Mutations of the KRAS oncogene are predictive for resistance to treatment with antibodies against the epithelial growth factor receptor in patients with colorectal cancer. Overcoming this therapeutic dilemma could potentially be achieved by the introduction of drugs that inhibit signaling pathways that are activated by KRAS mutations. To identify comprehensively such signaling pathways, we profiled pretreatment biopsies and normal mucosa from 65 patients with locally advanced rectal cancer-30 of which carried mutated KRAS-using global gene expression microarrays. By comparing all tumor tissues exclusively to matched normal mucosa, we could improve assay sensitivity, and identified a total of 22,297 features that were differentially expressed (adjusted P-value <0.05) between normal mucosa and cancer, including several novel potential rectal cancer genes. We then used this comprehensive description of the rectal cancer transcriptome as the baseline for identifying KRAS-dependent alterations. The presence of activating KRAS mutations is significantly correlated to an upregulation of 13 genes (adjusted P-value <0.05), among them DUSP4, a MAP-kinase phosphatase, and SMYD3, a histone methyltransferase. Inhibition of the expression of both genes has previously been shown using the MEK1-inhibitor PD98059 and the antibacterial compound Novobiocin, respectively. These findings suggest a potential approach to overcome resistance to treatment with antibodies against the epithelial growth factor receptor in patients with KRAS-mutant rectal carcinomas. (c) 2010 Wiley-Liss, Inc.

AIM: To investigate whether irradiation (IR) and partial hepatectomy (PH) may prepare the host liver for non-parenchymal cell (NPC) transplantation. METHODS: Livers of dipeptidyl peptidase IV (DPPIV)-deficient rats were pre-conditioned with external beam IR (25 Gy) delivered to two-thirds of the right liver lobules followed by a one-third PH of the untreated lobule. DPPIV-positive liver cells (NPC preparations enriched for liver sinusoidal endothelial cells (LSECs) and hepatocytes) were transplanted via the spleen into the recipient livers. The extent and quality of donor cell engraftment and growth was studied over a long-term interval of 16 wk after transplantation. RESULTS: Host liver staining demonstrated 3 different repopulation types. Well defined clusters of donor-derived hepatocytes with canalicular expression of DPPIV were detectable either adjacent to or in between large areas of donor cells (covering up to 90% of the section plane) co-expressing the endothelial marker platelet endothelial cell adhesion molecule. The third type consisted of formations of DPPIV-positive duct-like structures which co-localized with biliary epithelial CD49f. CONCLUSION: Liver IR and PH as a preconditioning stimulus enables multiple cell liver repopulation by donor hepatocytes, LSECs, and bile duct cells.

PURPOSE: The purpose of this study was to explore the cancer experience of survivors with pre-existing diagnoses of heart and/or lung disease following active treatment. METHOD: The Lance Armstrong Foundation recruited cancer survivors throughout the United States to complete a web-based survey to provide insight into post-treatment supportive care needs. Experts in survey methodology and oncology, as well as cancer survivors, provided input into the survey. RESULTS: Among the 2,307 respondents, 137 individuals had been told by their physicians that they had heart or lung problems. They were 50 years old on average, and most were more than 5 years past active treatment. Two thirds of these respondents reported pain for long periods, and 20% of them agreed that they now need help with everyday tasks that they did not need help with before their cancer. Among those who were tired, had no energy, or had trouble sleeping and/or resting, less than half (47%) agreed that they had received help with this problem. One third of these respondents indicated that they had decreased their physical activity since their cancer diagnosis because of fatigue, and 26% decreased their activities because of pain. More respondents indicated that their needs were met during their cancer treatment than afterwards. CONCLUSIONS: Researchers and healthcare providers are urged to consider the unmet supportive care needs of cancer survivors with co-morbid conditions following active treatment, particularly the necessity for careful monitoring of their complex health conditions.

The clinical impact of FLT3-internal tandem duplications (ITD), an adverse prognostic marker in adults age <60 years with primary cytogenetically normal acute myeloid leukemia (CN-AML), requires further investigation in older patients. In CN-AML patients age >/=60 years treated on CALGB frontline trials, we found that FLT3-ITD remained associated with shorter disease-free [DFS; P<.001; hazard ratio (HR)=2.10] and overall survival (OS; P<.001; HR=1.97) in multivariable analyses. This impact on DFS and OS was in patients 60-69 (P<.001, each) rather than in those >/=70 years. A FLT3-ITD-associated gene-expression signature revealed overexpression of FLT3, homeobox genes (MEIS1, PBX3, HOXB3), and immunotherapeutic targets (WT1, CD33) and underexpression of leukemia-associated (MLLT3, TAL1) and erythropoiesis-associated (GATA3, EPOR, ANK1, HEMGN) genes. A FLT3-ITD-associated microRNA-expression signature included overexpressed miR-155 and underexpressed miR-144 and miR-451. FLT3-ITD identifies older CN-AML patients with molecular high-risk and is associated with gene- and microRNA-expression signatures that provide biologic insights for novel therapeutic approaches.

Report of a 33-year-old woman who had sudden vision problems and homonymous hemianopia on the left. A cranial computed tomography (CCT) was carried out in a radiologic practice. A native homogeneous, smooth-edged hyperdense intracerebral mass of about 5.5 cm diameter on the right parietooccipital region with density values of +50 HU was found. Only a small proportion of about 2 cm diameter was more hyperdense with density values of +65 HU. Following intravenous administration of contrast medium, a patchy increase in density of about 1 cm was seen. The mass had only a thin hypodense rim. The patient was informed that she had a tumor. Three days later, magnetic resonance imaging was to be done for further evaluation. After the patient had returned home, she had headaches, nausea and vomiting in the evening. At night, she was admitted to a hospital as emergency case. With further increase of intracranial pressure, a craniotomy was done and a hemorrhage was removed. Histologically, a bleeding of a cavernous hemangioma was found.The patient appealed to the fact-finding board for medical liability questions because she had not been admitted to a hospital immediately after the CCT. Therefore, surgery was done delayed. The board found that the behavior of the radiologist was wrong. However, it cannot be proven that this medical malpractice is of importance for the existing postoperative complaints.

The report concerns a 44-year-old female patient with incidental left middle cerebral artery aneurysm. After endovascular therapy by coiling, a hemiparesis was observed following extubation. Disturbance of speech and disorientation added later. An infarct of the lenticular nucleus was found. The angiography showed an occlusion of a frontal opercular branch of the left middle cerebral artery. The fact-finding board for medical liability should investigate, if the infarct with continuous neurological deficits is explained by improper treatment and if the following management of complication was adequate. A neuroradiologic opinion was requested. Based on that, the board came to the result that no incorrect medical treatment was done.

Genes that are highly overexpressed in tumor cells can be required for tumor cell survival, and have the potential to be selective therapeutic targets. In an attempt to identify such targets, we combined a functional genomics and a systems biology approach to assess the consequences of RNAi-mediated silencing of overexpressed genes that were selected from 140 gene expression profiles from colorectal cancers (CRC) and matched normal mucosa. In order to identify credible models for in-depth functional analysis, we first confirmed the overexpression of these genes in 25 different CRC cell lines. We then identified five candidate genes that profoundly reduced the viability of CRC cell lines when silenced with either siRNAs or shRNAs, i.e., HMGA1, TACSTD2, RRM2, RPS2, and NOL5A. These genes were further studied by systematic analysis of comprehensive gene expression profiles generated following siRNA-mediated silencing. Exploration of these RNAi-specific gene expression signatures allowed the identification of the functional space in which the five genes operate, and showed enrichment for cancer specific signaling pathways, some known to be involved in CRC. By comparing the expression of the RNAi signature genes with their respective expression levels in an independent set of primary rectal carcinomas we could recapitulate these defined RNAi signatures, therefore establishing the biologically relevance of our observations. This strategy identified the signaling pathways that are affected by the prominent oncogenes HMGA1 and TACSTD2, established a yet unknown link between RRM2 and PLK1, and identified RPS2 and NOL5A as promising potential therapeutic targets in CRC.

In the present study, we analyzed the influence of xanthohumol (XN) on thyroid hormone (TH) distribution and metabolism in rats. A potent and selective competition of XN for thyroxine (T4) binding to transthyretin (IC(50)=1 muM at 1.7 nM [(125)I]T4) was found in human and rat sera in vitro. Female rats treated orally with XN showed increased hepatic expression of T4-binding globulin and decreased transthyretin and albumin. Thyrotropin levels and hepatic type 1 deiodinase activity were moderately increased. Northern blot analysis revealed diminished expression of liver sulfotransferase (Sult1a1) and uridine-diphosphate glucuronosyltransferase (Ugt1a1) after XN treatment. The transcript levels of constitutive androstane receptor (CAR), known to be involved in regulation of enzymes metabolizing hormones, drugs and xenobiotics, was lower in rats treated with >10 mg XN/kg body weight per day. Immunoblot analysis indicates reduced amounts of CAR protein. The phenobarbital-inducible cytochrome P450 mRNA level was decreased in rats treated with >10 mg XN/kg/day, in agreement with reduced CAR protein. Although only moderate changes in TH serum levels were observed, the XN-dependent altered expression of components involved in TH homeostasis might be important not only for hormone metabolism, but also for hepatic phase I and II elimination of drug metabolites and xenobiotics.

We previously reported the adverse prognostic impact of WT1 mutations in younger adult cytogenetically normal acute myeloid leukemia (CN-AML). Here, we investigated 243 older (>/=60 years) primary CN-AML patients. WT1 mutated (WT1mut) patients (7%) had FLT3-ITD more frequently (P<.001), lower hemoglobin (P=.01), higher WBC (P=.03) and % blood blasts (P=.03), and a shorter overall survival (P=.08) than WT1 wild-type (WT1wt) patients. Comparing older and younger WT1mut patients, they had similar pretreatment characteristics and outcome. By contrast, among WT1wt CN-AML, younger patients had a significantly better outcome. A WT1 mutation-associated gene-expression signature, reported here for the first time, included CD96, a leukemia stem-cell-specific marker, and genes involved in gene regulation (e.g., MLL, PML, SNRPN) and in proliferative and metabolic processes (e.g., INSR, IRS-2, PRKAA1) supporting the role of mutated WT1 in deregulating multiple homeostatic processes. Our results indicate WT1mut CN-AML represents a distinct entity with poor treatment response across age-groups. This study has been registered on www.clinicaltrials.gov as NCT00900224.

OBJECTIVES: To describe the perception of migraine by neurologists in France, to compare perceptions between neurologists who did and did not suffer from migraines and to describe treatments used for their own migraines. BACKGROUND: Patients with migraine are usually undertreated, as treatment guidelines are frequently not followed and, therefore, resulting treatment satisfaction is low. One reason for this may be inappropriate perceptions of physicians concerning the seriousness of the pathology and the need to treat. However, available information on physician perceptions of migraine is limited. METHODS: This was an observational, epidemiological survey conducted both in hospital- and community-based neurologists in France. Participating neurologists completed an anonymous questionnaire which collected data on demographics, migraine status, and perceptions of migraine. Neurologists who considered themselves migraineurs also provided data on migraine impact, treatment and on treatment satisfaction. Distributions of responses to questions on migraine perceptions were compared between migraineur and nonmigraineur neurologists. RESULTS: The study included 368 neurologists, of whom 179 (48.6%) were migraineurs themselves. Some 92.3% of participants claimed to be very or quite interested in migraine. Migraine was considered a real illness by 96.5% of neurologists and to be very or quite disabling by 96.6%. Around half perceived migraine as a challenging condition to manage with respect to unrealistic patient expectations (46.2%), time-consuming treatment (48.9%), and complications because of anxious or depressive comorbidity (59.9%) or medical nomadism (consulting multiple physicians for the same condition; 47.0%). No significant differences in any perception items were observed between migraineur and nonmigraineur neurologists. In total, 83.1% of neurologists were satisfied with acute headache treatments and 60.4% with prophylactic headache treatments. The most frequently reported treatments for neurologist's own migraines were nonsteroidal anti-inflammatory drugs (used by 57.0%) and triptans (50.3%). CONCLUSIONS: French neurologists are interested and concerned about migraine but find it challenging to treat. Migraine perceptions do not differ between neurologists who do and do not suffer from migraines themselves. Neurology training needs to prepare medical students adequately for the challenges of migraine treatment in terms of patient communication and psychiatric issues.

BACKGROUND: Response to preoperative radiochemotherapy (RCT) in patients with locally advanced rectal cancer is very heterogeneous. Pathologic complete response (pCR) is accompanied by a favorable outcome. However, most patients show incomplete response. The aim of this investigation was to find indications for risk stratification in the group of intermediate responders to RCT. METHODS: From a prospective database of 496 patients with rectal adenocarcinoma, 107 patients with stage II/III cancers and intermediate response to preoperative 5-FU based RCT (ypT2/3 and TRG 2/3), treated within the German Rectal Cancer Trials were studied. Surgical treatment comprised curative (R0) total mesorectal excision (TME) in all cases. In 95 patients available for statistical analyses, residual transmural infiltration of the mesorectal compartment, nodal involvement and histolologic tumor grading were investigated for their prognostic impact on disease-free (DFS) and overall survival (OS). RESULTS: Residual tumor transgression into the mesorectal compartment (ypT3) did not influence DFS and OS rates (p = 0.619, p = 0.602, respectively). Nodal involvement after preoperative RCT (ypN1/2) turned out to be a valid prognostic factor with decreased DFS and OS (p = 0.0463, p = 0.0236, respectively). Persistent tumor infiltration of the mesorectum (ypT3) and histologic tumor grading of residual tumor cell clusters were strongly correlated with lymph node metastases after neoadjuvant treatment (p < 0.001). CONCLUSIONS: Advanced transmural tumor invasion after RCT does not affect prognosis when curative (R0) resection is achievable. Residual nodal status is the most important predictor of individual outcome in intermediate responders to preoperative RCT. Furthermore, ypT stage and tumor grading turn out to be additional auxiliary factors. Future clinical trials for risk-adapted adjuvant therapy should be based on a synopsis of clinicopathologic parameters.

The biologic and clinical significance of KIT overexpression that associates with KIT gain-of-function mutations occurring in subsets of acute myeloid leukemia (AML) (i.e., core binding factor AML) is unknown. Here, we show that KIT mutations lead to MYC-dependent miR-29b repression and increased levels of the miR-29b target Sp1 in KIT-driven leukemia. Sp1 enhances its own expression by participating in a NFkappaB/HDAC complex that further represses miR-29b transcription. Upregulated Sp1 then binds NFkappaB and transactivates KIT. Therefore, activated KIT ultimately induces its own transcription. Our results provide evidence that the mechanisms of Sp1/NFkappaB/HDAC/miR-29b-dependent KIT overexpression contribute to leukemia growth and can be successfully targeted by pharmacological disruption of the Sp1/NFkappaB/HDAC complex or synthetic miR-29b treatment in KIT-driven AML.

Pre-therapeutic prediction of therapy response and clinical outcome is an important field in medicine and poses new challenges to statisticians. Statistical prediction rules for two-class problems are generally designated to maximize the overall correct classification rate and to reflect an optimal balance of sensitivity and specificity. In some clinical situations, however, correct prediction of one particular class is more important than of the other class. We therefore propose a new strategy of building prediction rules, which are designed to increase the sensitivity, while losing some specificity. This strategy is applied to artificial simulation data and to gene expression data from primary colon cancers. Our concept is generally applicable to most common classification methods.

PURPOSE: To analyze the frequency and associations with prognostic markers and outcome of mutations in IDH genes encoding isocitrate dehydrogenases in adult de novo cytogenetically normal acute myeloid leukemia (CN-AML). PATIENTS AND METHODS: Diagnostic bone marrow or blood samples from 358 patients were analyzed for IDH1 and IDH2 mutations by DNA polymerase chain reaction amplification/sequencing. FLT3, NPM1, CEBPA, WT1, and MLL mutational analyses and gene- and microRNA-expression profiling were performed centrally. RESULTS: IDH mutations were found in 33% of the patients. IDH1 mutations were detected in 49 patients (14%; 47 with R132). IDH2 mutations, previously unreported in AML, were detected in 69 patients (19%; 13 with R172 and 56 with R140). R172 IDH2 mutations were mutually exclusive with all other prognostic mutations analyzed. Younger age (< 60 years), molecular low-risk (NPM1-mutated/FLT3-internal tandem duplication-negative) IDH1-mutated patients had shorter disease-free survival than molecular low-risk IDH1/IDH2-wild-type (wt) patients (P = .046). R172 IDH2-mutated patients had lower complete remission rates than IDH1/IDH2wt patients (P = .007). Distinctive microarray gene- and microRNA-expression profiles accurately predicted R172 IDH2 mutations. The highest expressed gene and microRNAs in R172 IDH2-mutated patients compared with the IDH1/IDH2wt patients were APP (previously associated with complex karyotype AML) and miR-1 and miR-133 (involved in embryonal stem-cell differentiation), respectively. CONCLUSION: IDH1 and IDH2 mutations are recurrent in CN-AML and have an unfavorable impact on outcome. The R172 IDH2 mutations, previously unreported in AML, characterize a novel subset of CN-AML patients lacking other prognostic mutations and associate with unique gene- and microRNA-expression profiles that may lead to the discovery of novel, therapeutically targetable leukemogenic mechanisms.

A phase II clinical trial with single-agent decitabine was conducted in older patients (>/=60 years) with previously untreated acute myeloid leukemia (AML) who were not candidates for or who refused intensive chemotherapy. Subjects received low-dose decitabine at 20 mg/m(2) i.v. over 1 h on days 1 to 10. Fifty-three subjects enrolled with a median age of 74 years (range, 60-85). Nineteen (36%) had antecedent hematologic disorder or therapy-related AML; 16 had complex karyotypes (>/=3 abnormalities). The complete remission rate was 47% (n = 25), achieved after a median of three cycles of therapy. Nine additional subjects had no morphologic evidence of disease with incomplete count recovery, for an overall response rate of 64% (n = 34). Complete remission was achieved in 52% of subjects presenting with normal karyotype and in 50% of those with complex karyotypes. Median overall and disease-free survival durations were 55 and 46 weeks, respectively. Death within 30 days of initiation of treatment occurred in one subject (2%), death within 8 weeks in 15% of subjects. Given the DNA hypomethylating effect of decitabine, we examined the relationship of clinical response and pretreatment level of miR-29b, previously shown to target DNA methyltransferases. Higher levels of miR-29b were associated with clinical response (P = 0.02). In conclusion, this schedule of decitabine was highly active and well tolerated in this poor-risk cohort of older AML patients. Levels of miR-29b should be validated as a predictive factor for stratification of older AML patients to decitabine treatment.

OBJECTIVE: To examine the effects of a wellness intervention, Lifestyle Counts, for women with fibromyalgia syndrome on the level of self-efficacy for health-promoting behaviours, health-promoting activity and perceived quality of life. DESIGN: A randomized controlled single-blinded trial with treatment and attention-control groups. SETTING: Community in the southwestern United States. SUBJECTS: Convenience sample of 187 women (98 treatment, 89 attention control) with fibromyalgia syndrome (mean age = 53.08 years, SD 9.86). INTERVENTION: The two-phase Lifestyle Counts intervention programme included lifestyle change classes for eight weeks, with goal-setting and telephone follow-up for three months. Participants in the attention-control group were offered an equivalent amount of contact in classes on general disease-related information and health education topics and unstructured follow-up phone calls. Participants were followed for a total of eight months after baseline. OUTCOME MEASURES: Self-report instruments measuring self-efficacy for health behaviours, health-promotion behaviours and health-related quality of life (SF-36 and the Fibromyalgia Impact Questionnaire) were completed at baseline, two months (after the classes), five months (after telephone follow-up) and at eight months. RESULTS: Both groups improved significantly (P<0.05) over time on the measures of self-efficacy, health behaviours, fibromyalgia impact and quality of life. There were significant group x time interactions for scores on the Health Promoting Lifestyle II subscales of physical activity and stress management. CONCLUSIONS: The Lifestyle Counts wellness intervention holds promise for improving health-promoting behaviours and quality of life of women with fibromyalgia syndrome.

In the critical search for new antituberculosis lead compounds, bryophytes represent a largely untapped resource of chemically diverse structures. From the liverwort Jungermannia exsertifolia subsp. cordifolia, 11 new trachylobane diterpene derivatives, as well as three known compounds, were isolated. Their structures were elucidated by spectroscopic means, and full (1)H NMR spin analysis of one model compound confirmed the relative configurational assignments of the congeners. Four of the isolates exhibited noticeable activity against virulent Mycobacterium tuberculosis H(37)Rv with minimal inhibitory concentrations of 61-24 microg/mL. This finding suggests that bryophytes in general and trachylobanes in particular deserve further attention in the search for new antimycobacterial leads.