Treatment records were kept by a single nurse who recorded all HC

Treatment records were kept by a single nurse who recorded all HCV-related laboratory and pathology findings; she completed a flow sheet summarizing adverse reactions and changes in interferon MG-132 molecular weight and ribavirin dose for each patient at each visit to the GI department. Visits were scheduled at weeks 1-2 and at least every 4 weeks thereafter. Study measures extracted from these records included genotype (2 and 3 versus 1, 4, and 6), pretreatment viral load (<600,000 versus >600,000 IU/mL), and Metavir stage 3 or 4 (advanced fibrosis) versus stages 0-2 (not advanced). Stage was determined by histology, but in the absence of a liver biopsy, patients were also considered to have advanced fibrosis if they had a platelet count <110,000,

serum aspartate aminotransferase (AST)>ALT (serum alanine aminotransferase), and splenomegaly. Records contained data on all premature treatment discontinuations, including date and reason PD0332991 price (i.e., adverse reactions to treatment or noncompliance). Treatment that was appropriately stopped because of early nonresponse was coded as failure to obtain an SVR, not treatment discontinuation. Also extracted were data on ETR and SVR. Relations of known host and viral risk factors and pretreatment patterns of alcohol intake to SVR were examined using chi-square statistics for cross-tabulations. Cross-tabulation

analyses were also conducted to detect potentially confounding relationships between host and viral risk factors and patterns of alcohol intake. Multiple logistic regression analyses were used to determine the independent contributions of host, viral, and alcohol risk factors to SVR failure. Comparison of eligible patients who were and were not interviewed revealed that interviewed MCE patients tended to have somewhat higher SVR rates (60.6% versus 55.4%; P = 0.304) and were somewhat more likely to have a chemical dependency diagnosis mentioned in their medical record (30.9% versus 26.6%;

P = 0.357), or a record of recent treatment for chemical dependency (7.7% versus 4.5%; P = 0.207), but none of these differences were statistically significant. Cohort host, viral, and alcohol-related risk factors are characterized in Table 1 as they relate to SVR. Age and sex were not significantly related to SVR. SVR rates were significantly lower in patients with the following risk factors: a racial/ethnic background other than white non-Hispanic, pretreatment viral load ≥600,000 IU, HCV genotypes 1, 4, or 6, advanced fibrosis, or treatment discontinuation. However, no significant effect on SVR rates was associated with moderate or heavy drinking or with failure to abstain 6 months before treatment. Analyses investigating relations between host and viral risk factors and pretreatment alcohol measures are summarized in Tables 2 and 3. Pretreatment alcohol intake, categorized as total kg of ethanol consumed, is examined in Table 2. Sixty-three percent of patients reported drinking more than 100 kg of ethanol before HCV treatment.

226 Case reports have also described the outcome of patients with

226 Case reports have also described the outcome of patients with severe AH treated with leukocytapharesis after failing to improve substantially on steroids.227, 228 These reports are promising, but recommendations regarding their appropriate use must await results click here of comparative studies of

outcomes in these patients. A proposed treatment algorithm for alcoholic hepatitis is shown in Fig. 1. Recommendations: 8. All patients with alcoholic hepatitis should be counseled to completely abstain from alcohol (Class I, level B). 9. All patients with alcoholic hepatitis or advanced ALD should be assessed for nutritional deficiencies (protein-calorie malnutrition), as well as vitamin and mineral deficiencies. Those with severe disease should be treated aggressively with enteral nutritional therapy (Class I, level B).

10. Patients with mild-moderate alcoholic hepatitis—defined as a Maddrey score of <32, without hepatic encephalopathy, and with improvement in serum bilirubin BIBW2992 research buy or decline in the MDF during the first week of hospitalization—should be monitored closely, but will likely not require nor benefit from specific medical interventions other than nutritional support and abstinence (Class III, level A). 11. Patients with severe disease (MDF score of ≥32, with or without hepatic encephalopathy) and lacking contraindications to steroid use should be considered for a four week course of prednisolone (40 mg/day for 28 days, typically followed by discontinuation or a 2-week taper) (Class

I, level A). 12. Patients with severe disease (i.e., a MDF ≥ 32) could be considered for pentoxifylline therapy (400 mg orally 3 times daily for 4 weeks), especially MCE if there are contraindications to steroid therapy (Class I, level B). A proposed algorithm for the management of ALD is shown in Fig. 2. Protein calorie malnutrition is common in ALD, is associated with an increased rate of major complications of cirrhosis (infection, encephalopathy, and ascites), and indicates a poor prognosis.194 A total of 13 studies (seven randomized and six open-label studies) have examined the effect of oral or enteral nutritional supplementation in patients with alcoholic cirrhosis, with interventions that ranged from 3 days to 12 months (reviewed in Stickel et al.229). Most of these studies are limited by small sample sizes and short durations of therapy. In one study, enteral feeding for 3-4 weeks in 35 hospitalized, severely malnourished or decompensated patients with alcoholic cirrhosis seemed to improve survival (P < 0.065), hepatic encephalopathy, liver tests and Child-Pugh score, as compared with controls receiving a standard oral diet.197 In longer-term studies, equinitrogenous amounts of dietary branched chain amino acids (BCAA) were compared with casein supplements for 3-6 months in patients with chronic hepatic encephalopathy,230 and shown to improve encephalopathy, nitrogen balance and serum bilirubin compared with casein.

No new symptoms developed during the 4-year observation period A

No new symptoms developed during the 4-year observation period. A follow-up MRI of the brain was unchanged. this website Our patient with no traditional vascular risk factors or coagulopathy experienced brainstem stroke during status migrainosus with her typical brainstem aura. It is plausible that migraine was a contributing factor to the stroke, especially in view of evidence that brain hypoperfusion[2] and basilar artery narrowing,

and even occlusion,[3] occur during migraine with brainstem aura. Other potential contributory factors included repetitive triptan use, treatment with estrogen-containing oral contraceptive, pseudoephedrine-containing compound, selective serotonin reuptake inhibitor use, and basilar artery fenestration. Despite compelling arguments for a link between migraine and stroke in

our patient and others,[3] the patient would not be diagnosed with migrainous infarction according to the ICHD-3 beta criteria because her stroke symptoms were not part of her typical aura syndrome. By excluding patients with “extra-aural” symptoms at the time of infarction, ICHD-3 beta likely improves specificity of migrainous infarction criteria at the expense of sensitivity. This may lead to an underestimation of the role of migraine in stroke etiology. We would like to argue that a less restrictive category – “probable migrainous infarction” or “migraine-associated stroke” – could be introduced in the appendix to the final ICHD-3 to account for such patients who experience additional non-aura click here stroke symptoms during an otherwise typical migraine with aura attack, as we

believe such cases truly are complications of migraine. “
“Treatment with preventive migraine medication is necessary when migraine causes undue distress or dysfunction or the patient is at risk for clinical deterioration. Migraine preventives are generally not chosen based on demonstrated superior efficacy, since there is no evidence of such therapeutic superiority. Choices are made on the basis of comorbid conditions, to minimize unwanted side effects, or take advantage of potentially beneficial ones. Other considerations include costs, convenience, and previous response to medications. Among the anticonvulsants, the strongest evidence for efficacy is for valproic acid and topiramate. Gabapentin 上海皓元医药股份有限公司 is less effective. Amitriptyline and venlafaxine have been shown to be effective. Propranolol, timolol, and metoprolol are the beta-blockers with the strongest evidence of efficacy. Lisinopril and candesartan appear to be effective, while verapamil works weakly. Botulinum Toxin A is probably not effective for episodic migraine but is effective for chronic migraine. Butterbur extract is effective. Riboflavin, magnesium, coenzyme Q, thioctic acid (alpha lipoic acid), and fevefew may be effective migraine preventives. “
“The Neuropsychiatry of Headache is a book edited by neurologist, Mark W.

823 (Fig 3A) According to the ROC curve, the accuracy of predic

823 (Fig. 3A). According to the ROC curve, the accuracy of predicting VR was highest with a sensitivity of 86.8% and a specificity of 78.9% at log qHBsAg = 3.98 IU/mL, which is equivalent to approximately 9550 IU/mL (on a nonlogarithmic scale). The corresponding positive predictive value (PPV) and negative predictive value (NPV) were 89.2% and 75.0%, respectively. Among the on-treatment factors, declines of HBV DNA, qHBsAg, and qHBeAg between the baseline and 6 months were investigated. There

was a tendency toward differences in the decline in log qHBeAg with values of 0.72 Stem Cells antagonist ± 1.01 and 0.39 ± 0.34 PE IU/mL (P = 0.071) for the VR(+) and VR(−) groups, respectively. Meanwhile, the reductions of log HBV DNA were 4.13 ± 1.27 and 3.98 ± 1.84 copies/mL

(P = 0.722) in the VR(+) and VR(−) groups, respectively, and the reductions of log qHBsAg were 0.07 ± 0.53 and 0.21 ± 0.42 IU/mL (P = 0.322), respectively. In the analysis of SR predictors, no baseline characteristics were significant. As for on-treatment factors, only a decline of log qHBeAg through month 6 was significant, with a reduction of 1.71 ± 0.27 PE IU/mL in the SR(+) group versus 0.43 ± 0.63 PE IU/mL in the SR(−) group (P = 0.001). In the ROC curve, the accuracy of predicting SR was highest with a sensitivity of 75.0% and a specificity of 89.8% with a reduction of log qHBeAg to 1.00 PE IU/mL, which is equivalent to a 10-fold decrease on a nonlogarithmic scale (Fig. 3B). The corresponding PPV and NPV were 54.5% and 95.7%, respectively. Dabrafenib Overall, a modest correlation was detected between HBV DNA and qHBsAg in HBeAg(+) patients (n = 285, r = 0.328, P < 0.001), and a very weak correlation was found in HBeAg(−) patients (n MCE公司 = 190, r = 0.175, P = 0.016). A stronger correlation was detected between qHBsAg and qHBeAg (n = 285, r = 0.416, P < 0.001) and between HBV DNA and qHBeAg (n = 285, r = 0.570, P < 0.001). Analyses were further conducted with temporal ETV therapy. A significant correlation

between HBV DNA and qHBsAg was observed only in HBeAg(+) patients, with none evident in those with HBeAg(−) disease (Table 3). Although a small increase was observed in the early period, a decreasing tendency was seen for the correlation coefficient in HBeAg(+) patients with maintenance of ETV therapy (Fig. 4). Advances in the quantification of serum qHBsAg have opened a new path for furthering our understanding of HBV.27 qHBsAg is known to reflect cccDNA, which is the viral template for HBV replication in the maintenance of chronic infection, and the correlation between these two factors has been previously addressed.6, 7, 28 In addition, qHBsAg has a clinical role in predicting the response to antiviral therapy in patients undergoing PEG-IFN treatment.

Physical maturity was reached at between 14 and 17 yr of age, app

Physical maturity was reached at between 14 and 17 yr of age, apparently a few years after attainment of sexual maturity. Maximum lengths and weights of about 268 cm and BI 2536 order 240 kg were attained. Females appear to lose all their spots by 30 yr, although males may retain some spotting throughout life. Calving occurred throughout the year, with a broad peak from March to June. Of 60 females monitored at sea for >14 yr of the study, none were documented to have more than three calves, suggestive of low reproductive output or low calf survival. “
“The gray whale (Eschrichtius robustus) is a coastal species whose nearshore summer foraging grounds off the coast of British Columbia

offer an opportunity to study the fine

scale foraging response of baleen whales. We explore the relationship between prey density and gray whale foraging starting with regional scale (10 km) assessments of whale density (per square kilometer) and foraging effort as a response to regional mysid density (per cubic meter), between 2006 and 2007. In addition we measure prey density at a local scale (100 m), while following foraging whales during focal surveys. We found regional mysid density had a significant positive relationship with both gray whale density and foraging effort. We identify a threshold response to regional mysid density for both whale density and foraging effort. In 2008 the lowest average local prey density measured beside a foraging whale was 2,300 mysids/m3. This level was maintained even when regional prey Selleckchem NVP-LDE225 density was found to be substantially lower. Similar to other baleen whales, the foraging behavior of gray whales suggests a threshold response to prey density and a complex appreciation of prey availability across fine scales. “
“The conditioning of dolphins to human-interaction behaviors has been documented in several areas worldwide. However, the metrics used to report human-interaction behaviors vary among studies, making comparison across study areas difficult. The purpose of this study was to develop standard metrics for reporting human-interaction 上海皓元 behaviors and utilize these metrics

to quantify the prevalence of human-interaction behaviors by common bottlenose dolphins (Tursiops truncatus) near Savannah, Georgia. The four metrics used were percentage of days with human-interaction behaviors, percentage of sightings with human-interaction behaviors, percentage of the catalog that interacted with humans, and spatial extent of human-interaction behaviors. Human-interaction behaviors were observed on 69.6% of days and 23.5% of sightings near Savannah. In addition, 20.1% of the animals in the catalog were observed interacting with humans. These rates are much higher than those found in other areas with known issues with human-interaction behaviors. These behaviors were observed across an area of 272.6 km2, which is larger than other reported areas.

All observations were censored at the end of the review period (D

All observations were censored at the end of the review period (December 1, 2012) or at the date of the last known encounter for patients who were lost to follow-up. We used the Kaplan-Meier method to determine 5-year outcome probabilities. The time variable was calculated from the date of the liver disease diagnosis. The log-rank test was used to test for statistical differences among groups. The Kruskal-Wallis test and an analysis of variance were used to compare continuous variables, and chi-squared and Fisher exact tests were used to analyze categorical

variables as appropriate. All calculations were performed with Stata 11 (StataCorp, College Station, TX). All research activities were approved by the institutional review boards of both health care systems. We identified 1070 unique patients with at least Selleckchem XAV-939 one encounter

associated with an ICD-9 code for IBD. We identified 987 unique patients with at least one encounter associated with an ICD-9 code for liver biopsy, AIH, or cholangitis or via a text search for sclerosing GSK126 cholangitis. A diagnosis of IBD was confirmed in 607 patients. CD was found in 317 (52%), UC was found in 262 (43%), and indeterminate colitis was found in 28 (5%). The overall incidence and prevalence of IBD per 100,000 children in Utah were 5.7 and 22.3, respectively. The mean duration of follow-up for patients with liver disease was 5.9 years (range = 0.4-17.8 years). Demographic, laboratory, and comorbid illness data for the patients are detailed in Table 2. The intersection of IBD, PSC, and AIH is shown in Fig. 1. Comparisons of survival with the native liver and progression to complicated liver disease between subtypes of IMLD are shown in Figs. 2 and 3. We identified 上海皓元 29 cases of PSC. The

incidence and prevalence of PSC per 100,000 children in Utah were 0.2 and 1.5, respectively. Complicated liver disease developed in 11 of the 29 PSC patients (38%) during follow-up. Three individual patients developed ascites, six developed esophageal varices, and three developed cholangitis and required biliary stent placement. Two of the 29 PSC patients (6.9%) developed cholangiocarcinoma, and their characteristics are detailed in Table 3. One died of metastatic cholangiocarcinoma, and one was successfully treated with chemotherapy, radiation, and liver transplantation.[21] Five additional patients required liver transplantation. The probability of developing complicated liver disease within 5 years of the diagnosis of PSC was 37% [95% confidence interval (CI) = 21%-58%; Fig. 2]. The 5-year survival rate with the native liver from the time of the PSC diagnosis was 78% (95% CI = 54%-91%; Fig. 3). We identified 12 patients with ASC. The incidence and prevalence of ASC per 100,000 children in Utah were 0.1 and 0.6, respectively. Complicated liver disease developed in 5 of the 12 ASC patients (42%) during follow-up.

05)However,there was no significant difference in age(>55, 86%)

05).However,there was no significant difference in age(>55, 8.6%), systolic pressure, diastolic pressure, complicated with other organ injury(72.8%, 59/81), infuse erythrocyte(33.3%, 27/81) between two groups(P > 0.05). Selleckchem INCB024360 The complications about liver injury undergoing NOM is preffered for the care of penetrating trauma, combine peri-liver vascular injury, shock, injury grade and amount of hemoperitoneum,shock

and combine peri-liver vascular injury was the independently predict-factors,irrespective of age, systolic pressure, diastolic pressure, complicated with other organ injury and infuse erythrocyte Conclusion: NOM is safe and effective in traumatic hepatic injury,it appears when the hemodynamic is stability neither age, penetrating trauma, injury grade,nor degree of hemoperitoneum(amount of

intraperitoneal blood),are contraindications to NOM. Key Word(s): 1. traumatic injury; 2. NOM; 3. effect factor; 4. complication; Presenting Author: YUNHONG WU Additional Authors: LIANG ZHU Corresponding Author: LIANG ZHU Affiliations: School of Public Health, Dalian Medical University, Dalian Medical University; Department of Physiology, Dalian Medical University Objective: LDLT(living donor PD-0332991 supplier liver transplantation, LDLT) is an advanced medical technique for the treatment of patients with terminal stage for irreversible liver failure. However, related ethical issues arise with the development and application of the technique. We further studied the ethical issues of LDLT in china. Methods: Methods of literature review, comparative study, the research of situation, developmental study and case study and Delphi technique were adopted. The domestic and foreign research achievements about relevant techniques, policies, laws and regulations of LDLT 上海皓元医药股份有限公司 were systematically reviewed, analyzed and summarized. Computer-online search of Internet websites and professional periodical databases was undertaken

to identify the domestic relevant media reports, and research in the fields of Hygienic Law, Medical Science, and Medical Ethics. Ideas were exchanged with experts engaged in LDLT for many years and professors in teaching Hygienic Law and Medical Ethics for years. The research was analyzed based on the actuality of LDLT in china. Results: This paper given a rational thinking from censure of medical humanitarianism due to the principle of doing no harm in medical, question to the principle of family due to the different values of the members of family, guarantee of the equality in LDLT due to the serious shortage of living donors and commercialization the living organs due to the pursuit of profit. Conclusion: We should set up the newly ethical conception, prohibit the organ business, regulate the organ transplantation ethical review process, strengthen LDLT’s medical ethical review ability construction and examination ways and perfect LDLT related laws and regulations system.

Results: NASH recipients were mostly male (572%) and white (810

Results: NASH recipients were mostly male (57.2%) and white (81.0%) with a mean age of 55.2 years. Over a mean of 3.6 years of follow-up, 252 CVD deaths occurred. Pre-transplant risk factors for CVD mortality included age ≥ 55 (OR=1.39, 95% CI 1.03-1.88), male sex (OR=1.30, 95% CI 1.01-1.69), diabetes (OR=1.33, 95% CI 1.03-1.71), and renal impairment (OR=2.02, 95% CI 1.47-2.77). A score of 1 was assigned to sex, age, and diabetes, and a score of 2 to renal failure based on model coefficients. The cohort learn more was divided into 4 risk groups: low (score=0-1), intermediate (score=2), high (score=3-4) and very high (score=5) risk. Very high risk recipients

were twice as likely as low risk recipients to die from a CVD-related cause (incidence rate: 13.54 vs. 6.77 per 10 person-years; Figure 1, p<0.001). Conclusion:

A simple score of age ≥ 55, male sex, diabetes and renal impairment may be a useful tool for predicting CVD mortality after LT for NASH cirrhosis. Further validation, in a prospectively collected cohort, is needed to confirm the prognostic value of the model. Kaplan-Meier survival curve stratified by risk group (log-rank p<0.001) Disclosures: Mary E. Rinella - Advisory Committees or Review Panels: Gilead The following people have nothing to disclose: Lisa B. VanWagner, Brittany Lapin, Donald M. Lloyd-Jones, Anton I. Skaro BACKGROUND AND AIM: Oxidative stress plays a role in the pathogenesis of NAFLD. One of the enzymes that MCE neutralize oxidative stress is Cu/Zn superoxide dismutase, which depends on the availability of adequate Akt inhibitor amounts of copper. Copper deficiency has been linked to alterations on lipid metabolism and also to hepatic steatosis. We aimed to correlate ceruloplasmin levels and serum copper concentration with clinical, biochemical and histological parameters in patients with NAFLD. METHODS: We retrieved data from a database

organized from 2011 to 2013, of 95 consecutively admitted NAFLD patients that underwent liver biopsy, and had measured the levels of ceruloplasmin and serum cooper within 06 months from the biopsy date. These patients were divided in groups based on ceruloplasmin (cut off: 25 mg/ dL) and free cooper levels (cut off: 0 mcg/dL and 15 mcg/ dL), calculated through the formula “total seric copper – (ceru-loplasmin x 3.15)”. The risk factors for NAFLD in each group were compared. RESULTS: Body Mass Index (BMI) was lower in patients with ceruloplasmin levels <25 mg/dL (29.1±3.47 vs 32.8±6.24 Kg/m2; p=0.005) as were the levels of LDL, HDL and total cholesterol, when compared with their counterpart with ceruloplasmin >25 mg/dL (101±38 vs 116±35 mg/ dL, p= 0.05; 43±9 vs 51±16 mg/dL, p= 0.01; 174±43 vs 197±39mg/dL, p= 0.01, respectively). Otherwise, patients with negative free copper had higher total cholesterol, HDL and LDL levels (194±41 vs 187±42 mg/dL, p=0.39; 50±17 vs 47±12 mg/dL, p=0.89; 113±38 vs 109±35 mg/dL, p= 0.

As implemented in this study, intermittent presentation of feedba

As implemented in this study, intermittent presentation of feedback is more effective than continuous presentation in promoting self-modulation of brain activity.

Furthermore, it appears that the process of evaluating feedback involves many brain regions that can be isolated using intermittent presentation. Real-time” functional MRI (RTfMRI) is used to describe the analysis of data while scans are being acquired, as opposed to the more common approach of analyzing data at some time following scanning. It has been proposed that such real-time analysis may be useful for quality monitoring, for brain-computer 5-Fluoracil order interfaces, and for neurofeedback.1–5 RTfMRI feedback (RTfMRIf) provides individuals neurofeedback regarding their own brain function, thus theoretically allowing a subject or patient to dynamically self-manipulate brain activity during mental processes. There are a number of proposed research and clinical applications of RTfMRIf,4,6 yet fundamental questions surrounding the optimal procedures for RTfMRIf have not been systematically explored. Such questions include how to account for scanner signal drift and physiologic noise over time during a session, how best to select and quantify the signal to feedback, and,

perhaps most important, how to best provide the feedback to the subject.1–4,7–9 A variety of approaches have been used to present RTfMRIf, such as display of whole-brain activity,10 verbal feedback,7,11 a scrolling graph display,8,12 visual scales,13,14 and combinations of feedback display approaches.6,15 The first published report of RTfMRIf used intermittent feedback, BGJ398 nmr updating a functional map after each rest-task block.10 Following EEG feedback findings,8,16 many RTfMRIf studies have used continuous feedback, in which the visual display is updated after each acquired volume.6,8,12,13,15

It is important to note that there are temporal differences between 上海皓元 EEG and fMRI measurements of brain activity. The sampling rate of EEG (∼100 samples/second) is orders of magnitude faster than that of fMRI (∼.5 samples/second). Also, the EEG signal is tightly linked to neural activity in time, while fMRI measures a hemodynamic response that follows seconds after neural activity.17 The aim of this study was to directly compare an intermittent versus a continuous approach for providing feedback with RTfMRI to test whether this matters and to aid our group and others in future RTfMRIf study design. Continuous feedback theoretically may have some advantages. The more feedback that is given, the more opportunities are available to modify thoughts and brain activity to best manipulate brain function. Also, continuous feedback may provide greater interest or engagement in participating in the feedback paradigm and ensure greater attention. However, there may be some disadvantages to continuous feedback.

We examined heterogeneity of trials and pooled the effects

We examined heterogeneity of trials and pooled the effects CHIR-99021 mouse by meta-analysis. The quality of studies was graded according to the prospective randomization, methods of patient allocation, the list of exclusion criteria, outcome

definitions and the predefined salvage procedures for uncontrolled bleeding. Results:  Among 998 patients recruited in these five randomized trials, 119 received routine second-look endoscopy with thermal coagulation, and 374 received second-look with endoscopic injection and 505 had single endoscopic therapy. Less recurrent bleeding was reported after thermal coagulation (4.2%) than single endoscopy (15.7%) (relative risk [RR] = 0.29; 95% confidence interval [CI] = 0.11–0.73), but no reduction was reported for the requirement of surgical intervention and all-cause mortality. Injection therapy did not reduce re-bleeding (17.6%) when compared to single endoscopy (20.8%; RR = 0.85; 95% CI = 0.63–1.14), requirement for surgery and mortality. Conclusion:  Routine SAHA HDAC cost second-look endoscopy with thermal coagulation, but not injection therapy, reduced recurrent peptic ulcer bleeding. There is no proven benefit in reducing surgical intervention and overall mortality. “
“Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al. Intratumor heterogeneity and branched evolution revealed

by multiregion sequencing. N Engl J Med 2012;366:883-892. (Reprinted with permission.) Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies 上海皓元 that depend on results from single tumor-biopsy

samples. To examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression. Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor.