clonal hematopoiesis (CH) releases non-tumor somatic mutations into blood, causing false positive results in cfDNA-based tumor genotyping. It is still not clear if CH should be examined in all CRC patients undergoing cfDNA analysis.MethodsWe analyzed cfDNA KRAS, NRAS and BRAF genotypes in 236 metastatic CRC patients, who had matched tissue genotyping results, by next-generation sequencing using plasma cfDNA. The cfDNA-only mutations with allele frequencies (AFs) < 5% were highly suspicious for being CH-derived mutations. The origins of cfDNA mutations were confirmed by droplet digital polymerase chain reaction (ddPCR) using paired peripheral blood cells (PBCs) and CH-derived mutations were finally determined. One patient with a CH-derived mutation was followed up and the subpopulation of blood cells, in which CH was present, was investigated.ResultsThree CH-derived mutations, KRAS Q61H, KRAS G12D and KRAS G12V, were identified in the patient cohort. All three patients harboring corresponding CH-derived mutations had a prior chemotherapy history. The CH-derived KRAS G12V mutation in a patient was found only present in lymphocytes and persisting under treatment. For all cfDNA mutations, the CH-derived ones were clustered in the patients with < 5% mutation AF and prior chemotherapy.ConclusionThe prevalence of CH in CRC patients was limited, and prior chemotherapy was a contributing factor of CH. It is recommended for patients with < 5% mutation AF and prior chemotherapy to have genotyping analysis of their PBCs following plasma cfDNA genotyping.