Crossing borders: A systematic review with quantitative analysis of genetic mutations of carcinomas of the biliary tract.

Biliary tract carcinoma (BTC) comprises gallbladder and intra-/extrahepatic cholangiocarcinoma (GBC, ICC, EHC), which are currently classified by anatomical origin. Better understanding of the mutational profile of BTCs might refine classification and improve treatment. We performed a systematic review of studies reporting on mutational profiling of BTC. We included articles reporting on whole-exome/whole-genome-sequencing (WES/WGS) and targeted sequencing (TS) of BTC, published between 2000-2017. Pooled mutation proportions were calculated, stratified by anatomical region and sequencing technique. A total of 25 studies with 1806 patients were included. Overall, TP53 was the most commonly mutated gene in BTC. GBC was associated with mutations in PFKFB3, PLXN2 and PGAP1. Mutations in IDH1, IDH2 and FGFR fusions almost exclusively occurred in ICC patients. Mutations in APC, GNAS and TGFBR2 occurred exclusively in EHC patients. In conclusion, subtypes of BTCs exhibit minor differences in mutational profile, which is likely influenced by the cell of origin.

ADAM12 is a circulating marker for stromal activation in pancreatic cancer and predicts response to chemotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma that harbors tumor-promoting properties. No good biomarkers exist to monitor the effect of stromal targeting therapies or to predict response. We set out to identify such non-invasive markers for PDAC stroma and predict response to therapy. Gene expression datasets, co-culture experiments, xenografts, and patient samples were analyzed. Serum samples were measured from a cohort of 58 resected patients, and 87 metastatic or locally advanced PDAC patients. Baseline and follow-up levels were assessed in 372 additional metastatic PDAC patients who received nab-paclitaxel with gemcitabine (n = 184) or gemcitabine monotherapy (n = 188) in the phase III MPACT trial. Increased levels of ADAM12 were found in PDAC patients compared to healthy controls (p < 0.0001, n = 157 and n = 38). High levels of ADAM12 significantly associated with poor outcome in resected PDAC (HR 2.07, p = 0.04). In the MPACT trial survival was significantly longer for patients who received nab-paclitaxel and had undetectable ADAM12 levels before treatment (OS 12.3 m vs 7.9 m p = 0.0046). Consistently undetectable or decreased ADAM12 levels during treatment significantly associated with longer survival as well (OS 14.4 m and 11.2 m, respectively vs 8.3, p = 0.0054). We conclude that ADAM12 is a blood-borne proxy for stromal activation, the levels of which have prognostic significance and correlate with treatment benefit.

Comparison of two neoadjuvant chemoradiotherapy regimens in patients with potentially curable esophageal carcinoma.

The implementation of neoadjuvant chemoradiotherapy (CRT) in esophageal cancer (EC) patients has led to improved survival rates. Worldwide, different CRT regimens are applied. It is unknown how these regimens relate to each other regarding efficacy. Therefore, the aim of this study was to determine the preferred regimen regarding toxicity of, response to CRT, and long-term survival after esophagectomy in EC patients. EC patients in two centers who underwent CRT with different regimens prior to surgery were included in this study. CRT consisted of 50.4Gy combined with two cycles of cisplatin and 5-FU(center A), or 41.4Gy combined with five cycles of carboplatin and paclitaxel (center B). Toxicity, response to therapy and long-term survival were compared between groups. One hundred sisty-five patients were included. Forty-one percent of patients in center A developed ≥1 toxicity ≥ grade 3 versus 25% in center B (P = 0.025). CRT with a cisplatin-based regimen was an independent predictor for development of toxicity ≥ grade 3 (P = 0.043). There were no differences in response between both regimens (P = 0.904). Three-year survival was 61% (A) versus 57% (B) (P = 0.725). The carboplatin/paclitaxel/41.4Gy regimen causes less toxicity compared to the cisplatin/5-FU/50.4Gy regimen with nonsignificant differences in response rates and long-term survival; therefore our results support this regimen to be the preferred regimen for EC patients.

[Three patients with gynaecomastia]. / Drie patiënten met gynaecomastie.

In three patients gynaecomastia was diagnosed: a 22-year-old man with concomitant thyrotoxicosis due to an extensively metastasized extragonadal choriocarcinoma, a 53-year-old man with hypogonadism due to Klinefelter's syndrome that was biochemically obscured due to medications leading to elevated prolactin levels, and a 62-year-old man with acromegaly and secondary hypogonadism due to a mixed prolactin and growth hormone secreting pituitary adenoma. Gynaecomastia calls for thorough evaluation.

Hormone replacement therapy and endothelial function. Results of a randomized controlled trial in healthy postmenopausal women.

OBJECTIVE: To compare the effects of 3 months treatment with tibolone (a single entity synthetic steroid hormone with estrogenic, progestanic and androgenic activities), or continuous combined conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA), with placebo, on endothelial function. DESIGN: A single center, randomized, double-blind, placebo-controlled study. SETTING: Research center as part of the University Medical Center Utrecht. SUBJECTS: One hundred and five healthy postmenopausal women, sampled from the general population. INTERVENTIONS: Three months treatment with tibolone or CEE+MPA or placebo. MAIN OUTCOME MEASURE: At baseline and after 3 months, endothelial function was assessed non-invasively by measuring percent lumen diameter change in the brachial artery after reactive hyperemia and sublingual nitroglycerine spray. RESULTS: Results are presented as mean differences between treatment groups of endothelium dependent flow mediated dilatation (fmd) and endothelium independent nitroglycerine induced dilatation with 95% confidence intervals (95% CI). After treatment, there was a significant difference in mean fmd between the CEE+MPA group and the placebo group of 2.5% (95% CI: 0.3-4.6) while the tibolone group and the placebo group did not differ significantly (0.6%; 95% CI: 1.6-2.8). Nitroglycerine induced dilatation did not differ significantly between the groups. CONCLUSIONS: Hormone replacement therapy with CEE+MPA for 3 months increases endothelium dependent fmd of the brachial artery in healthy postmenopausal women. Tibolone did not alter fmd. The clinical significance of this improvement in fmd for cardiovascular disease risk needs to be established.

Effect of statin versus fibrate on postprandial endothelial dysfunction: role of remnant-like particles.

BACKGROUND: Postprandial lipemia is associated with endothelial dysfunction. Remnant-like particles (RLP) have been suggested to contribute to these adverse vascular effects. We investigated the effect of cerivastatin and gemfibrozil upon oral fat load induced changes in endothelial function and postprandial lipid profile in vivo. METHODS: In a randomized cross-over trial, 15 healthy volunteers received cerivastatin (0.4 mg once daily), gemfibrozil (900 mg once daily) or placebo for 3 weeks. Lipid profiles and flow mediated dilation (FMD) were assessed before and 4 h after an oral fat load. Endothelium-independent dilation was tested after nitroglycerine 0.4 mg sublingual spray. RESULTS: After the placebo period, the oral fat load induced an increase in triglycerides (TG) and RLP-cholesterol (RLP-C) (0.9 +/- 0.7 and 0.08 +/- 0.04 mmol/l, respectively) and a significant decrease in FMD (9.1 +/- 3.4 to 4.3 +/- 3.3%, P < 0.05). After gemfibrozil, TG increase was attenuated (0.5 +/- 0.5 mmol/l), whereas RLP-C increase (0.05 +/- 0.09 mmol/l) and FMD decrease (9.0 +/- 3.8 to 5.2 +/- 2.6%, P < 0.05) were not different from placebo therapy. Cerivastatin did not affect TG increase (0.7 +/- 0.8 mmol/l). RLP-C increase (0.02 +/- 0.07 mmol/l) and FMD (7.9 +/- 2.6 to 8.4 +/- 2.8%) change were attenuated significantly compared to placebo. Endothelium-independent vasodilatation remained unaltered throughout the protocol. CONCLUSION: Cerivastatin, but not gemfibrozil significantly reduces RLP-C increase after an oral fat load in combination with a reversal of fat-load induced endothelial dysfunction. The present data imply that lowering of RLP-C, rather than lowering of total TG levels, may contributes to the prevention of endothelial dysfunction after an oral fat load during statin use.

Determination of acetone in cow milk by Fourier transform infrared spectroscopy for the detection of subclinical ketosis.

Fourier transform infrared analysis (FTIR) was used in combination with partial least squares regression (PLS) to predict the concentration of acetone in milk. FTIR spectra were compared with results of a gas-chromatographic head space method. Principal component analysis of whole spectra (3000 to 1000 cm(-1)) suggested to reduce the spectrum of analysis for acetone to 1450 to 1200 cm(-1). A second derivative was applied to the spectra to remove baseline effects and further enhance the spectral features. Full cross-validation was used to compare the reference with predicted acetone concentrations of samples not included in model development. PLS applied to the full spectral range resulted in a complex 19-factor model with a cross-validation error of 0.22 mM. After reducing the spectrum and taking the second derivative, we obtained a model with seven factors that yielded a cross-validation error of 0.21 mM. This compares favorably with a previously reported model with 20 factors and an error of 0.25 mM. Using PLS predictions to identify cows with subclinical ketosis resulted in 95 to 100% sensitivity and 96 to 100% specificity when the threshold for subclinical ketosis was 0.4 to 1.0 mM. The corresponding positive predictive values were > or = 76% and the negative predictive values > 98% throughout an assumed range of subclinical ketosis prevalence of 10 to 30%.

Lipoprotein (a) is associated with endothelial function in healthy postmenopausal women.

BACKGROUND: Lipoprotein (a) (Lp(a)) is an independent risk factor for atherosclerotic cardiovascular disease. The atherogenic potential of Lp(a) may be by impairment of endothelial function. Objectives. We investigated the relation of Lp(a) plasma levels to endothelium dependent and independent dilatation of the brachial artery in healthy postmenopausal women. METHODS: One hundred and five healthy postmenopausal women aged 52-67 years were included in the study. Endothelial function was assessed non-invasively by measuring percent lumen diameter change in the brachial artery after reactive hyperemia and sublingual nitroglycerine spray. RESULTS: Flow mediated dilatation was inversely related to the plasma logLp(a) level. Mean change per unit logLp(a) increase:-2.83% (95% CI: -5.22--0.43). Elevated Lp(a) (>239 mg/l) (upper quartile) was associated with an impaired flow mediated vasodilatation (2.4%+/-1. 2) compared to Lp(a) < or =239 mg/l (5.2%+/-0.7). Adjustment for other cardiovascular risk factors did not change the magnitude of the association. Nitroglycerine-induced vasodilatation was not significantly lower in the high Lp(a) level group, compared to the group with normal levels of Lp(a) (< or =239 mg/l) (8.0+/-1.2 vs. 11.4%+/-0.8). CONCLUSION: Elevated lipoprotein (a) levels are associated with an impaired endothelial function in healthy postmenopausal women, independent of conventional risk factors for cardiovascular disease. Since Lp(a) may be pathogenetically important for early vascular damage, elevated Lp(a) levels might contribute to the increased cardiovascular risk seen in postmenopausal women.

Influence of folic acid on postprandial endothelial dysfunction.

Triglyceride-rich lipoproteins that circulate postprandially are increasingly being recognized as potentially atherogenic. These particles also have been shown to cause endothelial dysfunction. We recently demonstrated that acute parenteral administration of folic acid restores endothelial function in vivo in patients with increased LDL cholesterol levels. In vitro data suggested that this effect could be mediated by a reduction of radical stress. In the present study, therefore, we evaluated the effect of an acute oral fat load on both endothelial function and oxygen radical production. Next, we studied whether 2 weeks of pretreatment with 10 mg folic acid PO could prevent these fat-induced changes. We conducted a prospective, randomized, placebo-controlled study to evaluate the effect of oral folic acid administration (10 mg/d for 2 weeks) on basal endothelial function as well as endothelial function on an acute fat load in 20 healthy volunteers 18 to 33 years old. Endothelial function was assessed as flow-mediated dilatation (FMD). Endothelium-independent dilatation was measured after sublingual nitroglycerin spray. Oxygen radical stress was assessed by measurement of the urinary excretion of the stable radical-damage end product malondialdehyde. During administration of placebo, FMD decreased significantly after an acute oral fat load, with a median from 10.6% (8.3% to 12.2%) to 5.8% (3.0% to 10.2%), P<0.05. During folic acid administration, FMD was unaffected by a fat load, with a median from 9.6% (7.1% to 12.8%) to 9.9% (7.5% to 14.1%), P=NS. The increase in malondialdehyde excretion in the urine after fat loading was also prevented during folic acid administration (absolute increase after an acute fat load during placebo, 0.11+/-0.1 micromol/L versus folic acid, 0.02+/-0.1 micromol/L, P<0.05). The response to the endothelium-independent vasodilator nitroglycerin remained unaltered throughout the study. Pretreatment with oral folic acid prevents the lipid-induced decrease in FMD as well as the lipid-induced increase in urinary radical-damage end products. Because these observations were made in healthy volunteers with normal folate and homocysteine levels, it is suggested that a higher folate intake in the general population may have vasculoprotective effects.

Growth hormone (GH) treatment decreases postprandial remnant-like particle cholesterol concentration and improves endothelial function in adult-onset GH deficiency.

Premature atherosclerosis is a clinical feature in adult-onset GH deficiency. Evidence is accumulating that disturbances in triglyceride metabolism, reflected by abnormalities in circulating remnant lipoproteins, are associated with increased atherogenic potential. In a case-controlled intervention study, we investigated postprandial lipoprotein metabolism using a new remnant lipoprotein method based on immunoseparation principle [RLP-cholesterol (RLP-C)]. In addition, we analyzed retinyl ester (RE) analysis in plasma and in Sf < 1000 fraction. Endothelial function was assessed as flow-mediated dilatation (FMD). Eight patients diagnosed with acquired adult-onset GH deficiency and eight controls matched for gender, age, body mass index, and apolipoprotein (apo) E genotype were enrolled in the study. Oral vitamin A fat loading tests were performed at baseline in both groups and after 6 months of treatment with recombinant human GH (rh-GH) in the adult-onset GH-deficient patients. Adult-onset GH-deficient patients had significantly higher fasting RLP-C, postprandial RLP-C concentrations (plasma RLP-C, 0.29 +/- 0.14 mmol/L; and incremental area under the curve-RLP-C, 2.13 +/- 1.60 mmol*h/L, respectively) than controls (0.19 +/- 0.06 mmol/L and 1.05 +/- 0.72 mmol*h/L (P: < 0.05), respectively). They also had significantly higher postprandial RE in plasma and Sf < 1000 fraction. Treatment with rh-GH significantly reduced postprandial RLP-C concentrations (incremental area under the curve-RPL-C 0.73 +/- 0.34 mmol*h/L; P: < 0.05) but had no effects on the fasting RLP-C concentrations (0.317 +/- 0.09 mmol/L, P: < 0.05), or on the postprandial RE in plasma and in Sf < 1000 fraction. Endothelial function measured as FMD was improved from 5.9 +/- 3.3% to 10.2 +/- 4.0% (P: < 0.05) in patients treated with rh-GH. It is concluded that patients with adult-onset GH deficiency have increased levels of fasting and postprandial RLP-C and an impaired endothelial function as measured as FMD. Treatment with rh-GH resulted in a decrease of postprandial RLP-C concentration, thereby improving the postprandial atherogenic lipoprotein profile and improvement of endothelial function, however, the clearance of large chylomicron particles as reflected by RE remained disturbed.

Effect of angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor antagonism on postprandial endothelial function.

OBJECTIVES: The purpose of this study was to determine whether endothelial dysfunction as a consequence of direct postprandial lipid response might be favorably influenced by angiotensin-converting enzyme inhibitors or angiotensin AT1 receptor antagonists. BACKGROUND: Postprandial triglyceride-rich lipoproteins cause endothelial dysfunction. Angiotensin-converting enzyme inhibitors have been shown to improve vascular reactivity. For angiotensin II type 1 receptor antagonists this effect is as yet uncertain. METHODS: A randomized, double-blind, placebo-controlled crossover study in 30 healthy volunteers, aged 18 to 33 years, evaluated the effect of quinapril (40 mg daily for two weeks) and losartan (50 mg daily for two weeks) on basal as well as postprandial endothelial function measured noninvasively as percentage diameter change in the brachial artery after reactive hyperemia. Endothelium-independent dilation was measured after nitroglycerine spray sublingual. RESULTS: An acute oral fat load impaired endothelial function. Flow-mediated vasodilation (FMD) decreased from a median of 6.2% to 4.2% (p < 0.05). There was no significant difference in preprandial endothelial function after two weeks of treatment with either quinapril or losartan compared with placebo in these healthy volunteers. Both quinapril (FMD 6.4% to 6.3%) and losartan (7.1% to 5.4%) prevented endothelial dysfunction induced by an oral fat load, although the protective effect of quinapril appeared to be more profound. The response to the endothelium-independent vasodilator nitroglycerine was unaltered throughout the study. CONCLUSIONS: Both losartan and quinapril prevent endothelial dysfunction induced by triglyceride-rich lipoproteins in healthy volunteers. However, the protective effect of quinapril is more pronounced.

Preoperative injection using a diluted anesthetic/adrenaline solution significantly reduces blood loss in reduction mammaplasty.

Breast reductions are very common operations in the plastic surgical practice. The cosmetic results are generally satisfactory but are often accompanied with large volumes of blood lost. In this study, the reduction of blood loss together with other positive and negative effects of a preoperatively diluted anesthetic/adrenaline solution was tested. A group of 41 female patients treated with the infiltration solution was compared with a group of 29 female patients treated without the solution. No statistical differences were found in age at operation, weight, length, Quetelet index, amount of tissue resected, preoperative hemoglobin and hematocrit, postoperative drainage, duration of operation, and the viability of the skin flaps (p > 0.05). Blood loss was significantly less in the adrenaline-treated group measured in several ways (p < 0.0001). There were more adrenaline-treated patients with less hospitalization time compared with the nontreated group (p = 0.0858). In conclusion, diluted anesthetic/adrenaline solution significantly reduces blood loss in reduction mammaplasty without any adverse effects.

Incidence of clinical mastitis in dairy herds grouped in three categories by bulk milk somatic cell counts.

Incidence of clinical mastitis was studied in 274 herds grouped in three categories by bulk milk somatic cell count (SCC). Mean incidence rate of clinical mastitis was 0.278, 0.257, and 0.252 cases per 365 cow-days at risk in herds with low (< or = 150,000), medium (150,000 to 250,000), and high (250,000 to 400,000 cells/ml) bulk milk SCC, respectively. The incidence rate of clinical mastitis was not different among the three categories. Variance in the incidence of clinical mastitis among herds increased as bulk milk SCC decreased. Clinical mastitis caused by Gram-negative pathogens, such as Escherichia coli, Klebsiella spp., or Pseudomonas spp., occurred more often in herds with a low bulk milk SCC. Clinical mastitis caused by Staphylococcus aureus, Streptococcus dysgalactiae, and Streptococcus agalactiae occurred more often in herds with a high bulk milk SCC. Systemic signs of illness caused by clinical mastitis occurred more often in herds with a low bulk milk SCC. Both overall culling rate and culling rate for clinical mastitis were not different among groups catergorized by bulk milk SCC. In herds with a high bulk milk SCC, however, more cows that produced milk with a high SCC were culled. In herds with a low bulk milk SCC, more cows were culled for teat lesions, milkability, udder shape, fertility, and character than were cows in herds with a high bulk milk SCC. In herds with a low bulk milk SCC, cows were also culled more for export and production reasons.

HIS-PACS coupling: BAZIS/ZIS and Philips/MARCOM on speaking terms.

Nowadays a growing number of experts in the PACS field agree on the necessity of having an integrated HIS-PACS combination available in modern hospitals in order to manage the enormous amounts of patient data, both textual, numerical and image information, in an effective way. Since 1986 BAZIS (the Development and Support Group of the Hospital Information System), Philips Medical Systems and the University Hospital of Utrecht (AZU) are partners in the so-called Dutch PACS Project in the development and evaluation of a fully integrated image information system. The first phase of the coupling (sub)project consists of establishing a communication link between the BAZIS/ZIS and the Philips/MARCOM system with the following restrictions: the only data sent concerns the inpatients of one ward; data will only flow one way, from BAZIS/ZIS to Philips/MARCOM. In the second phase two-way communication will be realized and more departments can be part of the experiment. In phase 3 a more general HIS-PACS interface will be developed, independent of the manufacturers of HIS and PACS. In this paper the technical solution chosen for the first phase coupling, the format of the messages being transferred, and the events which result in sending the messages, will be described. Also, reference is made to the demonstration of the working HIS-PACS link, given during the 6th EuroPACS meeting in Utrecht and Leiden on 25-26 April 1988.