Is Sigstad's score really capable of detecting post-surgical late dumping syndrome?

BACKGROUND: This clinical trial explores the Sigstad score for late dumping syndrome in postoperative patients who have undergone sleeve gastrectomy (SG) or One Anastomosis Gastric Bypass (OAGB). The aims of this study are to investigate the correlations with late dumping syndrome, to evaluate the reliability and validity of the Sigstad score and to discuss a modified scoring system. METHODS: The study was conducted at the Obesity Center of the Westküstenklinikum Heide and included 271 patients. Data collection involved conducting interviews, diet diaries and measuring blood glucose levels. Non-parametric tests, logistic regression and McDonald's Omega were the selected statistical approaches. RESULTS: Body Mass Index (BMI) decreased over time (-9.67 kg/m2 at 4 months, -15.58 kg/m2 at 12 months). Preoperatively, the Sigstad score exhibited the highest value, and no occurrences of late dumping syndrome were observed. No significant differences were found in BMI concerning late dumping syndrome or Sigstad score among postoperative patients. Postoperative patients experienced an increase in gastrointestinal symptoms. The reliability test showed a McDonald's omega value of 0.509. The analysis conducted through binary logistic regression indicated dizziness as a significant predictor of late dumping syndrome; however, this finding did not hold up after performing Bonferroni correction. CONCLUSION: The Sigstad score is not a reliable or valid method for detecting late dumping syndrome after surgery for obesity and metabolic disorders. It is necessary to have alternatives that use objective measures and assess the quality of life, and that these alternatives be validated in large patient cohorts.

From dithiocarbamates to branched dithiocarbazates: Compounds with potent antischistosomal activity.

Schistosomiasis or bilharzia is caused by blood flukes of the genus Schistosoma and represents a considerable health and economic burden in tropical and subtropical regions. The treatment of this infectious disease relies on one single drug: praziquantel (PZQ). Therefore, new and potent antischistosomal compounds need to be developed. In our previous work, starting with the drug disulfiram, we developed dithiocarbamates with in vitro antischistosomal activities in the low micromolar range. Based on these results, we report in this study on the synthesis and biological testing of the structurally related dithiocarbazates against Schistosoma mansoni, one of the major species of schistosomes. In total, three series of dithiocarbazate derivatives were examined, and we found that the antischistosomal activity of N-unbranched dithiocarbazates increased by further N-substitution. Comparable tetra-substituted dithiocarbazates were rarely described in the literature, thus a synthesis route was established. Due to the elaborate synthesis, the branched dithiocarbazates (containing an N-aminopiperazine) were simplified, but the resulting branched dithiocarbamates (containing a 4-aminopiperidine) were considerably less active. Taken together, dithiocarbazate-containing compounds with an in vitro antischistosomal activity of 5 µM were obtained.

Synthesis of the l- and d-SH2 domain of the leukaemia oncogene Bcr-Abl.

The d- and l-versions of the Bcr-Abl SH2 domain (12.7 kDa) were synthesized. Key optimizations included pseudoproline incorporation, N-terminal hydrophilic tail addition and mild N-acetoxy succinimide acetylation. Their folding and activity are as for the recombinant protein. Our results will enable engineering of mirror-image monobody antagonists of the central oncoprotein Bcr-Abl.

Evaluation of the representativeness of the German Oncology Dynamics dataset.

OBJECTIVES: To evaluate the representativeness of the German Oncology Dynamics (OD) dataset by comparing its projected patient population structure with that outlined in published epidemiological literature. MATERIALS AND METHODS: The OD is an international cross-sectional semi-retrospective survey collecting anonymized patient cases from a representative panel of physicians via a web-based questionnaire; the cases are quality-checked and projected to the drug-treated prevalence using physician workload information. The present study verifies the OD 2018 projected patient proportions by indication and sex against prevalence figures in IARC's Globocan and the Cancer in Germany report by the Robert Koch Institute. Additionally, age group and metastasis presence distributions in gonadotropin-releasing hormone analog (GnRHa)-treated prostate cancer patients are compared with the findings of a registry-based study: Retrospective Analysis of Patients with Prostate Cancer Initiating GnRH Agonists/Antagonists Therapy Using a German Claims Database: Epidemiological and Patient Outcomes by Hupe et al. [3]. RESULTS: The OD demonstrated a cancer type distribution similar to the comparator sources. Cancer-specific sex distribution differences could be attributed to real-world diagnosis and treatment patterns. The age group distributions of GnRH-treated prostate cancer patients did not differ significantly between the OD and the Hupe et al. [3] study according to confidence interval comparisons and a Kolmogorov-Smirnov test. CONCLUSION: Projected patient distributions for the OD Germany were similar to those documented in the published literature. The dissimilarities can be attributed to the low drug-treated prevalence of some cancer types and sex-specific diagnosis timeline differences. Further investigations are needed to verify the reliability of histological biomarker data as well as patient demographics in other countries.

Fish oil supplementation in cancer patients. Capsules or nutritional drink supplements? A controlled study of compliance.

BACKGROUND & AIMS: Fish-oil, rich in Omega-3 long chain polyunsaturated fatty acids (n-3 LC PUFAs), may in high doses inhibit the development or progression of cancer cachexia. However, poor compliance to oral nutritional supplements is a well-known problem. We aimed to investigate acceptability and compliance to a nutritional drink with fish-oil compared to an equivalent dose of fish-oil administered as capsules in patients receiving chemotherapy for GI tract cancers. Moreover, we aimed to investigate, if there was a difference between a nutritional drink or capsules with respect to nutritional status and side effects. Finally, we aimed to examine, if n-3 LC PUFAs affect leukocyte and platelet counts, and markers of dose-limiting toxicities of chemotherapy. METHODS: We consecutively included 41 patients with advanced cancer in the controlled study. Patients were allocated (not randomized) to ingest either 10 capsules/day for four weeks or 400 mL/day of a nutritional drink with same dose of n-3 LC PUFA dose. Compliance was assessed by daily self-registration and n-3 LC PUFAs in whole blood. Side effects were assessed by 10 cm visual analog scales. RESULTS: Compliance and daily consumption of n-3 LC PUFAs were 96.4% (94.1-99.3) and 4.8 (4.7-4.9) g/day in the capsule group and 80.8 (55.4-93.6) % and 4.0 (2.8-4.7) g/day in the group, respectively (p ≤ 0.02). We found no differences between the groups with respect to changes in whole blood n-3 LC PUFAs, weight, nutritional status, acceptability or side effects. However, in the capsule group the whole blood n-3 LC PUFAs correlated negatively with the increase in nausea (rs = -0.39, p = 0.05), but not in the nutritional drink group. Nausea, reduced appetite and loose stools were of greatest importance for the deviations from recommended doses. The number of capsules had a negative impact on acceptability and compliance, whereas this was mainly related to taste and texture in the nutritional drink group. No changes in median thrombocyte or leukocyte blood counts were observed. CONCLUSIONS: Fish oil in capsules appeared to result in better compliance compared to a nutritional drink with an equivalent dose of n-3 LC PUFAs. However, capsules and the drink did not differ with respect to the effect on nutritional status or side effects. TRIAL REGISTRATION CLINICALTRIALS. GOV IDENTIFIER: NCT03751384.

Lipid-modifying therapy and low-density lipoprotein cholesterol goal attainment in patients with familial hypercholesterolemia in Germany: The CaReHigh Registry.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is amongst the most common genetic disorders encountered in primary care. Yet, only a minority of affected patients is diagnosed and treated. This interim analysis of the CaRe High Registry aims at examining the state of treatment and attainment of lipid goals in German FH patients. METHODS: The CaRe High registry includes FH patients from lipid clinics and private practices. Data have been collected using questionnaires filled in by the recruiting physicians and by interviewing the participating patients. RESULTS: We examined 512 F H patients diagnosed according to clinical criteria. Median age at the time of the first FH diagnosis was 39 (25th and 75th percentile: 27-50) years, median treatment naïve LDL cholesterol (LDL-C) was 239.4 mg/dl (6.19 mmol/l), 25th to 75th percentile 191.8-342.5 mg/dl (4.96-8.86 mmol/l). 27% of the participants did not receive lipid-lowering drugs. Among the patients treated with lipid-lowering drugs, 19% received a PCSK9 inhibitor (PCSK9i) in combination with a statin, 9% were treated with a PCSK9i alone and 3% were treated with a combination of PCSK9i and a non-statin drug. Patients with pre-existing CVD were more likely to be treated with lipid-lowering drugs and more likely to receive a PCSK9i, but LDL-C targets were only achieved by a minority of patients (<20%). Gap to target LDL-C was lowest and the median achieved LDL-C reduction was 1.4 times higher with PCSK9i treatment than with (oral) lipid-lowering therapy without PCSK9i. CONCLUSIONS: The Care High registry has included patients with the typical clinical features of familial hypercholesterolemia. PCSK9i treatment in addition to standard therapy allows attainment of target values in many patients with initially very high LDL-C.

Tropomyosin receptor kinase: a novel target in screened neuroendocrine tumors.

Tropomyosin receptor kinase (Trk) inhibitors are investigated as a novel targeted therapy in various cancers. We investigated the in vitro effects of the pan-Trk inhibitor GNF-5837 in human neuroendocrine tumor (NET) cells. The human neuroendocrine pancreatic BON1, bronchopulmonary NCI-H727 and ileal GOT1 cell lines were treated with GNF-5837 alone and in combination with everolimus. Cell viability decreased in a time- and dose-dependent manner in GOT1 cells in response to GNF-5837 treatment, while treatment in BON1 and NCI-H727 cells showed no effect on cellular viability. Trk receptor expression determined GNF-5837 sensitivity. GNF-5837 caused downregulation of PI3K-Akt-mTOR signaling, Ras-Raf-MEK-ERK signaling, the cell cycle and increased apoptotic cell death. The combinational treatment of GNF-5837 with everolimus showed a significant enhancement in inhibition of cell viability vs single substance treatments, due to a cooperative PI3K-Akt-mTOR and Ras-Raf-MEK-ERK pathway downregulation, as well as an enhanced cell cycle component downregulation. Immunohistochemical staining for Trk receptors were performed using a tissue microarray containing 107 tumor samples of gastroenteropancreatic NETs. Immunohistochemical staining with TrkA receptor and pan-Trk receptor antibodies revealed a positive staining in pancreatic NETs in 24.2% (8/33) and 33.3% (11/33), respectively. We demonstrated that the pan-Trk inhibitor GNF-5837 has promising anti-tumoral properties in human NET cell lines expressing the TrkA receptor. Immunohistochemical or molecular screening for Trk expression particularly in pancreatic NETs might serve as predictive marker for molecular targeted therapy with Trk inhibitors.

CaRe high - Cascade screening and registry for high cholesterol in Germany.

INTRODUCTION: Familial hypercholesterolemia (FH) is an inherited disorder of the LDL metabolism, leading to cardiovascular disease, even at young age. This risk can be significantly lowered by early diagnosis and treatment. About 270,000 patients affected in Germany are not diagnosed correctly and only a small number is treated properly. To improve FH diagnosis in the general population a cascade screening and registry data is warranted, yet missing in Germany. This project aims to fill this gap. METHODS: Study assistants approach physicians and lipid clinics to introduce the cascade screening and registry. The physicians identify potential FH patients and include them in the study. Patient data is acquired via questionnaires about medical history. Patients meeting at least two inclusion criteria (LDL-C >190 mg/dl or total cholesterol >290 mg/dl; tendon xanthomas; family history of hypercholesterolemia or early myocardial infarction) are included in the registry. Family members will be contacted and physicians get feedback about diagnosis and treatment options. Ethical approvals for all German states have been collected. RESULTS: So far physicians, lipid clinics and patients within the Rhein-Neckar region, the Saarland, North-Rhine-Westphalia, Upper Bavaria, Bremen, Saxonia and Berlin have joined the study. We expect to include more than 3000 patients during the next two years. CONCLUSION: After initial patient and data collection the project aims to improve FH-diagnosis and treatment. Utilizing registry data might advance diagnostic criteria and improve detection of FH and thus prevent CVD in this population.

Familial hypercholesterolemia in primary care in Germany. Diabetes and cardiovascular risk evaluation: Targets and Essential Data for Commitment of Treatment (DETECT) study.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is an inherited disorder of lipoprotein metabolism characterised by impaired removal of low-density lipoproteins (LDL) from the circulation, which leads to an increased risk of cardiovascular disease (CVD). This risk can be significantly lowered by early diagnosis and treatment. In Germany, reliable estimates of the prevalence of FH are lacking. We therefore examined the prevalence rate of FH in Germany in a primary care based cohort. METHOD: We utilized records of 4722 participants in the DETECT study, in whom complete data on blood lipids and medical history were available. Prevalence rates were assessed using the Dutch Lipid Clinics Network (DLCN) and the US-MEDPED criteria. We stratified for gender and age. Group differences were analyzed using Chi2 and ANOVA tests. RESULTS: Using the DLCN (probable or definite FH) and the US.MEDPED criteria yielded prevalence rates of 1:278 and 1:295, respectively. The established diagnostic scores used in this analysis identify different patients. In women below 50 years of age, the LDL-C concentration is lower than in men, leading to the possibility of under-diagnosing FH in this group because women under the age of 50 are less likely to reach a higher DLCN-Score. CONCLUSIONS: FH has a higher than expected prevalence in Germany. Clinical diagnostic algorithms may not be concordant.

Treatment of metastatic breast cancer in EU: Analysis of market research data from 4Q2013 till 3Q2014.

OBJECTIVE: Despite the scientific evidence undoubtedly influencing current guidelines on the management of metastatic Breast cancer (mBC), marketing research data suggests this may not be reflected in EU prescribing behavior. Specifically we would like to understand the use of combination chemotherapy vs monotherapy in mBC patients. METHODOLOGY: This study is based on IMS Oncology Analyzer™, a web-based physician panel survey set-up by IMS Health, a global company which specializes in health care information including market research data. Analysis was carried out on prescribing behavior reflected in marketing research data from IMS source (from MAT Q42013 till MAT Q32014) and comparing the data with the current guidelines recommendation in mBC (ESO-ESMO 2nd international consensus guidelines). RESULTS: In 1st line mBC around 17% of patients are treated with combination chemotherapy drugs. The combination chemotherapy are essentially anthracycline based than taxane based. In 2nd+ line mBC a higher proportion of monotherapy (chemotherapy+/-biologics) is being used. CONCLUSION: Despite the recommendation provided by current ESMO guidelines on mBC treatments, indicating the sequential use of single cytotoxic agents is a considerable alternative to standard multidrug chemotherapy regimens, marketing research data suggests this may not be reflected in EU prescribing behavior.

Epigenetic silencing of serine protease HTRA1 drives polyploidy.

BACKGROUND: Increased numbers and improperly positioned centrosomes, aneuploidy or polyploidy, and chromosomal instability are frequently observed characteristics of cancer cells. While some aspects of these events and the checkpoint mechanisms are well studied, not all players have yet been identified. As the role of proteases other than the proteasome in tumorigenesis is an insufficiently addressed question, we investigated the epigenetic control of the widely conserved protease HTRA1 and the phenotypes of deregulation. METHODS: Mouse embryonal fibroblasts and HCT116 and SW480 cells were used to study the mechanism of epigenetic silencing of HTRA1. In addition, using cell biological and genetic methods, the phenotypes of downregulation of HTRA1 expression were investigated. RESULTS: HTRA1 is epigenetically silenced in HCT116 colon carcinoma cells via the epigenetic adaptor protein MBD2. On the cellular level, HTRA1 depletion causes multiple phenotypes including acceleration of cell growth, centrosome amplification and polyploidy in SW480 colon adenocarcinoma cells as well as in primary mouse embryonic fibroblasts (MEFs). CONCLUSIONS: Downregulation of HTRA1 causes a number of phenotypes that are hallmarks of cancer cells suggesting that the methylation state of the HtrA1 promoter may be used as a biomarker for tumour cells or cells at risk of transformation.

The impact of treatment compliance on fracture risk in women with breast cancer treated with aromatase inhibitors in the United Kingdom.

No study has yet analyzed the impact of compliance with aromatase inhibitor(AI) treatments on fracture risk in a real-world setting in women with breast cancer. In this study, 8732 women with BC treated with AI, 8732 treated with tamoxifen (TAM), and 8732 age-matched women without BC selected from the Disease Analyzer database (IMS Health) were included. The main outcome measure was the impact of compliance with AI treatment on fracture risk. Demographic data included age, body mass index (BMI), and smoking status. Alcohol dependency, dementia, bone density, visual disturbances, diabetes, and use of corticosteroids were also assessed. Kaplan-Meier curves were used to analyze the proportion of patients with fracture over time, and multivariate Cox regression models were performed to assess the adjusted fracture risk. Mean age was 67.3 years. 17.6, 8.7, and 8.8 % of AI, TAM, and non-cancer patients, respectively, were diagnosed with fracture within 5 years after the index date (p < 0.001). The proportion of women receiving AI with fracture increased with treatment compliance, rising from 8.6 % when treatment persisted for less than a year to 18.0 % when it persisted for between 4 and 5 years (p < 0.001). By contrast, the proportion of fractures in women with BC receiving TAM for the same time periods decreased from 13.0 to 7.9 % (p < 0.001). The risk of fracture was higher in women with BC using AI than in the non-cancer group (HR = 3.00; p < 0.0001). Finally, current smoking status, BMI, dementia, and prescription of corticosteroids had significant impacts on fracture risk. Compliance with AI treatment in women with BC is associated with a clear increase in the risk of fracture, which is much higher than previously reported.

Treatment persistence evaluation of tamoxifen and aromatase inhibitors in breast cancer patients in early and late stage disease.

BACKGROUND: The aim of our study was to analyze the persistence with tamoxifen (TAM) and aromatase inhibitors (AIs) in postmenopausal women with hormone-receptor-positive breast cancer (BC) in early and late stage disease. METHODS: This study based on data from The IMS Oncology Analyzer (OA) including retrospective longitudinal patient treatment histories from diagnosis for all cancer types. 4,626 patients with a diagnosis of breast cancer with current or terminated treatment with TAM or AIs between January 2003 and March 2012 in Germany were included. RESULTS: Our results indicate a significantly increased risk for treatment discontinuation for patients in the age groups of 41 - 50 and 51 - 60 years compared to older patients as well as in patients with a stage IV tumor compared to patients with lower stage tumors. If treatment was initiated by a gynecologist, patients are less likely to discontinue their therapy compared to treatment initiated by an oncologist. Furthermore, the risk of therapy break up was significantly lower in patients treated in an office-based setting compared to the reference group of patients treated in general hospitals. CONCLUSION: In conclusion, persistence with endocrine treatment in woman with hormone-receptor-positive breast cancer is low, especially in later stage disease, and needs to be significantly increased to improve outcome in clinical practice. Further research is required to understand this complex, but important aspect.

Comparison of cone-beam and conventional multislice computed tomography for image-guided dental implant planning.

OBJECTIVES: To compare the accuracy of cone-beam CT (CBCT) and multislice CT (MSCT) with regard to its use in image-guided dental implant surgery in a prospective model based study. MATERIAL AND METHODS: Ten photopolymer-acrylate mandibula models, each with four precise metal reference markers, were scanned with MSCT and CBCT. The six reference distances between the markers were measured by a three-axis milling machine first. The distances were then measured by (1) navigation with the Medtronic StealthStation® TREON™ image-guided surgery system, (2) with the Medtronic planning-tool and (3) on the PC with the Mimics® software. Mean values were calculated for all three methods for CBCT and MSCT and were compared for statistical significance. RESULTS: Of all measurements, 83% of the arithmetic mean values were within the ±0.5 mm range (MSCT 88% and CBCT 78%) and 17% within the ±1.0 mm range (MSCT 12% and CBCT 22%). The absolute difference of the arithmetic mean values showed no statistically significant difference between MSCT and CBCT. The difference of the overall mean values to the reference was 0.43 mm for MSCT and 0.46 mm for CBCT. CONCLUSIONS: The data of our study prove that the application of CBCT for the indicated purpose yielded good results comparable to those of MSCT. All three measuring methods were feasible and accuracy was statistically not different between the data acquired by MSCT and CBCT within the setting of this study.

Identification of protein disulfide isomerase as a cardiomyocyte survival factor in ischemic cardiomyopathy.

OBJECTIVES: The aim of the study was to analyze the molecular mechanisms activated during postinfarction remodeling in human hearts. BACKGROUND: The molecular mechanisms of initial response to ischemic insult in the heart and the pathways involved in compensation and remodeling are still largely unknown. METHODS: Up-regulation or down-regulation of gene expression in the human viable peri-infarct (vs. remote) myocardial region was investigated by complementary deoxyribonucleic acid array technology and confirmed at a single-gene/protein level with reverse transcriptase polymerase chain reaction and immunohistochemistry. An in vitro model of cardiomyocyte hypoxia in HL1 cells was used to validate anti-apoptotic effects of the candidate gene/protein and to assess the associated downstream cascade. Finally, a mouse model of myocardial infarction was used to test the in vivo effects of exogenous transfection with the candidate gene/protein. RESULTS: Protein disulfide isomerase (PDI), a member of the unfolded protein response, is 3-fold up-regulated in the viable peri-infarct myocardial region, and in a postmortem model, its expression is significantly inversely correlated with apoptotic rate and with presence of heart failure (HF) and biventricular dilatation. Induced PDI expression in HL1 cells conferred protection from hypoxia-induced apoptosis. Adenoviral-mediated PDI gene transfer to the mouse heart resulted in 2.5-fold smaller infarct size, significantly reduced cardiomyocyte apoptosis in the peri-infarct region, and smaller left ventricular end-diastolic diameter versus mice treated with a transgene-null adenoviral vector. CONCLUSIONS: These results suggest that PDI promotes survival after ischemic damage and that zinc-superoxide dismutase is one of the PDI molecular targets. Pharmacological modulation of this pathway might prove useful for future prevention and treatment of HF.