Associations between diabetes and cancer: A 10-year national population-based retrospective cohort study.

AIMS: To investigate the risk of cancer in people with diabetes compared to the population without diabetes and to gain insight into the timely association between diabetes and cancer at national level. METHODS: A retrospective cohort study was conducted to analyse the role of diabetes in the development of cancer, based on service utilisation and antidiabetic dispensing data of the population between 2010 and 2021. Univariate and multivariate Cox regression were used to examine how diabetes status, in relationship with age and sex are related to the time to cancer diagnosis. RESULTS: Examining a population of 3 681 774 individuals, people with diabetes have a consistently higher risk for cancer diagnosis for each cancer site studied. Diabetes adds the highest risk for pancreatic cancer (HR = 2.294, 99 % CI: 2.099; 2.507) and for liver cancer (HR = 1.830, 99 % CI: 1.631; 2.054); it adds the lowest - but still significant - risk for breast cancer (HR = 1.137, 99 % CI: 1.055; 1.227) and prostate cancer (HR = 1.171, 99 % CI: 1.071; 1.280).The difference in cancer rate is driven by the younger age group (40-54 years: for patients with diabetes 5.4 % vs. controls 4.4 %; 70-89 years: for patients with diabetes 12.7 % vs. controls 12.4 %). There are no consistent results whether the presence of diabetes increases the risk of cancer diagnosis differently in males and females. The cancer incidence starts to increase before the diagnosis of diabetes and peaks in the year after. By the year after the start of the inclusion date, the incidence is 114/10,000 population in the control group, vs 195/10,000 population in the group with diabetes. Following this, the incidence drops close to the control group. CONCLUSIONS: Screening activities should be revised and the guidelines on diabetes should be complemented with recommendations on cancer prevention also considering that the cancer incidence is highest around the time of the diagnosis of diabetes. For prostate cancer, our results contradict many previous studies, and further research is recommended to clarify this.

Subclinical systolic and diastolic myocardial dysfunction in polyphasic polymyositis/dermatomyositis: a 2-year longitudinal study.

BACKGROUND: Cardiac involvement in patients with idiopathic inflammatory myopathies (IIM) is associated with increased morbidity and mortality risk; however, little is known about the progression of cardiac dysfunction and long-term data are scarce. In the present work, we intended to prospectively study echocardiographic parameters in patients with IIM for 2 years. METHODS: Twenty-eight IIM patients (41.9±1.6 years) without cardiovascular symptoms were enrolled. Patients with monophasic/polyphasic disease patterns were studied separately and compared to age-matched healthy individuals. Conventional echocardiographic and tissue Doppler imaging (TDI) parameters of systolic [LV: ejection fraction (EF), mitral annulus systolic movement (MAPSE), lateral s') and diastolic left (mitral inflow velocities, lateral anulus velocities: e', a', E/e') and right ventricular function (fractional area change: FAC, tricuspid annulus plane systolic excursion: TAPSE) were measured at the time of the diagnosis and 2 years later. RESULTS: Subclinical LV systolic dysfunction is characterized by reduced lateral s' (10.4 vs. 6.4 cm/s, p<0.05), EF (62.6±0.6%, vs. 51.7±0.7%) and MAPSE (18.5±0.6 vs. 14.5±0.6 mm) could be observed in IIM patients with polyphasic disease course 2 years after diagnosis compared to controls. Furthermore, diastolic LV function showed a marked deterioration to grade I diastolic dysfunction at 2 years in the polyphasic group (lateral e': 12.9 ±0.6, vs. 7.4±0.3 cm/s; lateral a': 10.7±0.3, vs. 17.3±0.8 cm/s; p<0.05) supported by larger left atrium (32.1±0.6 vs. 37.8±0.6 mm; p<0.05]. TDI measurements confirmed subclinical RV systolic dysfunction in polyphasic patients 2 years after diagnosis (FAC: 45.6±1.8%, vs. 32.7±1.4%; TAPSE: 22.7±0.5, vs. 18.1±0.3 mm; p<0.05). Similar, but not significant tendencies could be detected in patients with monophasic disease patterns. Polyphasic patients showed significantly (p<0.05) worse results compared to monophasic patients regarding EF (51.7±0.7% vs. 58.1±0.6%), lateral s' (6.4±0.4 cm/sec vs. 8.6±0.4 cm/s,), left atrium (37.8±0.6 mm vs. 33.3±0.8 mm), FAC (32.7±1.4% vs. 41.0±1.6%) and TAPSE (18.1±0.3 mm vs. 21.3±0.7 mm). CONCLUSIONS: Significant subclinical cardiac dysfunction could be detected in IIM patients with polyphasic disease course 2 years after diagnosis, which identifies them as a high-risk population. TDI is a useful method to detect echocardiographic abnormalities in IIM complementing conventional echocardiography and can recognize the high cardiac risk.

Improvement of Left Ventricular Graft Function Using an Iron-Chelator-Supplemented Bretschneider Solution in a Canine Model of Orthotopic Heart Transplantation.

Demand for organs is increasing while the number of donors remains constant. Nevertheless, not all organs are utilized due to the limited time window for heart transplantation (HTX). Therefore, we aimed to evaluate whether an iron-chelator-supplemented Bretschneider solution could protect the graft in a clinically relevant canine model of HTX with prolonged ischemic storage. HTX was performed in foxhounds. The ischemic time was standardized to 4 h, 8 h, 12 h or 16 h, depending on the experimental group. Left ventricular (LV) and vascular function were measured. Additionally, the myocardial high energy phosphate and iron content and the in-vitro myocyte force were evaluated. Iron chelator supplementation proved superior at a routine preservation time of 4 h, as well as for prolonged times of 8 h and longer. The supplementation groups recovered quickly compared to their controls. The LV function was preserved and coronary blood flow increased. This was also confirmed by in vitro myocyte force and vasorelaxation experiments. Additionally, the biochemical results showed significantly higher adenosine triphosphate content in the supplementation groups. The iron chelator LK614 played an important role in this mechanism by reducing the chelatable iron content. This study shows that an iron-chelator-supplemented Bretschneider solution effectively prevents myocardial/endothelial damage during short- as well as long-term conservation.

Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.

BACKGROUND: Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial. METHODS: We randomly assigned patients with previously untreated advanced melanoma to receive one of the following regimens: nivolumab (at a dose of 1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram every 2 weeks); nivolumab (3 mg per kilogram every 2 weeks) plus ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group. RESULTS: At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63). Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone. No new late toxic effects were noted. CONCLUSIONS: Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).

[Effects of therapeutic suggestions on the recovery of patients undergoing major orthopaedic surgery]. / Az ortopédiai nagymutétek során alkalmazott terápiás szuggesztiók hatása a beteg gyógyulására.

INTRODUCTION AND AIM: Hip and knee replacement surgery is very demanding for patients. Medication consumption is further increased by perioperative anxiety. Besides pain killer and anxiolytic medications, patients' recovery can be enhanced by applying therapeutic suggestions, which are easily applicable during the patient-physician communication. METHOD: In our prospective, randomized, controlled study we examined the effects of positive suggestions on patients undergoing hip or knee arthroplasty in spinal anaesthesia. Members of the suggestion group received the therapeutic suggestions during a pre-surgery physician visit, and by listening to an audio recording during surgery. RESULTS: Compared to the control group (n = 50), in the suggestion group (n = 45) the need of medication (pain killer and adjuvant pain medication) during the surgery was lower (p = 0.037), the mean change from baseline in the well-being of the patients was better on the 2nd [1.31 (0.57; 2.04); p<0.001] and 4th [0.97 (0.23; 1.7); p = 0.011] postoperative day and less transfusion had to be administered (OR: 2.37; p = 0.004). However, there was no difference between the two groups in the postoperative need of medications, in the length of hospitalisation and in the frequency of complications. Conslusion: Our results indicate that the administration of therapeutic suggestions in the perioperative period may be beneficial for orthopaedic surgery patients. Orv Hetil. 2018; 159(48): 2011-2020.

Efficacy of Sequential Ipilimumab Monotherapy versus Best Supportive Care for Unresectable Locally Advanced/Metastatic Gastric or Gastroesophageal Junction Cancer.

Purpose: Ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated protein-4 interactions, enhances T-cell activation and promotes tumor immunity. This phase II study evaluated the safety and efficacy of ipilimumab monotherapy versus best supportive care (BSC) among patients with advanced/metastatic gastric or gastroesophageal junction cancer who achieved at least stable disease with first-line chemotherapy.Experimental Design: Eligible patients were randomized to ipilimumab 10 mg/kg every 3 weeks for four doses, then 10 mg/kg every 12 weeks for up to 3 years, or BSC, which could include continuation of fluoropyrimidine until progression or toxicity. The primary endpoint was immune-related progression-free survival (irPFS); secondary endpoints included PFS by modified World Health Organization criteria and overall survival (OS).Results: Of 143 patients screened, 57 were randomized to each arm. irPFS with ipilimumab versus BSC was not improved [2.92 months, 95% confidence interval (CI), 1.61-5.16 vs. 4.90 months, 95% CI, 3.45-6.54, HR = 1.44; 80% CI, 1.09-1.91; P = 0.097], resulting in study cessation. At study closeout, which occurred 8 months after the interim analysis, the median OS durations were 12.7 months (95% CI, 10.5-18.9) and 12.1 months (95% CI, 9.3-not estimable), respectively. Grade 3/4 treatment-related adverse events occurred in 23% of ipilimumab-treated patients, in whom diarrhea (9%) and fatigue (5%) were most frequent, and in 9% of active BSC-treated patients.Conclusions: Although ipilimumab at 10 mg/kg was manageable, it did not improve irPFS versus BSC. However, comparable median OS of approximately 1 year and a favorable safety profile support the investigation of ipilimumab in combination with other therapies for advanced gastric cancer. Clin Cancer Res; 23(19); 5671-8. ©2017 AACR.

Effects of Positive Suggestions on the Need for Red Blood Cell Transfusion in Orthopedic Surgery.

This study examined whether positive suggestions applied without a hypnotic induction in the perioperative period reduces the need for red blood cell transfusions in patients who underwent total hip or knee arthroplasties with spinal anesthesia. No hypnotic assessment was performed. Ninety-five patients were randomly assigned to the suggestion group (n = 45) and to the control group (n = 50). Patients in the suggestion group received verbal suggestions before and audiotaped suggestions during the surgery for reducing blood loss, anxiety, postoperative pain, and fast recovery. Our study showed that using positive suggestions in the perioperative period significantly decreases the necessity for transfusion.

Examples of positive suggestions given to patients undergoing orthopaedic surgeries.

In the Department of Orthopaedic Surgery in the University of Debrecen, Debrecen, Hungary, we examined the effectiveness of positive suggestions used in the perioperative period in hip and knee arthroplasties performed under spinal anaesthesia. The goal of the suggestions was to reduce the need for red blood cell transfusion and for analgesics, and to increase the patients' satisfaction. The objective of this article is to present our method with concrete examples of positive suggestions which were given first before the surgery (via personal conversation), then during the operation as well (via audiotaped method). We hope that our article will contribute to the wide-spread awareness of this relatively easy to learn communication method.

Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial.

BACKGROUND: Brain metastases commonly develop in patients with melanoma and are a frequent cause of death of patients with this disease. Ipilimumab improves survival in patients with advanced melanoma. We aimed to investigate the safety and activity of this drug specifically in patients with brain metastases. METHODS: Between July 31, 2008, and June 3, 2009, we enrolled patients with melanoma and brain metastases from ten US centres who were older than 16 years into two parallel cohorts. Patients in cohort A were neurologically asymptomatic and were not receiving corticosteroid treatment at study entry; those in cohort B were symptomatic and on a stable dose of corticosteroids. Patients were to receive four doses of 10 mg/kg intravenous ipilimumab, one every 3 weeks. Individuals who were clinically stable at week 24 were eligible to receive 10 mg/kg intravenous ipilimumab every 12 weeks. The primary endpoint was the proportion of patients with disease control, defined as complete response, partial response, or stable disease after 12 weeks, assessed with modified WHO criteria. Analyses of safety and efficacy included all treated patients. This trial is registered with ClinicalTrials.gov, number NCT00623766. FINDINGS: We enrolled 72 patients: 51 into cohort A and 21 into cohort B. After 12 weeks, nine patients in cohort A exhibited disease control (18%, 95% CI 8-31), as did one patient in cohort B (5%, 0·1-24). When the brain alone was assessed, 12 patients in cohort A (24%, 13-38) and two in cohort B (10%, 1-30) achieved disease control. We noted disease control outside of the brain in 14 patients (27%, 16-42) in cohort A and in one individual (5%, 0·1-24) in cohort B. The most common grade 3 adverse events in cohort A were diarrhoea (six patients [12%]) and fatigue (six [12%]); in cohort B, they were dehydration (two individuals [10%]), hyperglycaemia (two [10%]), and increased concentrations of serum aspartate aminotransferase (two [10%]). One patient in each cohort had grade 4 confusion. The most common grade 3 immune-related adverse events were diarrhoea (six patients [12%]) and rash (one [2%]) in cohort A, and rash (one individual [5%]) and increased concentrations of serum aspartate aminotransferase (two [10%]) in cohort B. One patient in cohort A died of drug-related complications of immune-related colitis. INTERPRETATION: Ipilimumab has activity in some patients with advanced melanoma and brain metastases, particularly when metastases are small and asymptomatic. The drug has no unexpected toxic effects in this population. FUNDING: Bristol-Myers Squibb.

Mechanism of neopterin-induced myocardial dysfunction in the isolated perfused rat heart.

Neopterin is a sensitive marker for diseases involving increased activity of the cellular immune system in humans. Many studies, however, provide evidence for neopterin not only as a marker, but also for its characteristic effects. Recently, we were able to demonstrate a considerable influence of exogenous neopterin at a concentration of 100 mumol/l on cardiac performance in the Langendorff model of isolated perfused rat hearts. The present study was designed to investigate its possible mechanism. During co-infusion of neopterin at a concentration of 100 mumol/l with the unspecific nitric oxide synthase inhibitor N(G)-monomethyl-l-arginine monoacetate, the nitric oxide donor PAPA NONOate, the free radical scavenger N-acetylcysteine, or the pro-inflammatory cytokine tumor necrosis factor-alpha the effects on cardiac contractility parameters and coronary vascular resistance were studied in 67 male Sprague-Dawley rats. The temperature-controlled and pressure-constant Langendorff apparatus was used with retrograde perfusion of the aorta and a Krebs-Henseleit buffer. Neither the unspecific nitric oxide synthase inhibitor nor the nitric oxide donor excludes nitric oxide from playing a mechanistic role in our perfusion studies. Tumor necrosis factor-alpha was without any synergistic or antagonistic effects when co-treated with neopterin. N-acetylcysteine was most effective in abolishing neopterin-dependent effects on cardiac function. The negative effects of neopterin on cardiac performance might be due to an enhancement of oxidative stress by neopterin that can be attenuated by the antioxidant N-acetylcysteine. Neopterin has to be considered a pathogenic factor in the development of cardiac dysfunction in chronic disease states with high neopterin levels secondary to activation of the immune system.