Incident Cancer Risk of Patients with Prevalent Type 2 Diabetes Mellitus in Hungary (Part 2).

(1) Background: Among the chronic complications of type 2 diabetes mellitus, cancer has become the leading cause of death in several countries. Our objective was to determine whether prevalent type 2 diabetes mellitus is associated with a higher incidence of cancer. (2) Methods: This study comprised a nationwide analysis conducted in Hungary. The study population was divided into two groups: a type 2 diabetes mellitus group vs. a non-diabetic group. The primary outcome was the risk related to overall cancer incidence; a key secondary outcome was the overall incidence of cancer in distinct study years; and a further outcome was the annual percent changes. (3) Results: The odds ratio related to the overall incidence of cancer was 2.50 (95% confidence interval: 2.46-2.55, p < 0.0001) in patients with diabetes as related to non-diabetic controls. The odds ratio was higher in males than in females [ORmales: 2.76 (2.70-2.82) vs. ORfemales: 2.27 (2.22-2.33), p < 0.05 for male-to-female comparison]. The annual cancer incidence rate declined in non-diabetic controls, but not in patients with diabetes [-1.79% (-2.07--1.52%), p < 0.0001] vs. -0.50% (-1.12-+0.10%), p = 0.0991]. Several types of cancer showed a decreasing tendency in non-diabetic controls, but not in patients with type 2 diabetes. (4) Conclusions: Type 2 diabetes is associated with a higher risk of cancer. While the cancer incidence decreased for non-diabetic individuals with time, it remained unchanged in patients with T2DM.

Incident Cancer Risk in Patients with Incident Type 2 Diabetes Mellitus in Hungary (Part 1).

(1) Background: Patients with type 2 diabetes mellitus (T2DM) are at higher risk of cancer but how these two diseases associate is still debated. The goal of this study was the assessment of the overall incidence of cancer among patients with newly diagnosed T2DM in Hungary. (2) Methods: A nationwide, retrospective, longitudinal study was performed using a Hungarian database. After exclusion of cases of age < 18 years, with gestational diabetes, with polycystic ovary syndrome, and with type 1 and prevalent type 2 diabetes mellitus, the incident T2DM (approx. 50,000 cases yearly) and for comparison, the diabetes-free Hungarian adult population (approx. 7,000,000 cases yearly) was included in the study. The primary endpoints were the overall and site-specific incidence and annual percentage change of the incidence of cancer in both populations. (3) Results: The overall incidence of cancer in patients amounted to 29.4/1000 and 6.6/1000 with or without T2DM, respectively, and the OR (95%CI) of cancer of the T2DM group was 4.32 (4.14-4.53), p < 0.0001. The risk of having cancer was age dependent. The incidence of cancer was declining in the non-diabetic but was unchanged in the T2DM population. The average lag time of diagnosing cancer after the detection of T2DM was 3.86 months. (4) Conclusions: Incident T2DM is associated with a significantly higher overall risk of incident cancer, with a reverse correlation of age. Newly registered T2DM patients were suggested to be screened for cancer within 6 months.

Expression of Wilms-tumor 1 antigen, vimentin and corticotropin releasing factor in human kidney with focal segmental glomerulosclerosis and effect of oxidative stress on these markers in HEK 293 cells.

INTRODUCTION: Wilms-tumor 1 antigen (WT1) expression in podocytes has the important role of maintaining their integrity and glomerular function. Vimentin also plays a role in preserving podocyte function and in morphologic changes observed after injury. Corticotropin releasing factor (CRF) is important in stress and in maintaining homeostasis. According to our previous studies, tyrosine (Tyr) isoforms (meta- and ortho-Tyr) may play a role in the development of many diseases. INTRODUCTION: Wilms-tumor 1 antigen (WT1) expression in podocytes has the important role of maintaining their integrity and glomerular function. Vimentin also plays a role in preserving podocyte function and in morphologic changes observed after injury. Corticotropin releasing factor (CRF) is important in stress and in maintaining homeostasis. According to our previous studies, tyrosine (Tyr) isoforms (meta- and ortho-Tyr) may play a role in the development of many diseases. METHODS: Our aim was to investigate the expression of WT1, vimentin and CRF in human kidney and in HEK 293 cell cultures. Histological and clinical feature of 42 FSGS patients were evaluated and compared to patients with thin-basement membrane as a control group. Cells were cultured in medium containing para-, meta-, and ortho-tyrosine, and their expression of WT1, vimentin, and CRF were determined by immunocytochemistry. Podocyte foot process effacement was investigated by electron microscope (EM). RESULTS: The intensity of WT1 staining in glomeruli was the same in focal segmental glomerulosclerosis (FSGS) and control groups, but it was lower in the tubulointerstitium of FSGS patients. Vimentin was lower in glomeruli of FSGS patients (p=0.009), and it was higher in the tubulointerstitium compared to the control group (p=0.003). CRF intensity was lower in the glomeruli (p=0.002). Podocyte foot process effacement determined by electron microscope (EM) showed correlation with vimentin and CRF in glomeruli. WT1 staining intensity was lower in meta- and ortho-Tyr group (p=0.001; p=0.009). Vimentin was lower in the meta-Tyr group (p=0.001). DISCUSSION: Our observations on kidney biopsy samples support that the reduction of WT1 and vimentin could be characteristic for FSGS. Our results on HEK cells suggest that meta- and ortho-tyrosine may play a role in the development of FSGS.

Sodium-Glucose Co-Transporter 2 Inhibitors May Change the Development of Urinary Tract and Hematological Malignancies as Compared With Dipeptidyl Peptidase-4 Inhibitors: Data of the Post-Hoc Analysis of a Nationwide Study.

BACKGROUND: In diabetes mellitus, during the last years, cancer became of equivalent importance as a cardiovascular disease in terms of mortality. In an earlier study, we have analyzed data of the National Health Insurance Fund (NHIF) of Hungary with regards all patients treated with sodium-glucose co-transporter 2 (SGLT2) inhibitors (SGLT2is) vs. those treated with dipeptidyl peptidase-4 (DPP-4) inhibitors (DPP-4is) in a given timeframe. In propensity score-matched groups of SGLT2i- vs. DPP-4i-treated patients, we found a lower incidence of cancer in general. In this post-hoc analysis, we aimed to obtain data on the incidence of site-specific cancer. PATIENTS AND METHODS: All patients starting an SGLT2i or a DPP-4i between 2014 and 2017 in Hungary were included; the two groups (SGLT2i vs. DPP-4i) were matched for 54 clinical and demographical parameters. The follow-up period was 639 vs. 696 days, respectively. Patients with a letter "C" International Classification of Diseases, 10th Revision (ICD-10) code have been chosen, and those with a known malignancy within a year before the onset of the study have been excluded from the analysis. RESULTS: We found a lower risk of urinary tract [HR 0.50 (95% CI: 0.32-0.79) p = 0.0027] and hematological malignancies [HR 0.50 (95% CI: 0.28-0.88) p = 0.0174] in patients treated with SGLT2i vs. those on DPP-4i. Risk of other types of cancer (including lung and larynx, lower gastrointestinal (GI) tract, rectum, pancreas, non-melanoma skin cancers, breast, or prostate) did not differ significantly between the two groups. When plotting absolute risk difference against follow-up time, an early divergence of curves was found in case of prostate, urinary tract, and hematological malignancies, whereas late divergence can be seen in case of cancers of the lung and larynx, the lower GI tract, and the breast. CONCLUSIONS: Urinary tract and hematological malignancies were less frequent in patients treated with SGLT2i vs. DPP-4i. An early vs. late divergence could be observed for different cancer types, which deserves further studies.

Risk of morbidity and mortality in patients with type 2 diabetes treated with sodium-glucose cotransporter-2 inhibitor and/or dipeptidyl peptidase-4 inhibitor: a nationwide study.

INTRODUCTION: Mortality and disability in diabetes mellitus are determined mostly by cardiovascular complications and cancer. The impact of dipeptidyl peptidase-4 inhibitor (DPP-4i) and sodium-glucose cotransporter-2 inhibitor (SGLT2i) monotherapy or combination on long-term complications of type 2 diabetes mellitus was studied. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes treated with DPP-4i or SGLT2i during a 3-year period were identified in the database of the National Institute of Health Insurance Fund in Hungary. All-cause mortality, acute myocardial infarction, stroke, hospitalization for heart failure (HHF), lower limb amputation (LLA) and cancer were assessed. Outcomes of add-on SGLT2i to DPP-4i treatment in comparison with switching DPP-4i therapy to SGLT2i were also evaluated. After propensity score matching, survival analysis was performed with a Cox proportional hazards model. RESULTS: After propensity score matching, both SGLT2i and DPP-4i groups included 18 583 patients. All-cause mortality (HR, 0.80; 95% CI 0.68 to 0.94; p=0.0057), HHF (HR, 0.81; 95% CI 0.71 to 0.92; p=0.0018), and risk of cancer (HR, 0.75; 95% CI 0.66 to 0.86; p<0.0001) were lower in the SGLT2i population compared with DPP-4i. Risk of LLA was higher in the SGLT2i group (HR, 1.35; 95% CI 1.03 to 1.77; p=0.0315). SGLT2i in combination with DPP-4i results in lower all-cause mortality (HR, 0.46; 95% CI 0.31 to 0.67; p=0.0001), with a lower trend in stroke, LLA, HHF and cancer, but without any statistical difference. CONCLUSIONS: SGLT2i treatment leads to a lower risk of overall mortality, HHF and cancer when compared with DPP-4i treatment. Adding SGLT2i to DPP-4i instead of switching from DPP-4i to SGLT2i further lowers the risk of all-cause mortality.

[Possibilities of immunotherapy in cancer patients with autoimmune disease]. / A tumor-immunterápia lehetõségei autoimmun betegekben.

The immune checkpoint inhibitors (ICI) opened a new era in anticancer treatment. This type of treatment is beneficial for a subset of patients who had a restricted success in the past. However, manipulation of the immune system may lead to the flare up of preexisting autoimmune diseases, requiring intervention. Furthermore, immune suppression strongly influences the outcome of ICI treatment. The ICI treatment of cancer patients with autoimmune disease is a complex task: pre-treatment assessment of the patients, early management of flare ups, and introduction of effective immune suppression is required to achieve the best outcome.

Adipose tissue infiltration in minor salivary glands of patients with Sjögren's syndrome: Lack of significant correlation with the disease. An image analysis of 174 cases.

Fatty infiltration in minor salivary gland biopsies and its correlation to systemic autoimmune diseases are controversial in the literature. Presence and extent of fatty infiltration in minor salivary glands of 107 Sjögren's syndrome patients and 67 age-matched sicca controls were compared with statistical analyses. No significant difference was found regarding the presence or the extent of fatty infiltration between the two groups. Fatty infiltration seems to be unrelated to Sjögren's syndrome thus its examination in salivary gland biopsy samples cannot improve the diagnostic accuracy of the disease.

Image analysis of fatty infiltration in labial salivary gland biopsies: extent and its correlation to age, obesity and diabetes.

BACKGROUND: Fatty infiltration of minor salivary gland parenchyma is relatively frequent, but not extensively examined histopathological phenomenon in biopsy samples. Its extent and relation to several suspected background diseases are not well understood. METHODS: In this study, we examined the presence and extent of fatty infiltration on digitally scanned versions of the periodic acid/Schiff-stained minor salivary gland slides of 275 patients. As a result of the image analysis, fatty infiltration was expressed in per cent of the whole selected area. The presence and extent of this change were compared to age, diabetes mellitus and body mass index in various statistical analyses. RESULTS: Significantly higher age and body mass index values were found in the fatty infiltration positive than in the negative group. We also found that not only the number of fatty infiltration positive cases was increased significantly in the gradually worsened body mass index groups, but the extent of fatty infiltration also increased as the obesity worsened. Age also showed significant correlation with the extent of fatty infiltration. DISCUSSION: All of these findings support that the age (which seemed the only independent variable) shows strong correlation with the presence of the fatty infiltration but obesity may also play important role in the development and the extent of this change. Because of its frequency in elderly, at least partly, the fatty infiltration might be responsible for the xerostomia. We also think that presence of fatty infiltration should be mentioned in the histopathological report of salivary gland biopsies.

[The role of immune system in the control of cancer development and growth]. / Hogyan ellenorzi az immunrendszer a daganatok kialakulásának és növekedésének folyamatát?

The role of immune system is the maintenace of the integritiy of the living organism. The elements of the immune system are connected by several ways forming a complex biological network. This network senses the changes of the inner and outer environment and works out the most effective response against infections and tumors. Dysfunction of the immune system leads to the development of cancer development and chronic inflammatory diseases. Modulation of the checkpoints of the immune system opened new perspecitves in the treatment of rheumatological and oncological diseases as well. Beside the potent antiinflammatory activity, new therapies are able to stimulate anticancer activity of the immune system. The result of these recent developments is a better outcome of malignant diseases, which had an unfavorable outcome in the past. Orv. Hetil., 2016, 157(Suppl. 2), 3-8.

[Tolosa-Hunt syndrome]. / A Tolosa-Hunt-szindróma.

Both men and women are affected by the rare disease called Tolosa-Hunt syndrome. We don't know exactly what causes it to evolve. It is usually put into the categories of either idiopathic inflammation or pseudotumor. Its pathological feature is a non-specific inflammatory process with fibroblastic, lymphocytic, plasmocytic infiltration, which can be found, for the most part, in the wall of the sinus cavernosus. Granulocytic and giant-cell infiltrations have been described too. The possibility of autoimmune disease has also come up. In our current study we describe the case of a female patient who recovered with the help of a steroid therapy. Through examining her, we also found immunological alterations, which should urge us to thoroughly examine the further observations of this kind.

Effect of heat shock protein peptide DiaPep277 on beta-cell function in paediatric and adult patients with recent-onset diabetes mellitus type 1: two prospective, randomized, double-blind phase II trials.

BACKGROUND: Aim of this trial was to test whether heat shock protein peptide DiaPep277 treatment in adult and paediatric patients with recent-onset type 1 diabetes (T1D) is safe and whether it can preserve endogenous insulin production. METHODS: Two studies were performed in a prospective, multicentre, double-blind, placebo-controlled trial. Fifty adult (study p520, aged 16-44 years) and 49 paediatric patients (study p521, 4-15 years) with recent-onset T1D were treated subcutaneously at four different time points with 0.2 mg or 1.0 mg DiaPep277 versus placebo and followed for 18 months. Adult patients were treated with 0.2 mg, 1.0 mg or 2.5 mg DiaPep277 versus placebo. Stimulated C-peptide served as readout for functional beta-cell-mass. RESULTS: DiaPep277-treatment was not associated with severe side effects. No differences were found in placebo and DiaPep277 treated groups. In adults, a modest trend towards better maintenance of beta-cell function was observed in the 0.2 mg and 1.0 mg group, while there was significant loss of stimulated C-peptide in the placebo and 2.5 mg group. Paediatric patients with low HLA risk showed stable C-peptide levels until 13 months upon treatment with 1 mg DiaPep277. Despite similar stimulated C-peptide levels at baseline, children exhibited a more pronounced loss of beta-cell function over 18 months than adults (p = 0.0003). CONCLUSION: Administration of DiaPep277 seems safe and may have beneficial effects on C-peptide levels over time in some patients with T1D, but this finding was not accompanied by reduced HbA1c or insulin requirement. Studies with more patients and longer follow-up are needed to further study the effect of DiaPep277.

Crohn's disease is associated with polymorphism of CARD15/NOD2 gene in a Hungarian population.

Crohn's disease (CD) is commonly classified as an immune-mediated disorder, but genetic and environmental factors seem to be important in its pathogenesis. Mutations within the CARD15/NOD2 gene have been associated with CD in the Caucasian population. The aim of our work was to investigate the allele frequency and clinical impact of the three common mutations in Hungarian CD patients and healthy controls. Seventy-four CD patients and 107 controls were examined. The genotyping of the three common CARD15/NOD2 mutations (Arg702Trp, Gly908Arg, and Leu1007fsinsC) was carried out by restriction fragment length polymorphism (RFLP) and amplification refractory mutation system (ARMS) techniques. The demographic and clinical parameters were correlated with chi(2) analysis. The overall prevalence of CARD15/NOD2 mutations in the Hungarian CD patients (33.78%) was significantly higher than in healthy control individuals (16.23%) (P < 0.025). The allele frequency of the Gly908Arg mutation did not differ, but the Arg702Trp and Leu1007fsinsC mutation were more common in CD patients than in controls. The onset of CD occurs about three years earlier in CARD15/NOD2 carriers. Carriage of the Arg702Trp and Leu1007fsinsC allele within the CARD15/NOD2 gene is associated with CD. These data are in line with similar findings showing a role of the CARD15/NOD2 protein in the etiopathogenesis of CD. The genotyping of these mutations might be used to identify high-risk patients.

[Prevalence of Leiden mutation in various gastrointestinal disorders]. / A Leiden-mutáció prevalenciája a különbözó gastrointestinalis kórképekben.

Molecular biological examinations have been carried out by the authors from 1995 in patients with different haemostasis, very recently these types of the studies were done in patients with different gastrointestinal (Helicobacter pylori-induced gastritis, hepatitis C infection, ileitis terminalis, ulcerative colitis, colon polyposis and adenocarcinoma in polyps) disorders. AIM, PATIENTS, METHOD: The Leiden mutation was detected by polymerase chain reaction (PCR) in 1354 healthy persons and patients with different GI disorders. RESULTS: The results of Leiden prevalence in patients with different gastrointestinal disorders were compared to those obtained in patients with venous thrombosis and familiar thrombophilia. The authors indicated that the prevalence of heterozygous Leiden positive persons was 5.9% in healthy (n = 87) and blood donors (n = 600). The prevalence of heterozygous Leiden mutation was 27% in patents who under went venous thrombosis (n = 300; P < 0.001), 38% in patients with familial thrombophilia (n = 116; P < 0.001). The prevalence of Leiden mutation was 0 in patients with Helicobacter pylori-induced gastritis (n = 24), 8% in hepatitis C infections (n = 75), 14.28% in Crohn's disease, (n = 49; P < 0.01), 27.5% in ulcerative colitis (n = 35; P < 0.001), 44% in colon polyposis (n = 59; P < 0.001) and 55% in situ adenocarcinomas (in polyposis) (n = 9; P < 0.001). CONCLUSION: The presented results suggest that the Leiden mutation is involved in patients with different inflammatory bowel disease, colon polyposis, as one of the suggested genetic factors.