ABSTRACT
BACKGROUND: POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs. PATIENTS AND METHODS: In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/- anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures. RESULTS: POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% confidence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature. CONCLUSIONS: Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival.
Subject(s)
Colorectal Neoplasms , DNA Polymerase III , DNA Polymerase II , Immune Checkpoint Inhibitors , Mutation , Poly-ADP-Ribose Binding Proteins , Humans , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Male , Female , Immune Checkpoint Inhibitors/therapeutic use , Middle Aged , Aged , DNA Polymerase II/genetics , Poly-ADP-Ribose Binding Proteins/genetics , DNA Polymerase III/genetics , Adult , Microsatellite Instability , Aged, 80 and over , DNA Mismatch RepairABSTRACT
The change from the sociology of medicine to the sociology of health comes about in a post-modern social context characterized by a complex and ambiguous situation. This is particularly true in the case of maternity where communication between people of different knowledge is fundamental: the researcher, doctor and female patient tend to lean towards an auto-referential relationship based on an informative communication method (as emerged from a survey on how women patients received information in the cities of Bologna and Urbino). Adopting a relational type communication based on listening, the three subjects can create a common system which, thanks also to the support of modern technology, can help to easily overcome the difficulties encountered.
Subject(s)
Communication , Maternal Behavior , Patient Education as Topic , Professional-Patient Relations , Female , Humans , Physician-Patient Relations , Pregnancy , Research , SociologyABSTRACT
This study was undertaken in order to evaluate the plasma glucose response to oral glucose tolerance test (OGTT, 100 g) and the HbA1c values in pregnant women at different gestational ages. One-hundred twenty-nine OGTTs have been performed in 75 pregnancies. The results obtained show a decrease in glucose tolerance during pregnancy. Mean HbA1c value was significantly higher in women with gestational diabetes mellitus, but values of subjects with gestational diabetes and normal glucose tolerance overlapped widely. In conclusion, HbA1c is not a sensitive parameter in the diagnosis of gestational diabetes mellitus. Further studies are necessary to evaluate its specificity and prognostic significance.
Subject(s)
Pregnancy in Diabetics/blood , Administration, Oral , Adult , Blood Glucose/analysis , Body Weight , Female , Glucose Tolerance Test , Glycated Hemoglobin/analysis , Humans , Maternal Age , Pregnancy , Pregnancy in Diabetics/diagnosis , PrognosisABSTRACT
Renal hemodynamic changes and insulin-resistance are normally observed in pregnancy. This study was aimed at evaluating the presence of microalbuminuria in normotensive pregnant subjects with normal or abnormal glucose tolerance. Nineteen pregnant women have been evaluated by oral glucose tolerance test (OGTT, 100 g) and by urine testing for microalbuminuria at 10 weeks of gestation. Eighteen and 14 women have been reexamined respectively at 24 and 32 weeks of gestation. In the subjects examined there was no correlation between microalbuminuria and abnormal glucose tolerance. Microalbuminuria, however, absent when the subjects were examined at 10 weeks of pregnancy, was present in 36% of women examined at 32 weeks of gestation. In conclusion, probably due to renal hemodynamic changes, microalbuminuria appears frequently in late pregnancy.
