Vaccine therapy for metastatic melanoma: systematic review and meta-analysis of clinical trials

Clinical trials of melanoma vaccines have yielded inconclusive data on whether a positive melanoma-specific immune response predicts treatment benefit. The objective of this study was to evaluate the effect of different melanoma vaccine strategies and the association between immunologic response and survival. The authors conducted a systematic review and meta-analysis of phase II and III clinical trials of melanoma vaccine. Outcomes assessed included overall disease control, overall survival, and impact on immune response. For binary variables, proportions were reported for one-arm studies and risk ratios for controlled studies. For survival data, medians were reported for one-arm studies and hazard ratios for controlled studies. The existence and extent of heterogeneity between trials was evaluated using Cochran's Q statistic. A two-sided P value of less than 0.05 for meta-analysis results was considered statistically significant. Of 56 studies reporting data on 4375 patients, overall disease control was seen in 25.3% [95% confidence interval (CI): 20.7-30.5%] of patients. Subgroup analysis revealed that overall disease control for peptide vaccines plus interleukin-2 (IL-2) was improved compared with interleukin-2 alone (pooled risk ratio: 2.79, 95% CI: 1.62-4.80). Overall survival varied among six studies comparing vaccine with other treatments. Subgroup analysis revealed that tumor-specific immune response was associated with prolonged overall survival compared with the lack of response (pooled hazard ratio: 2.15, 95% CI: 1.88-2.44). Severe toxicity associated with vaccine treatment was uncommon. Overall, a melanoma-specific immune response predicted longer overall survival, although no evidence was found that vaccine therapy provides better overall disease control or overall survival compared with other treatments.     

Cytomics and nanobioengineering

The finding that an individual's genome differs as much as by many million variants from that of the human reference assembly diminished the great enthusiasm that every disease could be predicted based on nucleotide polymorphisms. Even individual cells of an organ may be specifically equipped to perform specific tasks and that the information of individual cells in a cell system is key information to understand function or dysfunction. Therefore, cytomics received great attention during the last years as it allows to quantitatively and qualitatively analyzing great number of individual cells, cell constituents, and of their intracellular and functional interactions in a cellular system and also giving the concept of analysis of these data.Exhaustive data extraction from multiparametric assays and multiple tests are the prerequisite for prediction of drug toxicity. Cytomics, as novel approach for unsupervised data analysis give a chance to find the most predictive parameters, which describe best the toxicity of a chemical. Cytomics is intrinsically connected to drug development and drug discovery.Focused on small structures, nanobioengineering is the ideal partner of cytomics, the systems biological discipline for cell population analysis. Realizing the idea "from the molecule to the patient" develops and offers chemical compounds, proteins, and other biomolecules, cells as well as tissues as instruments and products for a wide variety of biotechnological and biomedical applications.The integrative nanobioengineering combining different disciplines of nanotechnology will promote the development of innovative therapies and diagnostic methods. It can improve the precision of the measurements with focus on single cell analysis. By nanobioengineering and whole body imaging techniques, cytomics covers the field from molecules through bacterial cells, eukaryotic tissues, and organs to small animal live analysis. Toxicological testing and medical drug development are currently strongly broadening. It harbors the promise to substantially impact on various fields of biomedicine, drug discovery, and predictive medicine.As the number of scientific data is rising exponentially, new data analysis tools and strategies like cytomics and nanobioengineering take a lead and get closer to application. Bionanoengineering may strongly support the quantitative data supply, thus strengthening the rational for cytomics approach.     

Delineation variation of lymph node stations for treatment planning in lung cancer radiotherapy.

PURPOSE: To assess the variability among clinicians in the delineation of mediastinal and hilar lymph node stations (LNS) according to the published recommendations in the treatment planning of elective nodal irradiation for lung cancer. METHODS: Nine observers delineated on axial CT scans of five cases the LNS according to the guidelines of the published Atlas. Next, the Volumes of Consensus (VC)--fitting strictly the guidelines--for each LNS and case were collectively defined. Volume of Intersection (VI) as the overlap of the Delineated Volume (DV) for each LNS, case and observer with respective VC was computed. The Concordance Index (CI) for respective LNS and observers was defined as "VI/VC x 100%". The Discordance Index (DI) for respective LNS and observers was defined as "(1-VI/VD) x 100%". RESULTS: Mean values of CI and DI for all observers were 69% and 36%, respectively. For five radiation oncologists who used to work as a team the ways of delineation were similar. The poorest reproducibility was shown for LNS 5, 7, 10R, and 10L. CONCLUSIONS: Although detailed guidelines are used there is still substantial room for improvement. More training in the use of the Atlas is recommended.     

Dose escalating study of biweekly gemcitabine and carboplatin in patients with advanced cancer

Combination chemotherapy with gemcitabine and carboplatin administered on a 3-week cycle is used commonly in the treatment of cancer. The purpose of our study was to establish a safe dose of combined gemcitabine and carboplatin when administered on a biweekly schedule to patients with advanced solid tumors. Gemcitabine was given intravenously over 30 minutes followed by carboplatin also given intravenously over 30 minutes once every 2 weeks (one cycle). Five dose levels were examined, ranging from gemcitabine at 1250 mg/m2 to 2000 mg/m2 and carboplatin at an area under the curve of 2.5 to 3.0. Twenty-six patients were studied (18 male and 8 female) with a median age of 57 years (range, 41-83 years); ECOG performance status was 0 or 1 in 22 patients (85%); median number of prior chemotherapy regimens was 2 (range, 0-4); median number of cycles administered per patient was 3 (range, 1-9) with a total of 89 cycles. Two dose-limiting toxicities were observed. Delay in treatment was seen in a total of 8 cycles with 6 of the delays due to myelosuppression. Grade 3 or 4 hematologic toxicity rates were as follows: anemia in one cycle (1%), neutropenia in 13 cycles (15%), and thrombocytopenia in one cycle of chemotherapy (1%). There were no hospitalizations for neutropenic fever. Mild fatigue was the most common nonhematologic toxicity. The median time to progression was 40 days (mean, 49 days; range, 4-133 days). Of the 21 evaluable patients, partial response or stable disease was observed in 11 (42%). The maximum tested dose of gemcitabine at 2000 mg/m2 and carboplatin at area under the curve of 3.0 was well tolerated on a biweekly schedule. Our findings indicate that further investigation of this biweekly regimen is warranted in patients with advanced cancer.     

Sonography for assessment of thoracic duct anatomy and physiology before and after meals

The interest in clinical anatomy of the thoracic duct (TD) has recently grown, owing to discoveries linking its morphology to pathologies such as heart failure or liver cirrhosis. In the light of this knowledge, a cost-efficient and reliable in-vivo imaging method of TD should be devised. Ultrasonography satisfies these criteria and hence is a promising tool for assessment of TD's anatomy and function. Thirty-one healthy volunteers attended the examination after 6 h of fasting and 2 h without drink. Ultrasound of the left supraclavicular fossa was performed in search of TD's orifice into the venous angle. In each case, the largest diameter, number of orifices, presence of valves, tributaries, and motility of the TD were examined. We performed examinations in three sessions: after fasting, after standardized meal and 1 h after the meal. The statistical significance has varied among the three sessions. The strongest connection was shown in the third examination. The TD was visualized in 31 cases, 35 orifices were found, most of which drained into the venous angle. Multiple orifices were seen in four cases and valves in 15 cases. Tributaries were present in 17 cases. Mean widest and orifice diameter measured 3.23 and 2.0 mm, respectively. Spontaneous peristaltic-like movements of the TD were observed in 25 cases. We demonstrated that ultrasound is useful for assessment of TD's anatomy, allowing to visualize and quantify its key features. Moreover, our study is presumably the first to capture and describe TD's motility in vivo.     

Appendicitis in diabetic pregnancy--case report

We present a case report of a 22-year-old pregnant patient with type 1 diabetes mellitus diagnosed with an appendicitis at 21st week of gestation, who underwent laparotomy and appendectomy. In later pregnancy she required treatment for recurrent urinary tract infections and nephrolithiasis. Despite having several risk factors for an unfavorable perinatal outcome, she had caesarean section performed at term and delivered a healthy full-term newborn. In this patient, we also discuss clinical conundrum of pregnancy complicated with several conditions that may manifest with acute abdominal symptoms and perioperative care for a pregnant woman with type 1 diabetes..     

Effect of tobacco smoking on endothelial function in patients with coronary arteriosclerosis

Smoking is one of the most important risk factors of atherosclerosis and ischaemic heart disease. Endothelial dysfunction is a pathological result of smoking. The aim of the study was to examine the influence of cigarette smoking on biochemical parameters of endothelial function in persons with angiographically confirmed coronary arteries atherosclerosis. The study group included 117 men: 55 patients (mean age 58.8 +/- 10.4) with ischaemic heart disease and 62 healthy subjects (mean age 47.1 +/- 9.3) of control group. In all patients blood lipid concentrations, biochemical parameters of endothelial function (nitric oxide, endothelin-1, sICAM, selectin-E), and inflammation parameters (interleukin-1 beta, interleukin-6) were measured. In a group of smoking patients both: with atherosclerosis and in control subjects nitric oxide (NO) concentrations in serum were decreased in comparison to nonsmokers. In patients with diagnosed coronary arteries atherosclerosis interleukin-6 and sICAM concentrations were increased in comparison to non-smokers. It is concluded that cigarette smoking activates or maintains inflammatory reaction in vessels with atherosclerotic changes.     

Borderline coronary lesions may lead to serious coronary events--long-term outcome in 65 conservatively treated patients

BACKGROUND: The choice of optimal therapy in a patient with borderline coronary lesion is difficult. The long-term outcome of conservatively treated patients has not yet been well defined. AIM: To analyse long-term outcome in patients with a borderline lesion in a single coronary artery who were selected for conservative treatment. METHODS: The study group consisted of 65 patients (mean age 59.4+/-7.4 years, 48 males) with (1) stable angina (CCS class I/II), (2) isolated single borderline coronary lesion (40-70% stenosis demonstrated by quantitative coronary angiography) and (3) no demonstrable ischaemia during non-invasive tests. Patients with heart failure, left ventricular ejection fraction <50% or acute coronary syndrome within 6 months preceding the study were not included. All patients were prescribed statins, angiotensin converting enzyme inhibitors and aspirin. Follow-up end-points included cardiac death, new myocardial infarction (MI) with or without ST segment elevation and revascularisation of the target coronary artery. RESULTS: The follow-up duration was 18.4+/-8.5 months (range 12-33, median 18 months). Forty nine (75%) patients remained free from angina during daily activity. Coronary events occurred in 16 (25%) patients, including three (5%) serious complications -- sudden death, new MI with ST elevation and new MI without ST elevation. The remaining 13 (20%) patients underwent percutaneous revascularisation of the target coronary artery. Coronary angiography was repeated in 16 (25%) patients. When the patients were divided into two groups according to the follow-up results (with or without coronary event), no differences in the clinical characteristics, lesion localisation and length or degree of stenosis were noted. CONCLUSIONS: (1) Conservatively treated patients with stable angina and borderline coronary stenosis have a high rate of coronary events, especially revascularisation, during a long-term follow-up. (2) Clinical parameters and quantitative coronary angiography do not identify those patients with borderline coronary lesions who are at increased risk of future coronary events.     

Calculation of site-specific carbon-isotope fractionation in pedogenic oxide minerals

Ab initio molecular dynamics and quantum chemistry techniques are used to calculate the structure, vibrational frequencies, and carbon-isotope fractionation factors of the carbon dioxide component [CO₂(m)] of soil (oxy)hydroxide minerals goethite, diaspore, and gibbsite. We have identified two possible pathways of incorporation of CO₂(m) into (oxy)hydroxide crystal structures: one in which the C⁴⁺ substitutes for four H⁺ [CO₂(m)_A] and another in which C⁴⁺ substitutes for (Al³⁺,Fe³⁺) + H⁺ [CO₂(m)_B]. Calculations of isotope fractionation factors give large differences between the two structures, with the CO₂(m)_A being isotopically lighter than CO₂(m)_B by ≈10 per mil in the case of gibbsite and nearly 20 per mil in the case of goethite. The reduced partition function ratio of CO₂(m)_B structure in goethite differs from CO₂(g) by <1 per mil. The predicted fractionation for gibbsite is >10 per mil higher, close to those measured for calcite and aragonite. The surprisingly large difference in the carbon-isotope fractionation factor between the CO₂(m)_A and CO₂(m)_B structures within a given mineral suggests that the isotopic signatures of soil (oxy)hydroxide could be heterogeneous.