Hematopoietic stem cell transplantation does not increase the risk of infection-related complications for pediatric patients with Hodgkin and non-Hodgkin lymphomas: A multicenter nationwide study.

BACKGROUND: Hodgkin (HL) and non-Hodgkin lymphoma (NHL) represent a spectrum of lymphoid malignancies that are often curable with currently applied treatment regimens; however, 15%-30% of lymphoma patients still suffer from relapsed or refractory (rel/ref) disease. Although hematopoietic stem cell transplantation (HSCT) improves outcomes of second-line therapy for lymphoma in childhood, the complication rates in this group of patients, especially infectious complications (IC), remain unclear. OBJECTIVE: The aim of this population-based cohort study was a retrospective analysis of incidence, epidemiology and profile of bacterial infections (BI), invasive fungal disease (IFD), and viral infections (VI) in primary or rel/ref lymphoma patients, both HL and NHL. PATIENTS AND METHODS: We subdivided lymphoma patients into three groups: patients with primary conventional chemotherapy/radiotherapy regimens (group A), patients with rel/ref lymphoma treated with second-line chemotherapy (group B), and rel/ref lymphoma patients who underwent HSCT (group C). The medical records of the patients were biannually reported by each pediatric oncology center, and the data were analyzed centrally. RESULTS: Within 637 patients with primary lymphoma, at least one IC was diagnosed in 255 (40.0%), among 52 patients with rel/ref lymphoma 24 (46.2%) ICs were observed, and in transplanted group, 28 (57.1%) out of 49 children were diagnosed with IC (P = .151). The distribution of etiology of IC differed between the patient groups (A, B, C), with a predominance of BI in group A (85.6% vs 72.0% and 47.9%, respectively), VI in group C (9% and 16.0% vs 46.6%, respectively), and IFD in group B (5.4% vs 12.0% vs 5.5%, respectively). Overall, 500 (68.0%) episodes of bacterial IC were diagnosed in the entire group. Apart from HL patients treated with chemotherapy, in all the other subgroups of patients Gram-positives were predominant. The rate of multidrug-resistant bacteria was high, especially for Gram-negatives (41.1% in group A, 62.5% in group B, and 84.6% in group C). The infection-related mortality was comparable for each group. CONCLUSIONS: The incidence of IC was comparable during first- and second-line chemotherapy and after HSCT, but their profile was different for primary or re/ref lymphoma and depended on the type of therapy.

Incidence, course, and outcome of Clostridium difficile infection in children with hematological malignancies or undergoing hematopoietic stem cell transplantation.

Clostridium difficile infection (CDI) is one of the most common causes of nosocomial infectious diarrhea in children during anticancer therapy or undergoing hematopoietic stem cell transplantation (HSCT) in Europe. Immunosuppression in these patients is a risk factor for CDI. Malignant diseases, age, acute graft-versus-host disease (aGVHD), HLA mismatch, or use of total body irradiation may play an important role in CDI course. The aim of this study was to evaluate the incidence, course, and outcome of CDI in children treated for malignancy or undergoing HSCT. Between 2012 and 2015, a total number of 1846 patients were treated for malignancy in Polish pediatric oncological centers (PHO group) and 342 underwent transplantation (HSCT group). In PHO group, episodes of CDI occurred in 210 patients (14%). The incidence of CDI was higher in patients with hematological malignancies in comparison to that with solid tumors. Patients with acute myeloblastic leukemia had shorter time to episode of CDI than those with acute lymphoblastic leukemia. Patients over 5 years and treated for acute leukemia had more severe clinical course of disease in PHO group. In HSCT group, CDI occurred in 29 (8%) patients. The incidence of CDI was higher in patients transplanted for acute leukemia. The recurrence rate was 14.7% in PHO and 20.7% in HSCT patients. CDI incidence was highest in patients with hematological malignancies. Most of patients experienced mild CDI. Age < 5 years and diagnosis other than acute leukemia were the positive prognostic factors influencing clinical CDI course.

High frequency of GJA12/GJC2 mutations in Turkish patients with Pelizaeus-Merzbacher disease.

Pelizaeus-Merzbacher disease is an early onset dysmyelinating leukodystrophy. About 80% of PMD cases have been associated with duplications and mutations of the proteolipid protein 1 (PLP1) gene. Pelizaeus-Merzbacher-like disease is a genetically heterogeneous autosomal recessive disease and rarely caused by mutations in gap junction protein α12 (GJA12/GJC2) gene. The molecular basis of the disease was investigated in a cohort of 19 Turkish families. This study identified novel chromosomal rearrangements proximal and distal to, and exclusive of the PLP1 gene, showed equal frequencies of PLP1 and GJA12/GJC2 mutations at least in our cohort, and suggested further genetic heterogeneity.

Evidence for disease penetrance relating to CNV size: Pelizaeus-Merzbacher disease and manifesting carriers with a familial 11 Mb duplication at Xq22.

The potential causes for the incomplete penetrance of Pelizaeus-Merzbacher disease (PMD) in female carriers of PLP1 mutations are not well understood. We present a family with a boy having PMD in association with PLP1 duplication and three females who are apparent manifesting carriers. Custom high-resolution oligonucleotide array comparative genomic hybridization (aCGH) and breakpoint junction sequencing were performed and revealed a familial complex duplication consisting of a small duplicated genomic interval (∼56 kb) and a large segmental duplication (∼11 Mb) that resulted in a PLP1 copy number variation gain. Breakpoint junction analysis implicates a replication-based mechanism underlying the rearrangement formation. X-inactivation studies (XCI) showed a random to moderate advantageous skewing pattern in peripheral blood cells but a moderate to extremely skewed (≥90%) pattern in buccal cells. In conclusion, our data show that complex duplications involving PLP1 are not uncommon, can be detected at the level of genome resolution afforded by clinical aCGH and duplication and inversion can be produced in the same event. Furthermore, the observation of three manifesting carriers with a large genomic rearrangement supports the contention that duplication size along with genomic content can be an important factor for penetrance of the PMD phenotype in females.

Disruption of the SCN2A and SCN3A genes in a patient with mental retardation, neurobehavioral and psychiatric abnormalities, and a history of infantile seizures.

Mutations in genes encoding voltage-gated sodium channels are significant factors in the etiology of neurological diseases and psychiatric disorders, including various types of idiopathic epilepsy. Using a clinical exon-targeted oligonucleotide array comparative genomic hybridization (aCGH), we have identified a de novo ~110-kb deletion involving exons 1-2 of SCN2A and non-coding exon 1a of SCN3A in a 25-year-old female with mental retardation, neurobehavioral and psychiatric abnormalities, and a history of infantile seizures with abnormal EEG. We propose that haploinsufficiency of SCN2A may play an important role in the genetic basis of neurodevelopmental and neurobehavioral disorders and emphasize the efficacy of detecting exonic copy-number variation (CNV) by exon-targeted oligo aCGH.

Hyperglycaemia and cardiovascular disease.

Coronary artery disease and type 2 diabetes are chronic diseases of substantial and growing prevalence. Their coincidence is common, markedly enhancing mortality and morbidity. The risk for cardiovascular disease increases along a spectrum of blood glucose concentrations already apparent at levels regarded as normal. Accordingly, strategies for the early detection of glucometabolic disturbances are needed to find ways to prevent the occurrence of cardiovascular complications or to treat them already at an early stage. More specifically, abnormal glucose tolerance is almost twice as common amongst patients with a myocardial infarction as in population-based controls and a normal glucose regulation is indeed less common than abnormal glucose metabolism also amongst patients with stable coronary artery disease. Already an abnormal glucose tolerance is a strong risk factor for future cardiovascular events after an acute myocardial infarction. An oral glucose tolerance test should, therefore, be a part of the evaluation of total risk in all patients with coronary artery disease. As glucose disturbances are common and easy to detect, they may be suitable targets for novel secondary preventive efforts.

Oral glucose tolerance test is needed for appropriate classification of glucose regulation in patients with coronary artery disease: a report from the Euro Heart Survey on Diabetes and the Heart.

BACKGROUND: Patients with coronary artery disease (CAD) and abnormal glucose regulation (AGR) are at high risk for subsequent cardiovascular events, underlining the importance of accurate glucometabolic assessment in clinical practice. OBJECTIVE: To investigate different methods to identify glucose disturbances among patients with acute and stable coronary heart disease. METHODS: Consecutive patients referred to cardiologists were prospectively enrolled at 110 centres in 25 countries (n = 4961). Fasting plasma glucose (FPG) and glycaemia 2 h after a 75-g glucose load were requested in patients without known glucose abnormalities (n = 3362). Glucose metabolism was classified according to the World Health Organization and American Diabetes Association (ADA; 1997, 2004) criteria as normal, impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or diabetes. RESULTS: Data on FPG and 2-h post-load glycaemia were available for 1867 patients, of whom 870 (47%) had normal glucose regulation, 87 (5%) had IFG, 591 (32%) had IGT and 319 (17%) had diabetes. If classification had been based on the ADA criterion from 1997, the proportion of misclassified (underdiagnosed) patients would have been 39%. The ADA 2004 criterion would have overdiagnosed 8% and underdiagnosed 33% of the patients, resulting in a total misclassification rate of 41%. For ethical concerns and practical reasons, oral glucose tolerance test (OGTT) was not conducted in 1495 of eligible patients. These patients were more often women, had higher age and waist circumference, and were therefore more likely to have AGR than those who were included. A model based on easily available clinical and laboratory variables, including FPG, high-density lipoprotein cholesterol, age and the logarithm of glycated haemoglobin A1c, misclassified 44% of the patients, of whom 18% were overdiagnosed and 26% were underdiagnosed. CONCLUSION: An OGTT is still the most appropriate method for the clinical assessment of glucometabolic status in patients with coronary heart disease.

Beta cell dysfunction in patients with acute myocardial infarction but without previously known type 2 diabetes: a report from the GAMI study.

AIMS/HYPOTHESIS: Patients with acute myocardial infarction (AMI) but without previously known type 2 diabetes have a high prevalence of undiagnosed IGT and type 2 diabetes. Such perturbations have dismal prognostic implications. The aim of this study was to characterise AMI patients in terms of insulin resistance and beta cell function. METHODS: A total of 168 consecutive AMI patients were classified by means of an OGTT before hospital discharge as having NGT, IGT or type 2 diabetes. The homeostasis model assessment (HOMA-IR) was used to estimate insulin resistance. Beta cell responsiveness was quantified as insulinogenic index (IGI) at 30 min (DeltaI(30)/DeltaG(30)). RESULTS: According to the HOMA-IR, patients with type 2 diabetes were more insulin resistant than those with IGT or NGT (p=0.003). Beta cell responsiveness deteriorated with decreasing glucose tolerance as measured by the IGI (median [quartile 1, quartile 3] in pmol/mmol: NGT, 70.1 [42.7, 101.4]; IGT, 48.7 [34.7, 86.8], type 2 diabetes, 38.1 [25.7, 61.6]; p<0.001). The IGI was significantly related to admission capillary blood glucose (r=-0.218, p=0.010) and to the area under the curve for glucose (r=-0.475, p<0.001). CONCLUSIONS/INTERPRETATION: Glucose abnormalities are very common in patients with AMI but without previously known type 2 diabetes. To a significant extent, this seems to be related to impaired beta cell function and implies that dysglycaemia immediately after an infarction is not a stress epiphenomenon but reflects stable disturbances of glucose regulation preceding the AMI. Early beta cell dysfunction may have important pathophysiological implications and may serve as a future target for treatment strategies.

Newly detected abnormal glucose tolerance: an important predictor of long-term outcome after myocardial infarction.

AIMS: Recent data revealed that patients with myocardial infarction (MI) have a high prevalence of previously unknown diabetes mellitus (DM) and impaired glucose tolerance (IGT). The added prognostic importance of this finding has not been prospectively explored. To investigate whether a newly detected abnormal glucose tolerance (IGT or DM) assessed early after an MI, is related to long-term prognosis. METHODS AND RESULTS: Patients (n=168; age 63.5+/-9.3 years) with MI, no previous DM and admission blood glucose <11.0 mmol/l were followed for major cardiovascular events defined as the composite of cardiovascular death, non-fatal MI, non-fatal stroke or severe heart failure (HF). According to an oral glucose tolerance test (OGTT) before hospital discharge, 55 patients had normal and 113 abnormal glucose tolerance (GT). During the follow-up of median 34 months there were eight cardiovascular deaths, 15 patients had a recurrent MI, six had a stroke and ten severe HF. All patients who died from cardiovascular causes had abnormal GT. The composite cardiovascular event occurred in 31 (18%) patients. The probability of remaining free from cardiovascular events was significantly higher in patients with normal than abnormal GT (p=0.002). Together with previous MI, abnormal GT was the strongest predictor of future cardiovascular events (hazard ratio 4.18; CI 1.26-13.84; p=0.019). CONCLUSIONS: Abnormal glucose tolerance is a strong risk factor for future cardiovascular events after myocardial infarction. Since it is common and possible to detect even during the hospital phase it may be a target for novel secondary preventive efforts.

Abnormal glucose tolerance--a common risk factor in patients with acute myocardial infarction in comparison with population-based controls.

BACKGROUND: A high prevalence of newly detected diabetes and impaired glucose tolerance (abnormal glucose tolerance) was recently reported in patients with acute myocardial infarction. It is important to verify whether this finding is specific for the patients or attributable to the population, from which they were recruited. OBJECTIVE: To verify whether abnormal glucose tolerance is more prevalent in patients than in controls chosen from the same population and to compare metabolic characteristics between the two groups. DESIGN AND SUBJECTS: The metabolic state was assessed in patients (n = 181) admitted with acute myocardial infarction and no history of diabetes before discharge and after 3 months. Sex- and age-matched controls (n = 185) without previously known diabetes or cardiovascular disease except hypertension were recruited from the general population. MAIN OUTCOME MEASURES: Oral glucose tolerance test, glucosylated haemoglobin A1c (HbA1c), insulin, proinsulin, lipid profile, fibrinolytic function and inflammatory markers. RESULTS: Abnormal glucose tolerance was more common (number/all classified) in patients at discharge 113/168 (67%) and after 3 months 95/145 (66%) than in controls 65/185 (35%) (P < 0.001). Dyslipidaemia (70% vs. 29%; P < 0.001) and previously treated hypertension (32% vs. 18%; P = 0.028) were more frequent amongst patients whilst obesity (18% vs. 24%) did not differ significantly. Blood glucose, HbA1c, proinsulin, proinsulin/insulin ratio, triglycerides, insulin resistance (by HOMA) and fibrinogen were consistently higher in patients than controls (P < 0.01). CONCLUSIONS: Abnormal glucose tolerance was almost twice as common amongst patients with acute myocardial infarction as in matched controls. Impaired glycaemic control accompanied by insulin resistance, dyslipidaemia, hypertension, together with increased plasma fibrinogen and proinsulin levels were main features characterizing patients.

[Prevalence of main risk factors for ischemic heart disease in a cohort of 41,972 participants from Southern Poland Epidemiological Survey]. / Wystepowanie glównych czynników ryzyka choroby niedokrwiennej serca w grupie 41 927 osób objetych akcja prewencji pierwotnej w Polsce Poludniowej (Southern Poland Epidemiological Survey--SPES).

Southern Poland Epidemiological Survey (SPES) was carried out in 1997 in the former Katowice and Bielsko voivodeships with the aim of cardiovascular disease prevention. One of the objectives of SPES was to establish the prevalence of the risk factors for atherosclerosis. This paper describes a group of 41,927 adults (24,985 women and 16,942 men) with no signs and symptoms of ischaemic heart disease who participated in the study, comprising 83.7% of all the examined cohort. Hypercholesterolemia and hypertension, present in 55.8% and 45.3% of subjects respectively, were found to be the main risk factors in both men and women. Hypercholesterolemia was more prevalent in older age groups. 33.7% of women and 46.3% of men were overweight, 23.9% and 17% respectively were obese. 22.4% of women and 31.9% of men were active smokers. Smoking was more common in younger age groups. 25.3% of women and 21.5% of men had a positive family history for ischaemic heart disease before the age of 60 years. High prevalence of classical risk factors in the examined group indicates that population strategy should be introduced in primary prevention of cardiovascular disease in this area.

[Normalization of lipid metabolism disturbances and clinical course after percutaneous coronary angioplasty: 6 month observation]. / Normalizacja zaburzen gospodarki lipidowej a przebieg kliniczny po zabiegu przezskórnej angioplastyki wiencowej: 6-miesieczna obserwacja.

UNLABELLED: The recurrent stenosis of previously successfully dilated coronary arteries still remains a matter of concern despite of the improved short and long term results of percutaneous coronary angioplasty. The role of dyslipidaemia in the origin of restenosis after coronary angioplasty is still controversial. The aim of our study was to evaluate the efficacy of hypolipemic treatment in patients undergoing coronary angioplasty and to find out whether successful lowering of lipid parameters to normal limits is related to improvement exercise capacity and systolic function of left ventricle. The study group comprised 152 patients (17 women, 135 men), aged 52 +/- 8.8 years, who were reffered for percutaneous coronary angioplasty (PTCA). The patients were divided, according to the ratio of total cholesterol to HDL cholesterol (CH/ch-HDL), into two subgroups: subgroup I with CH/ch-HDL > 5.0 and subgroup II with CH/ch-HDL < or = 5.0. In all patients following parameters: total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides and body mass index were measured before PTCA, 1 month and 6 months after the procedure. At the same times a treadmill test and echocardiography were performed. Baseline total cholesterol, HDL cholesterol and triglycerides were significantly higher in subgroup I. In subgroup I Ch/ch-HDL ratio was at baseline 7.4 +/- 2.0 and decreased 6 months after PTCA to 5.2 +/- 1.7, p < 0.001. The CH/ch-HDL ratio was 4.2 +/- 0.6 in subgroup II before PTCA and remained the same 4.1 +/- 1.2 after 6 months. Before PTCA, the exercise capacity did not differ between groups 9.1 +/- 2.5 vs 9.6 +/- 3.3 MET, p = ns. A significant improvement of exercise capacity was observed in subgroup I 1 month after PTCA 9.1 +/- 2.5 to 11.2 +/- 2.7 MET, p < 0.001, remaining at the same level after 6 months. The differences seen in group II did not reach the statistical significance. Echocardiography revealed improvement of left ventricle contractility in both subgroups, with statistically significant increase in group I (1.24 +/- 0.36 to 1.14 +/- 0.27, p < 0.001). The left ventricle systolic function was within normal limits in all patients before coronary angioplasty and increased significantly 1 month after PTCA in subgroup I (56.1 to 60.4%, p < 0.001). 6 months after PTCA no further significant changes were observed. CONCLUSIONS: The dyslipidaemic state recognised before PTCA does not influence clinical outcomes after the procedure. Lipid lowering therapy should be offered to every patient undergoing coronary angioplasty regardless of the baseline value of total cholesterol to HDL cholesterol ratio. Optimal treatment of dyslipidaemia leading to lower total cholesterol, triglycerides and total cholesterol to HDL cholesterol ratio, to normal limits, is associated with improved exercise capacity and systolic function of left ventricle six months after successful coronary angioplasty.

[Albumin excretion with urine in a population of healthy individuals]. / Wydalanie albumin z moczem w populacji ludzi zdrowych.

Increased urine albumin excretion is the significant prognostic factor for diabetes, hypertension and coronary artery disease. Divergences of the evaluation of albuminuria in different ethnic groups were found. The aim of our study was to evaluate albumin excretion in large group of healthy individuals. 301 healthy subjects (110 female and 191 male), age 20-60 years (mean 32.9 +/- 9.7), were admitted. A questionnaire including data concerning familial history, smoking habits was fulfilled. Subsequently nighttime urine sample was collected in all examined subjects and albumin to creatinine ratio (A/K) was counted. A/K value varied between 0.03-14.1 mg/mmol of creatinine median 1.18. Significantly higher albuminuria in female v male group was found (respectively 1.39; 0.14-14.1 and 1.03; 0.03-11.4 p < 0.05). Reference value for albuminuria was estimated at 3.35 mg/mmol in whole group, and respectively 4 mg/mmol in female and 2.6 mg/mmol in male. There were not differences in A/K ratio in relation to familial history however smoking men excreted more albumin v non smoking (respectively 1.27, 0.03-11.4 and 0.95, 0.14-14.1 mg/mmol p < 0.005). Performed analysis allowed to calculate the value for albuminuria in healthy subjects. Analysis also showed significant influence of gender and smoking habits and no influence of familial history for albumin excretion.