Genetic Risk of Second Malignant Neoplasm after Childhood Cancer Treatment: A Systematic Review.

Second malignant neoplasm (SMN) is one of the most severe long-term risks for childhood cancer survivors (CCS), significantly impacting long-term patient survival. While radiotherapy and chemotherapy are known risk factors, the observed inter-individual variability suggests a genetic component contributing to the risk of SMN. This article aims to conduct a systematic review of genetic factors implicated in the SMN risk among CCS. Searches were performed in PubMed, Scopus, and Web of Sciences. Eighteen studies were included (eleven candidate gene studies, three genome-wide association studies, and four whole exome/genome sequencing studies). The included studies were based on different types of first cancers, investigated any or specific types of SMN, and focused mainly on genes involved in drug metabolism and DNA repair pathways. These differences in study design and methods used to characterize genetic variants limit the scope of the results and highlight the need for further extensive and standardized investigations. However, this review provides a valuable compilation of SMN risk-associated variants and genes, facilitating efficient replication and advancing our understanding of the genetic basis for this major risk for CCS.

Skin autofluorescence of advanced glycation end-products relates to new cardiovascular events in type 2 diabetes: A longitudinal observational study.

BACKGROUND: Cardiovascular disease is frequent in type 2 diabetes mellitus (T2DM). We investigated the relationship between skin autofluorescence (SAF) of advanced glycation end-products and later cardiovascular events (CVEs) in patients with T2DM. RESEARCH DESIGN AND METHODS: We conducted a retrospective analysis of 504 patients hospitalized for uncontrolled and/or complicated T2DM between 2009 and 2017. SAF was measured using an AGE-Reader. Participants were followed up from admission to December 2020, for the onset of a CVE (myocardial infarction, stroke, revascularization procedures or cardiovascular death). The relationship between SAF and CVE was analyzed by multivariable Cox regression. Log-rank curves were used to compare CVE-free survival in patients whose SAF at admission was above versus below the whole-population median. The analysis was repeated in subjects without/with macroangiopathy (defined as myocardial infarction, stroke, peripheral revascularization) at baseline. FINDINGS: During 54 months of follow-up, 69 (13.7%) patients had a CVE. Baseline SAF was significantly higher in patients with T2DM who later experienced a CVE (2.89 ± 0.70 arbitrary units versus 2.64 ± 0.62 in others, P = 0.002). This relationship was significant after adjusting for age, sex, conventional risk factors (diabetes duration, HbA1c, arterial hypertension, dyslipidemia, smoking, body mass index), vascular complications, C-reactive protein, and treatments for diabetes. The CVE-free survival curves differed between subjects whose SAF was above the whole-population median (log-rank: P = 0.002) and those whose SAF was above the macroangiopathy-free sub-population median (log-rank: P = 0.016). CONCLUSION: SAF of advanced glycation end-products was related to a higher incidence of later CVE in patients with T2DM.

The skin autofluorescence may help to select patients with Type 2 diabetes candidates for screening to revascularization procedures.

Chen et al. recently related the skin autofluorescence (SAF) of Advanced Glycation End-products to subclinical cardiovascular disease in the 3001 participants from the general population (Rotterdam study), with a particularly close relationship for the 413 subjects with diabetes. Because conventional vascular risk factors do not capture the risk in diabetes very well, this relationship may help to select high-risk individuals for the screening of silent myocardial ischemia, which has yet to prove its benefit in randomized controlled trials. Among 477 patients with uncontrolled and/or complicated Type 2 Diabetes, we measured the SAF ten years ago, and we registered new revascularizations during a 54-months follow-up. The patients with SAF > 2.6 Arbitrary units (AUs), the median population value, experienced more revascularizations of the coronary (17/24) and lower-limb arteries (13/17) than patients with a lower SAF, adjusted for age, sex, diabetes duration, vascular complications, and smoking habits: HR 2.17 (95% CI: 1.05-4.48), p = 0.035. The SAF has already been reported to predict cardiovascular events in three cohorts of people with diabetes. We suggest that its measurement may help to improve the performance of the screening before vascular explorations and revascularizations.

More new cancers in type 2 diabetes with diabetic foot disease: A longitudinal observational study.

OBJECTIVE: Cancer has been proposed as the primary cause of death in type 2 diabetes (T2D). The life expectancy is reduced after a diabetic foot ulcer. We investigated whether Diabetic Foot Disease related to an increased risk of developing a new cancer. RESEARCH DESIGN AND METHODS: We conducted a retrospective analysis on a cohort of patients hospitalized for T2D between 2009 and 2017, stratified for the risk of diabetic foot ulcer (International Working Group on Diabetic Foot classification). We highlighted new cancers in their medical records until December 2020. The relationship between Diabetic Foot Disease and later cancers was analyzed by multivariable Cox regression and survival curves were compared. RESULTS: Among 519 patients, 27% had a Diabetic Foot Disease, and 159 were classified as grades 1 or 2 (at risk). As compared to the 218 patients graded 0 according to the IWGDF, they were more men, older, with a longer duration of diabetes, more vascular complications, a greater incidence of insulin use, and a higher skin autofluorescence. During the 54 months of follow-up, 63 (12.1%) new cancers were diagnosed. Baseline Diabetic Foot Disease was significantly associated with a higher risk of cancer (multivariable adjusted Hazard ratio: 2.08, 95%CI: 1.02-4.25), whereas the relation was not significant for subjects at risk of DFU (HR: 1.65, 95%CI:0.81-3.35) CONCLUSION: The risk of cancer was increased twofold in T2D with Diabetic Foot Disease.

Predictive utility of stress tests in the detection of asymptomatic coronary artery disease in atherosclerotic stroke patients.

INTRODUCTION: Whether and how atherosclerotic ischemic stroke patients should be investigated for asymptomatic coronary artery disease (CAD) is controversial. Our aim was to carry out a prospective observational study to determine the frequency and predictors of functionally significant coronary stenosis in these patients as well as the predictors of major adverse cardiovascular events (MACE) during post-stroke follow-up. MATERIAL AND METHODS: From January 2014 to June 2018, patients with atherosclerotic ischemic stroke were referred from the stroke unit to our cardiovascular department 3+/- 1 months after the acute event where they benefited from evaluation of cardiovascular risk factors, vascular and myocardial disease. Main outcome was defined as the prevalence of myocardial ischemia defined by perfusion stress echography 3 months after stroke. Secondary outcome (MACE) was defined as the incidence of stroke, transient ischemic attack (TIA), acute coronary syndrome, cardiovascular (CV) death or coronary or peripheral revascularization during a 3 year follow-up. RESULTS: Three hundred and twenty five patients (92% of strokes and 8% TIA) were included and median follow-up was 1075 days. At 3 months post-stroke, myocardial ischemia was found in 17 patients (5.2%). During the 3 year follow-up, 11 MACE occurred (3.4%, all in the non-ischemic group) of which 6 were recurrent strokes. In multivariate analysis, myocardial ischemia was significantly associated with the number of atheromatous vascular beds (OR 4.3; 95% CI, 1.7 to 10.6) and ECG signs of necrosis (OR 6.5; 95% CI, 1.9 to 21.9). MACE were also associated with ECG signs of necrosis (OR 3.5; 95% CI, 1.3 to 9.1), and unrelated to myocardial ischemia. CONCLUSION: Myocardial ischemia and CV events were infrequent and both strongly associated with ECG signs of necrosis, suggesting a low yield of stress tests and the potential for a more straightforward algorithm in the choice of patients eligible to coronary angiogram or other coronary imaging in post-stroke setting.

The skin autofluorescence of advanced glycation end-products relates to the development of foot ulcers in type 2 diabetes: A longitudinal observational study.

OBJECTIVES: The long-term glycemic memory contributes to vascular complications in type 2 diabetes, including those patients with Diabetic Foot Ulcers (DFU). We investigated whether the skin autofluorescence (SAF) of Advanced Glycation End-products related to later DFUs. RESEARCH DESIGN & METHODS: SAF was measured with an AGE-Reader in a retrospective cohort of patients hospitalized from 2009 to 2017 for Type 2 Diabetes. New DFUs were registered until the year 2020 and survival analyses were performed. RESULTS: The 517 patients (men: 58.0 %), were 62 ± 9 years old at baseline, with a duration of diabetes of 14 ± 10 years, HbA1c: 8.7 ± 1.8 %, complications included 33.8 % macroangiopathies, 44.9 % diabetic kidney diseases and 26.7 % retinopathies. According to the IWGDF classification, the grades of risk for DFU were 0 for 43.2 %, 1 for 23.9 %, 2 for 7.2 %, and 3 for 25.7 %. During the 53 months of follow-up, 58 new DFUs occurred, mostly in patients with SAF higher than its median value (2.65 AU). Adjusted for age and sex, conventional risk factors (duration and control of diabetes, arterial hypertension, dyslipidemia, smoking), and other complications (macroangiopathy, diabetic kidney disease, retinopathy), SAF related to later DFUs. Adjusted for the IWGDF classification, SAF related to new DFUs (HR: 1.81, 95%CI:1.25-2.62). This relationship was significant for the 403 subjects without previous history of DFU (HR: 2.32, 95%CI: 1.36-3.95). SAF did not predict recurrence for patients with a previous history of DFUs. CONCLUSION: SAF, a simple non-invasive marker of glycemic memory, independently predicts the occurrence of a first foot ulcer in patients with Type 2 Diabetes.

Diabetic retinopathy relates to the incidence of foot ulcers and amputations in type 2 diabetes.

AIMS: We investigated whether Diabetic Retinopathy (DR) is related to Diabetic Foot Ulcer (DFU) development, adjusted for the stratification of the International Work Group on Diabetic Foot (IWGDF) guidance. MATERIALS AND METHODS: DR and IWGDF stratification was registered retrospectively in patients hospitalised from 2009 to 2017 for uncontrolled and/or complicated type 2 diabetes. New DFUs were registered until 2020. Survival analyses categorised the subjects for DR, and multivariate Cox regression adjusted for confounders. RESULTS: The 522 patients (57.9% male) were 62 ± 9 years old with a diabetes duration of 14 ± 10 years, HbA1c of 8.7 ± 1.8%, 33.9% macroangiopathies and 44.8% diabetic kidney diseases. Their grades of DFU risk were 0 for 43.3%, 1 for 23.9%, 2 for 7.1%, and 3 for 25.6%. During the 52 months follow-up (Inter Quartile Range: 32-71), 58 new DFUs and 18 lower-limb amputations occurred, mostly in patients with DR present in 140 (26.8%) patients. Adjusted for age, sex and conventional risk factors (duration and control of diabetes, arterial hypertension, and dyslipidemia), and other complications (macroangiopathy and diabetic kidney disease), DR was associated with a greater incidence of DFUs. Adjusted for the IWGDF classification, DR was related to new DFUs (HR: 2.51, 95%Confidence Interval [CI]: 1.48-4.26) and amputations (HR: 3.56, 95%CI: 1.26-10.07). This relationship persisted in ascending IWGDF grades with incidences of DFUs from 2/1000 (grade 0, no DR) to 121/1000 patient-years (grade 3 and DR) and amputations from 0 (grade 0, no DR) to 38/1000 patient-years (grade 3 and DR). CONCLUSIONS: Diabetic retinopathy independently relates to the incidence of foot ulcers and amputations in patients hospitalised for type 2 diabetes.

Cardiovascular events after a dramatic reduction of HbA1c in hospitalized subjects with type 2 diabetes and high long-term glucose exposure.

OBJECTIVE: In long-lasting diabetes, a dramatic reduction of HbA1c can precede adverse events such as worsening retinopathies or painful neuropathies. We have now analyzed its possible link with later cardiovascular events in subjects with type 2 diabetes, according to their long-term glucose exposure evaluated by skin autofluorescence (SAF) measured with an AGE-READER (Diagnoptics, Groningen, The Netherland). RESEARCH DESIGN AND METHODS: We studied retrospectively a cohort of patients hospitalized for uncontrolled and/or complicated type 2 diabetes from 2009 to 2017. A previous dramatic reduction of HbA1c was defined by more than -1.5 %/4 months, and later cardiovascular events as myocardial infarction, stroke, revascularization procedures, and cardiovascular-related death. Survival analyses were performed before and after categorizing the subjects for their SAF. RESULTS: The 386 subjects were 57.5 % men, 62 ± 9 years old, with a 14 ± 9 years duration of diabetes, most were treated by insulin (63.7 %). The dramatic HbA1c reducers (-3.0 ± 1.5 %) represented 16.5 % of the population. During the 51 months (IQR: 30-71) of follow-up, 53 cardiovascular events occurred and were related to the SAF (2.70 ± 0.64 AUs). Linkage was established between the SAF, the reduction of HbA1c and the cardiovascular events (p = 0.017). With a SAF higher than the median (2.65 AUs), the dramatic reduction of HbA1c was related to later cardiovascular events (HR: 3.84, 95%CI: 1.68-8.76). CONCLUSIONS: A dramatic decline of HbA1c leads to a higher risk of cardiovascular events in hospitalized subjects with type 2 diabetes and a high long-term glucose exposure.

Skin autofluorescence predicts cancer in subjects with type 2 diabetes.

INTRODUCTION: Subjects with type 2 diabetes have an excess risk of cancer. The potential role of advanced glycation end products (AGEs) accumulated during long-term hyperglycemia in cancer development has been suggested by biological studies but clinical data are missing. AGEs can be estimated by measuring the skin autofluorescence. We searched whether the skin autofluorescence could predict new cancers in persons with type 2 diabetes. RESEARCH DESIGN AND METHODS: From 2009 to 2015, we measured the skin autofluorescence of 413 subjects hospitalized for uncontrolled or complicated type 2 diabetes, without any history of cancer. The participants were followed for at least 1 year and the occurrences of new cancers were compared according to their initial skin autofluorescences. RESULTS: The participants were mainly men (57.9%), with poorly controlled (HbA1c 72±14 mmol/mol or 8.7%±1.8%) and/or complicated type 2 diabetes. Their median skin autofluorescence was 2.6 (2.2-3.0) arbitrary units. Forty-five new cancer cases (10.9%) were registered during 4.8±2.3 years of follow-up: 75.6% of these subjects had skin autofluorescence higher than the median (χ2: p=0.001). By Cox regression analysis adjusted for age, gender, body mass index, history of smoking and renal parameters, skin autofluorescence >2.6 predicted a 2.57-fold higher risk of cancer (95% CI 1.28 to 5.19, p=0.008). This association remained significant after excluding the eight cancers that occurred in the 4 years after inclusion (OR 2.95, 95% CI 1.36 to 6.38, p=0.006). As a continuous variable, skin autofluorescence was also related to new cancers (OR 1.05, 95% CI 1.01 to 1.10, p=0.045). CONCLUSIONS: Skin autofluorescence, a potential marker of glycemic memory, predicts the occurrence of cancer in subjects with type 2 diabetes. This relation provides a new clinical argument for the role of AGEs in cancer. Their estimation by measuring the skin autofluorescence may help select subjects with diabetes in cancer screening programs.