Clinical features and biological implications of different U2AF1 mutation types in myelodysplastic syndromes

Abstract

U2AF1 mutations (U2AF1MT) occur commonly in myelodysplastic syndromes (MDS) without ring sideroblasts. The aim of this study was to investigate the clinical and biological implications of different U2AF1 mutation types in MDS. We performed targeted gene sequencing in a cohort of 511 MDS patients. Eighty-six patients (17%) were found to have U2AF1MT, which occurred more common in younger patients (P=0.001) and represented ancestral lesions in a substantial proportion (71%) of cases. ASXL1MT and isolated +8 were significantly enriched in U2AF1MT-positive cases, whereas TP53MT, SF3B1MT and complex karyotypes were inversely associated with U2AF1MT. U2AF^S34 subjects were enriched for isolated +8 and were inversely associated with complex karyotypes. U2AF1MT was significantly associated with anemia, thrombocytopenia, and poor survival in both lower risk and higher risk MDS. U2AF1^S34 subjects had more frequently platelet levels of <50 × 10⁹/L (P=0.043) and U2AF1^Q157/U2AF1^R156 subjects had more frequently hemoglobin concentrations at <80 g/L (P=0.008) and more often overt fibrosis (P=0.049). In conclusion, our study indicates that U2AF1MT is one of the earliest genetic events in MDS patients and that different types of U2AF1MT have distinct clinical and biological characteristics. This article is protected by copyright. All rights reserved.

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Clinical features and biological implications of different U2AF1 mutation types in myelodysplastic syndromes

Abstract

U2AF1 mutations (U2AF1MT) occur commonly in myelodysplastic syndromes (MDS) without ring sideroblasts. The aim of this study was to investigate the clinical and biological implications of different U2AF1 mutation types in MDS. We performed targeted gene sequencing in a cohort of 511 MDS patients. Eighty-six patients (17%) were found to have U2AF1MT, which occurred more common in younger patients (P=0.001) and represented ancestral lesions in a substantial proportion (71%) of cases. ASXL1MT and isolated +8 were significantly enriched in U2AF1MT-positive cases, whereas TP53MT, SF3B1MT and complex karyotypes were inversely associated with U2AF1MT. U2AF^S34 subjects were enriched for isolated +8 and were inversely associated with complex karyotypes. U2AF1MT was significantly associated with anemia, thrombocytopenia, and poor survival in both lower risk and higher risk MDS. U2AF1^S34 subjects had more frequently platelet levels of <50 × 10⁹/L (P=0.043) and U2AF1^Q157/U2AF1^R156 subjects had more frequently hemoglobin concentrations at <80 g/L (P=0.008) and more often overt fibrosis (P=0.049). In conclusion, our study indicates that U2AF1MT is one of the earliest genetic events in MDS patients and that different types of U2AF1MT have distinct clinical and biological characteristics. This article is protected by copyright. All rights reserved.

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The relationship between physical and psychological symptoms and health care utilization in hospitalized patients with advanced cancer

BACKGROUND

Patients with advanced cancer often experience frequent and prolonged hospitalizations; however, the factors associated with greater health care utilization have not been described. We sought to investigate the relation between patients' physical and psychological symptom burden and health care utilization.

METHODS

We enrolled patients with advanced cancer and unplanned hospitalizations from September 2014-May 2016. Upon admission, we assessed physical (Edmonton Symptom Assessment System [ESAS]) and psychological symptoms (Patient Health Questionnaire 4 [PHQ-4]). We examined the relationship between symptom burden and healthcare utilization using linear regression for hospital length of stay (LOS) and Cox regression for time to first unplanned readmission within 90 days. We adjusted all models for age, sex, marital status, comorbidity, education, time since advanced cancer diagnosis, and cancer type.

RESULTS

We enrolled 1,036 of 1,152 (89.9%) consecutive patients approached. Over one-half reported moderate/severe fatigue, poor well being, drowsiness, pain, and lack of appetite. PHQ-4 scores indicated that 28.8% and 28.0% of patients had depression and anxiety symptoms, respectively. The mean hospital LOS was 6.3 days, and the 90-day readmission rate was 43.1%. Physical symptoms (ESAS: unstandardized coefficient [B], 0.06; P < .001), psychological distress (PHQ-4 total: B, 0.11; P = .040), and depression symptoms (PHQ-4 depression: B, 0.22; P = .017) were associated with longer hospital LOS. Physical (ESAS: hazard ratio, 1.01; P < .001), and anxiety symptoms (PHQ-4 anxiety: hazard ratio, 1.06; P = .045) were associated with a higher likelihood for readmission.

CONCLUSIONS

Hospitalized patients with advanced cancer experience a high symptom burden, which is significantly associated with prolonged hospitalizations and readmissions. Interventions are needed to address the symptom burden of this population to improve health care delivery and utilization. Cancer 2017. © 2017 American Cancer Society.

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The relationship between physical and psychological symptoms and health care utilization in hospitalized patients with advanced cancer

BACKGROUND

Patients with advanced cancer often experience frequent and prolonged hospitalizations; however, the factors associated with greater health care utilization have not been described. We sought to investigate the relation between patients' physical and psychological symptom burden and health care utilization.

METHODS

We enrolled patients with advanced cancer and unplanned hospitalizations from September 2014-May 2016. Upon admission, we assessed physical (Edmonton Symptom Assessment System [ESAS]) and psychological symptoms (Patient Health Questionnaire 4 [PHQ-4]). We examined the relationship between symptom burden and healthcare utilization using linear regression for hospital length of stay (LOS) and Cox regression for time to first unplanned readmission within 90 days. We adjusted all models for age, sex, marital status, comorbidity, education, time since advanced cancer diagnosis, and cancer type.

RESULTS

We enrolled 1,036 of 1,152 (89.9%) consecutive patients approached. Over one-half reported moderate/severe fatigue, poor well being, drowsiness, pain, and lack of appetite. PHQ-4 scores indicated that 28.8% and 28.0% of patients had depression and anxiety symptoms, respectively. The mean hospital LOS was 6.3 days, and the 90-day readmission rate was 43.1%. Physical symptoms (ESAS: unstandardized coefficient [B], 0.06; P < .001), psychological distress (PHQ-4 total: B, 0.11; P = .040), and depression symptoms (PHQ-4 depression: B, 0.22; P = .017) were associated with longer hospital LOS. Physical (ESAS: hazard ratio, 1.01; P < .001), and anxiety symptoms (PHQ-4 anxiety: hazard ratio, 1.06; P = .045) were associated with a higher likelihood for readmission.

CONCLUSIONS

Hospitalized patients with advanced cancer experience a high symptom burden, which is significantly associated with prolonged hospitalizations and readmissions. Interventions are needed to address the symptom burden of this population to improve health care delivery and utilization. Cancer 2017. © 2017 American Cancer Society.

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A Case of Nivolumab-Induced Severe Mononeuropathy Multiplex and Rhabdomyolysis

We report an 81-year-old man with multiple liver metastases after tumorectomy for primary mediastinal malignant melanoma, who experienced limb weakness and sensory disturbance after nivolumab monotherapy. He was diagnosed with nivolumab-induced mononeuropathy multiplex and rhabdomyolysis based on serologic examination, muscle biopsy, magnetic resonance imaging of the limbs, and a nerve conduction study. A course of intravenous methylprednisolone (mPSL) was initiated at 1 g/day for 3 days. After that, oral prednisolone (PSL) was started at 1 mg/kg/day and gradually tapered. Limb muscle strength improved, but when PSL was reduced to 0.3 mg/kg/day, the weakness recurred, and a nerve conduction study showed exacerbation of mononeuropathy multiplex. The patient was again administered intravenous mPSL (0.5 g/day for 3 days) followed by oral PSL at 0.5 mg/kg/day, and his neurological symptoms improved. Nivolumab, an immune checkpoint inhibitor, is used for the treatment of advanced melanoma and other cancers and causes various immune-related adverse events (irAEs). However, neurological irAEs related to nivolumab are rare. Furthermore, there are no reports of simultaneous nerve and muscle impairment. Unexpected irAEs affecting various organs should be recognized and treated appropriately.

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[Abnormalities of DNA repair and gynecological cancers].

Related Articles

[Abnormalities of DNA repair and gynecological cancers].

Bull Cancer. 2017 Oct 17;:

Authors: Auguste A, Leary A

Abstract
The demonstration of frequent defects in the DNA damage response in high grade ovarian cancer has paved the way for a new therapeutic approach aimed at exploiting this unique vulnerability. The efficacy of poly (ADP) ribose polymerase inhibitors (PARPi) in patients with homologous recombination (HR) DNA repair deficient ovarian cancer (OC) resulting from a BRCA1/2 mutation has provided the proof of concept for synthetic lethality. Thus, olaparib is now approved by the EMA as maintenance therapy after response to a platinum regimen for patients with recurrent, platinum-sensitive, high-grade serous, BRCA1/2-mutated ovarian cancer. Furthermore, several recent trials in OC have demonstrated that the benefit of PARPi may not be limited to patients with BRCA mutations. These data, combined with genomic studies suggesting that a significant proportion of OC may harbor somatic and germline alterations in other HR genes open huge perspectives for exploiting DNA repair as a therapeutic strategy. The current priorities are to (i) determine whether new biomarkers of homologous recombination deficiency may identify the BRCA wild-type subset likely to derive benefit from PARPi; (ii) to determine whether the efficacy of PARPi can be improved by combinatorial strategies (with chemotherapy, radiotherapy, immunotherapy, anti-angiogenesis or DNA repair inhibitors) and (iii) to develop new approaches exploiting DNA repair deficiencies in ovarian and other gynecological tumors.

PMID: 29054544 [PubMed - as supplied by publisher]

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