Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial

BACKGROUND No effective standard treatment exists for patients with radioiodine-refractory, advanced differentiated thyroid carcinoma. We aimed to assess efficacy and safety of vandetanib, a tyrosine kinase inhibitor of RET, VEGFR and EGFR signalling, in this setting. METHODS In this randomised, double-blind, phase 2 trial, we enrolled adults (aged ≥18 years) with locally advanced or metastatic differentiated thyroid carcinoma (papillary, follicular, or poorly differentiated) at 16 European medical centres. Eligible patients were sequentially randomised in a 1:1 ratio with a standard computerised scheme to receive either vandetanib 300 mg per day (vandetanib group) or matched placebo (placebo group), balanced by centre. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population based on investigator assessment. This study is registered with ClinicalTrials.gov, number NCT00537095. FINDINGS Between Sept 28, 2007, and Oct 16, 2008, we randomly allocated 72 patients to the vandetanib group and 73 patients to the placebo group. By data cutoff (Dec 2, 2009), 113 (78%) patients had progressed (52 [72%] patients in the vandetanib group and 61 [84%] in the placebo group) and 40 (28%) had died (19 [26%] patients in the vandetanib group and 21 [29%] in the placebo group). Patients who received vandetanib had longer PFS than did those who received placebo (hazard ratio [HR] 0·63, 60% CI 0·54-0·74; one-sided p=0·008): median PFS was 11·1 months (95% CI 7·7-14·0) for patients in the vandetanib group and 5·9 months (4·0-8·9) for patients in the placebo group. The most common grade 3 or worse adverse events were QTc prolongation (ten [14%] of 73 patients in the vandetanib group vs none in the placebo group), diarrhoea (seven [10%] vs none), asthenia (five [7%] vs three [4%]), and fatigue (four [5%] vs none). Two patients in the vandetanib group and one in the placebo group died from treatment-related serious adverse events (haemorrhage from skin metastases and pneumonia in the vandetanib group and pneumonia in the placebo group). INTERPRETATION Vandetanib is the first targeted drug to show evidence of efficacy in a randomised phase 2 trial in patients with locally advanced or metastatic differentiated thyroid carcinoma. Further investigation of tyrosine-kinase inhibitors in this setting is warranted. FUNDING AstraZeneca.

Baylor History of Medicine Society Schedule 2007-2008

"Medicine: Perspectives in History and Art" (Robert E. Greenspan) Eight Practical Lessons from Osler That Will Better Your Life (Bryan Boutwell) History of the American Mental Hospital: From networking to not working & Back (Ed Fann) Ambiguities and Amputations: Methods, mishaps, and the surgical quest to cure breast cancer (Student Essay Contest Winner) (Matt Luedke) An Automated, Algorithmic, Retrospective Analysis of the Growing Influence of Statistics in Medicine (Student Essay Contest Winner) (Ryan Rochat) What’s Special about William Osler? (Charles S. Bryan) The Virtuous Physician: Lessons from Medical Biography (Charles S. Bryan) Legacy: 50 Years of Loving Care – The History of Texas Children’s Hospital, 1954-2004 (Betsy Parish) The Education of a University President: Edgar Odell Lovett of Rice University (John B. Boles) Artists and Illness: The Effect of Illness on an Artist’s Work (David Bybee)

Expression and function of $\beta$-tubulin isotypes in Chinese hamster ovary (CHO) cells

The availability of isotype specific antisera for $\beta$-tubulin, coupled with genetic and biochemical analysis, has allowed the determination of $\beta$-tubulin isotype expression and distribution in Chinese hamster ovary (CHO) cells. Using genetic manipulations involving selection for colcemid resistance followed by reversion and reselection for drug resistance, we have succeeded in isolating cell lines that exhibit three major and one minor $\beta$-tubulin spots by two-dimensional gel electrophoresis. In concert with isotype specific antibodies, analysis of these mutants demonstrates that CHO cells express two copies of isotype I, at least one copy of isotype IV, and very small amounts of isotype V. Their stoichiometry is approximately 1:1:0.7:0.2. All three isotypes assemble into both cytoplasmic and spindle microtubules, and are similar in their responses to cold, colcemid, and calcium induced depolymerization. They have comparable turnover rates and are equally sensitive to depression of synthesis upon colchicine treatment. These results suggest that $\beta$-tubulin isotypes are used interchangeably to assemble microtubule structures in CHO cells. However, of 18 colcemid resistant mutants with a demonstrable alteration in $\beta$-tubulin, all were found to have the alteration in isotype I, thus leaving open the possibility that subtle differences in isotype properties may exist. Under various conditions of the cell growth, the relative proportion of each expressed isotype does not significantly seem to change except in the early G1 phase of the cell cycle. At this time the synthesis of isotype V increases more than two fold relative to isotype I and IV, while at the same time, total $\beta$-tubulin synthesis is decreased about 60-70%. ^

GENE EXPRESSION IN CHRONIC MYELOGENOUS LEUKEMIA

The goal of the present work was to identify and characterize gene sequences that are preferentially expressed in CML in an effort to better understand the molecular basis of the disease. As high abundance mRNAs generally encode proteins that are phenotypically characteristic of cells, positive-negative screening of a CML cDNA library was used to identify cDNA clones containing sequences preferentially transcribed in CML. One cDNA sequence that fulfilled this criterion, C-A3, has been characterized in some detail. It represents a small mRNA ((TURN)496 nucleotides) that is highly abundant ((TURN)2% of the poly(A('+))RNA) in cells from the chronic phase of CML. In situ hybridization to whole cells indicates the principal leukocytes that express C-A3 sequences are eosinophils, basophils and immature myelocytes. Surprisingly, CML patients with high numbers of myeloblasts do not have an abundance of C-A3 transcripts, although transcript levels remain elevated in patients with lymphoblasts. In AML, high transcript levels are only found sporadically and occasionally different sized transcripts can be detected. Sequences from the 3' end of the C-A3 message are present in 2-5 copies per haploid genome. The 3' end of C-A3 localizes to bands 8q21.1 and 8q23 by in situ chromosomal hybridization. This is a region that is often involved in hematopoietic malignancies. Restriction digests of human genomic DNA show a correlation between the presence of a 2.3 kb Hind III fragment and certain types of leukemia. All of the leukemic DNAs tested had this fragment. In comparison, only one of five normal DNAs had a band this size. Analysis of the nucleotide sequence indicates that C-A3 probably encodes a small, hydrophobic peptide which may be part of a larger protein. ^

How Comprehensible, Interesting and Relevant is Current Research in Traditional Chinese Medicine for Practitioners?

Purpose: In traditional Chinese medicine (TCM) as in other fields of complementary medicine, research does not necessarily follow the sequence from in vitro studies via phase I to phase IV clinical trials, but all steps are being investigated simultaneously. Here, we aimed to investigate which kinds of studies were interesting and relevant for practitioners. Methods: Thirty abstracts from articles on TCM published between April and June 2012 were randomly chosen, including 5 abstracts each of in vitro studies, animal studies, case reports or series, studies with healthy volunteers, trials with patients, or reviews and meta-analyses. Six TCM practitioners (2 female, 5 non-medical, average age 46 years, average practical TCM experience 9 years) rated 10 abstracts each on a 5 point Likert scale (1=very poor to 5=very good) regarding comprehensibility, interest, relevance to practice, information for patients, and promoting reputation of TCM. Average ratings for each group of abstracts were calculated. Results: Comprehensibility of the abstracts was generally rated as good. Case reports/series, studies in healthy volunteers and trials with patients were rated interesting by the practitioners (average rating = 3.7, 3.8 and 3.7, respectively). Relevance to practice was mediocre for all types (2.5 to 3.5). In vitro studies and reviews/meta-analyses were not rated useful as information for patients (2.0). Reviews/Meta-analyses were considered negative for the reputation of TCM (2.2). Conclusions: Practitioners of TCM find abstracts of study results generally comprehensible and interesting. Case reports/series were rated in a similar way as trials with patients. Although TCM is commonly taught by means of case reports, practitioners seemed to value clinical trials. Abstracts of reviews/meta-analyses were rated rather uninformative, which was possibly due to several inconclusive results and the lack of detailed information in these abstracts.

Impaired cortical energy metabolism but not major antioxidant defenses in experimental bacterial meningitis.

The loss of soluble brain antioxidants and protective effects of radical scavengers implicate reactive oxygen species in cortical neuronal injury caused by bacterial meningitis. However, the lack of significant oxidative damage in cortex [J. Neuropathol. Exp. Neurol. 61 (2002) 605-613] suggests that cortical neuronal injury may not be due to excessive parenchymal oxidant production. To see whether this tissue region exhibits a prooxidant state in bacterial meningitis, we examined the state of the major cortical antioxidant defenses in infant rats infected with Streptococcus pneumoniae. Adenine nucleotides were co-determined to assess possible changes in energy metabolism. Arguing against heightened parenchymal oxidant production, the high NADPH/NADP(+) ratio ( approximately 3:1) and activities of the major antioxidant defense and pentose phosphate pathway enzymes remained unchanged at the time of fulminant meningitis. In contrast, cortical ATP, ADP and total adenine nucleotides were on average decreased by approximately 25%. However, energy depletion did not lead to a significant decrease in adenylate energy charge (AEC). ATP depletion was likely a consequence of metabolic degradation, since it correlated with both the loss of total adenine nucleotides and accumulation of purine degradation products. Furthermore, the loss of ATP and decrease in AEC correlated significantly with the extent of neuronal injury. These results strongly suggest that energy depletion rather than parenchymal oxidative damage is involved in the observed cortical neuronal injury.

Competitive fitness in coronaviruses is not correlated with size or number of double-membrane vesicles under reduced-temperature growth conditions.

Positive-stranded viruses synthesize their RNA in membrane-bound organelles, but it is not clear how this benefits the virus or the host. For coronaviruses, these organelles take the form of double-membrane vesicles (DMVs) interconnected by a convoluted membrane network. We used electron microscopy to identify murine coronaviruses with mutations in nsp3 and nsp14 that replicated normally while producing only half the normal amount of DMVs under low-temperature growth conditions. Viruses with mutations in nsp5 and nsp16 produced small DMVs but also replicated normally. Quantitative reverse transcriptase PCR (RT-PCR) confirmed that the most strongly affected of these, the nsp3 mutant, produced more viral RNA than wild-type virus. Competitive growth assays were carried out in both continuous and primary cells to better understand the contribution of DMVs to viral fitness. Surprisingly, several viruses that produced fewer or smaller DMVs showed a higher fitness than wild-type virus at the reduced temperature, suggesting that larger and more numerous DMVs do not necessarily confer a competitive advantage in primary or continuous cell culture. For the first time, this directly demonstrates that replication and organelle formation may be, at least in part, studied separately during infection with positive-stranded RNA virus. IMPORTANCE The viruses that cause severe acute respiratory syndrome (SARS), poliomyelitis, and hepatitis C all replicate in double-membrane vesicles (DMVs). The big question about DMVs is why they exist in the first place. In this study, we looked at thousands of infected cells and identified two coronavirus mutants that made half as many organelles as normal and two others that made typical numbers but smaller organelles. Despite differences in DMV size and number, all four mutants replicated as efficiently as wild-type virus. To better understand the relative importance of replicative organelles, we carried out competitive fitness experiments. None of these viruses was found to be significantly less fit than wild-type, and two were actually fitter in tests in two kinds of cells. This suggests that viruses have evolved to have tremendous plasticity in the ability to form membrane-associated replication complexes and that large and numerous DMVs are not exclusively associated with efficient coronavirus replication.

Cortical thickness decreases with age in very preterm born school-children but not in term born controls

Background: Cortical gray matter thinning occurs during childhood due to pruning of inefficient synaptic connections and an increase in myelination. Preterms show alterations in brain structure, with prolonged maturation of the frontal lobes, smaller cortical volumes and reduced white matter volume. These findings give rise to the question if there is a differential influence of age on cortical thinning in preterms compared to controls. Aims: To investigate the relationship between age and cortical thickness in preterms when compared to controls. Study design and outcome measures: The automated surface reconstruction software FreeSurfer was applied to obtain measurements of cortical thickness based on T1-weighted MRI images. Subjects: Forty-one preterms (< 32 weeks gestational age and/or < 1500 gram birth weight) and 30 controls were included in the study (7-12 years). Results: Cortical thickness was lower in bilateral frontal and left parietal regions and higher in left temporal gyri in preterms compared to controls. However, these differences depended on age. In preterms, age correlated negatively with cortical thickness in right frontal, parietal and inferior temporal regions. Accordingly, cortical thickness was higher in young compared to old preterms in bilateral frontal, parietal and temporal regions. In controls, age was not associated with cortical thickness. Conclusion: In preterms, cortical thinning still seems to occur between the age of 7 and 12 years, mainly in frontal and parietal areas whereas in controls, a substantial part of cortical thinning appears to be completed before they reach the age of 7 years. These data indicate slower cortical thinning in preterms than in controls.

Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial

BACKGROUND Postoperative hemithoracic radiotherapy has been used to treat malignant pleural mesothelioma, but it has not been assessed in a randomised trial. We assessed high-dose hemithoracic radiotherapy after neoadjuvant chemotherapy and extrapleural pneumonectomy in patients with malignant pleural mesothelioma. METHODS We did this phase 2 trial in two parts at 14 hospitals in Switzerland, Belgium, and Germany. We enrolled patients with pathologically confirmed malignant pleural mesothelioma; resectable TNM stages T1-3 N0-2, M0; WHO performance status 0-1; age 18-70 years. In part 1, patients were given three cycles of neoadjuvant chemotherapy (cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 given every 3 weeks) and extrapleural pneumonectomy; the primary endpoint was complete macroscopic resection (R0-1). In part 2, participants with complete macroscopic resection were randomly assigned (1:1) to receive high-dose radiotherapy or not. The target volume for radiotherapy encompassed the entire hemithorax, the thoracotomy channel, and mediastinal nodal stations if affected by the disease or violated surgically. A boost was given to areas at high risk for locoregional relapse. The allocation was stratified by centre, histology (sarcomatoid vs epithelioid or mixed), mediastinal lymph node involvement (N0-1 vs N2), and T stage (T1-2 vs T3). The primary endpoint of part 1 was the proportion of patients achieving complete macroscopic resection (R0 and R1). The primary endpoint in part 2 was locoregional relapse-free survival, analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00334594. FINDINGS We enrolled patients between Dec 7, 2005, and Oct 17, 2012. Overall, we analysed 151 patients receiving neoadjuvant chemotherapy, of whom 113 (75%) had extrapleural pneumonectomy. Median follow-up was 54·2 months (IQR 32-66). 52 (34%) of 151 patients achieved an objective response. The most common grade 3 or 4 toxic effects were neutropenia (21 [14%] of 151 patients), anaemia (11 [7%]), and nausea or vomiting (eight [5%]). 113 patients had extrapleural pneumonectomy, with complete macroscopic resection achieved in 96 (64%) of 151 patients. We enrolled 54 patients in part 2; 27 in each group. The main reasons for exclusion were patient refusal (n=20) and ineligibility (n=10). 25 of 27 patients completed radiotherapy. Median total radiotherapy dose was 55·9 Gy (IQR 46·8-56·0). Median locoregional relapse-free survival from surgery, was 7·6 months (95% CI 4·5-10·7) in the no radiotherapy group and 9·4 months (6·5-11·9) in the radiotherapy group. The most common grade 3 or higher toxic effects related to radiotherapy were nausea or vomiting (three [11%] of 27 patients), oesophagitis (two [7%]), and pneumonitis (two [7%]). One patient died of pneumonitis. We recorded no toxic effects data for the control group. INTERPRETATION Our findings do not support the routine use of hemithoracic radiotherapy for malignant pleural mesothelioma after neoadjuvant chemotherapy and extrapleural pneumonectomy. FUNDING Swiss Group for Clinical Cancer Research, Swiss State Secretariat for Education, Research and Innovation, Eli Lilly.

Comparison of telomere length in black and white teachers from South Africa: the sympathetic activity and ambulatory blood pressure in Africans study

OBJECTIVE Telomere length is a marker of biological aging that has been linked to cardiovascular disease risk. The black South African population is witnessing a tremendous increase in the prevalence of cardiovascular disease, part of which might be explained through urbanization. We compared telomere length between black South Africans and white South Africans and examined which biological and psychosocial variables played a role in ethnic difference in telomere length. METHODS We measured leukocyte telomere length in 161 black South African teachers and 180 white South African teachers aged 23 to 66 years without a history of atherothrombotic vascular disease. Age, sex, years having lived in the area, human immunodeficiency virus (HIV) infection, hypertension, body mass index, dyslipidemia, hemoglobin A1c, C-reactive protein, smoking, physical activity, alcohol abuse, depressive symptoms, psychological distress, and work stress were considered as covariates. RESULTS Black participants had shorter (median, interquartile range) relative telomere length (0.79, 0.70-0.95) than did white participants (1.06, 0.87-1.21; p < .001), and this difference changed very little after adjusting for covariates. In fully adjusted models, age (p < .001), male sex (p = .011), and HIV positive status (p = .023) were associated with shorter telomere length. Ethnicity did not significantly interact with any covariates in determining telomere length, including psychosocial characteristics. CONCLUSIONS Black South Africans showed markedly shorter telomeres than did white South African counterparts. Age, male sex, and HIV status were associated with shorter telomere length. No interactions between ethnicity and biomedical or psychosocial factors were found. Ethnic difference in telomere length might primarily be explained by genetic factors.

A double-blind randomised study to evaluate the efficacy and safety of bindarit in preventing coronary stent restenosis.

AIMS Bindarit (BND) is a selective inhibitor of monocyte chemotactic protein-1 (MCP-1/CCL2), which plays an important role in generating intimal hyperplasia. Our aim was to explore the efficacy and safety of bindarit in preventing restenosis following percutaneous coronary intervention. METHODS AND RESULTS A phase II, double-blind, multicentre randomised trial included 148 patients randomised into three arms (BND 600 mg, n=48; BND 1,200 mg, n=49; PLB, n=51). Bindarit was given following PCI and continued for 180 days. Monthly clinical follow-up and six-month coronary angiography were conducted. The primary endpoint was in-segment late loss; the main secondary endpoints were in-stent late loss and major adverse cardiovascular events. Efficacy analysis was carried out on two populations, ITT and PP. There were no significant differences in the baseline characteristics among the three treatment groups. In-segment and in-stent late loss at six months in BND 600, BND 1,200 and PLB were: (ITT 0.54 vs. 0.52 vs. 0.72; p=0.21), (PP 0.46 vs. 0.53 vs. 0.72; p=0.12) and (ITT 0.74 vs. 0.74 vs. 1.05; p=0.01), (PP 0.66 vs. 0.73 vs. 1.06; p=0.003), respectively. The MACE rates at nine months among treatment groups were 20.8% vs. 28.6% vs. 25.5% (p=0.54), respectively. CONCLUSIONS This was a negative study with the primary endpoint not being met. However, significant reduction in the in-stent late loss suggests that bindarit probably exerts a favourable action on the vessel wall following angioplasty. Bindarit was well tolerated with a compliance rate of over 90%. A larger study utilising a loading dose and targeting a specific patient cohort may demonstrate more significant results.

The Role of the European Imperial Powers throughout the Armenian Schism in the 1870s

The Bull "Reversurus" (1867) and its dogmatic legitimization at the First Vatican Council in 1870 caused not only ecclesiastical controversy and Schism in the Armenian Catholic Church, but it had also wide political consequences for the Armenian Catholics in the Ottoman Empire. The conflict originally between the Armenian Catholics and Rome attracted very soon the attention of the European imperial Powers. France, the British Empire, the German Empire, Austria-Hungary and Russia were the main political powers who were involved in the Armenian affair. A full picture of the role of all these powers for the course of the Armenian Schism is missing. Mostly the role of France is foregrounded in the printed sources, as the main power, which supported the papacy to win during the Armenian affair. The role and the motives of the other imperial powers is almost missing. This article will try to describe as completely as possible the historical and political background, which brought to the escalation of the Armenian conflict beyond the national frontiers and led to number of conflicts at the international and transnational level. It will be shown that the imperial policy in Europe in the 19th century have played an enormous role throughout the Armenian Schism. It will be explained that several historical circumstances in Europe, especially the relation of the European imperial powers to each other as well as their expectations from the Ottoman Empire and its Armenian subjects were decisive for the duration and conclusion of the Armenian Schism.

Role of FbpA and FbpB in the pathogenesis and mycolyltransferase activity of Mycobacterium tuberculosis

Mycobacterium tuberculosis infects more people worldwide each year than any other single organism. The Antigen 85 Complex, a family of fibronectin-binding proteins (Fbps) found in several species of mycobacteria and possibly involved in host interaction, is considered among the putative virulence factors of M. tuberculosis. These proteins are implicated in the production of trehalose dimycolate (TDM) and arabinogalactan-mycolate (AG-M), two prominent components of the mycobacterium cell wall and potent modulators of the immune system during infection. For these reasons, the principal members of the complex, FbpA and FbpB, were the focus of these studies. The genes encoding these proteins, fbpA and fbpB, were each disrupted by insertion of a kanamycin resistance cassette in a pathogenic strain of M. tuberculosis, H37Rv. Neither mutation affected growth in routine broth culture. Thin layer chromatography analysis of TDM and AG-M showed no difference in content between the parent strain H37Rv and the FbpA- and FbpB-deficient mutants grown under two different culture conditions. However, metabolic radiolabeling of the strains showed that the production of TDM (but not its precursor TMM) was delayed in the FbpA- and FbpB-deficient mutants compared to the parent H37Rv. During this same labeling period, FbpA-deficient mutant LAa1 failed to produce AG-M and in the FpbB-deficient mutant LAb1 production was decreased. In macrophage tissue culture assay, LAa1 failed to multiply when bacteria in early log phase were used to infect monolayers while LAb1 grew like the parent strain. The growth deficiency of LAa1 as well as the deficiencies in TDM and AG-M production were restored by complementing LAa1 with a functional fbpA gene. These results suggest that the FbpA and FbpB proteins are involved in synthesis of TDM (but not its precursor TMM) as well as AG-M. Other members of the complex appear to compensate for defects in synthesis caused by mutation of single genes in the complex over time. Mutation of the FbpA gene causes greater in vivo effect than mutation of the FbpB gene despite very similar deficiencies in the rate of production of mycolate containing molecules on the cell surface. ^