bluuebunny/crossref_metadata_2025 huggingface dataset:
New approaches to noninvasive assessment of pulmonary artery pressure
Authors: Mirrakhimov M. M. , Tenenbaum A. M. , Moldotashev I. K. , Niazova Z. A. , Zlatkovsky M. L.
Published: August 2009

Direct measurement of pulmonary artery pressure (PAP) was performed in 36 patients; right ventricular (RV) isovolumic relaxation time (IRT) and RV systolic output acceleration time (AcT) values were assessed by pulsed Doppler and 2‐M echocardiography. There was a fairly good correlation between RV IRT and systolic PAP (r=0.898; SEE=7.8 mmHg) and a somewhat weaker one between RV AcT and systolic PAP (r=‐0.880; SEE=8.37 mmHg). Correlation coefficients were the highest between systolic PAP and the

(RVIRT/RVIRT+RV AcT)2 predictor.r:=145x2+14 (r=0.972; SEE=4.14), and also between mean PAP and the 10−RV AcT/100 predictor: y=158x + 6.7 (r=0.951; SEE = 3.48 mmHg). With ±5 mmHg deviations, systolic PAP measurements were accurate in 78% and those of mean PAP in 98% of the patients. The double‐blind assessment of the reproducibility of the suggested noninvasive PAP measurement was performed in 18 subsequent patients; the interstudy variability of the measurement was 0.88 ± 0.94 mmHg and 1.22 ± 1.23 mmHg (p>0.05), whereas interobserver variability was 1.90±1.70 mmHg and 1.67±1.63 mmHg, respectively (p>0.05). Thus, a combined use of the most informative intervals of RV cycle—IRT and AcT—contributes to the accuracy of noninvasive PAP measurement.
Fosinopril monotherapy: Relationship between blood pressure reduction and time of administration
Authors: Ford Neville F. , Fulmor I. Edgar , Nichola Peter S. , Alpin Pamela G. , Herron Jarry M.
Published: August 2009

The time to peak antihypertensive effect and the trough‐to‐peak ratio were determined in 64 Caucasian patients (19 men, 45 women) with mild to moderate hypertension [supine diastolic blood pressure (DBP) 95 to 115 mmHg]. They received placebo or fosinopril 10, 20, or 40 mg once daily for 4 weeks. The study consisted of a 4‐week placebo lead‐in, 4 weeks' double‐blind treatment, and a 1‐week placebo washout period. Vital signs were determined biweekly before dosing, and blood pressures were measured every 1 to 2 h during two 27‐h periods at the beginning and end of treatment. After the first and last doses of all three regimens, the peak effect on blood pressure occurred 5 to 7 h after all three dosages. Neither peak nor trough blood pressure changes showed a clear dose‐response relationship. Trough to peak ratios for the first dose, corrected for placebo effects, were 79% for fosinopril 10 mg, 48% for fosinopril 20 mg, and 74% for fosinopril 40 mg, and the trough‐to‐peak ratios for the last dose were 41% for fosinopril 10 mg, 32% for fosinopril 20 mg, and 44% for fosinopril 40 mg. In the 38 responders among the 48 patients receiving fosinopril (supine DBP decrease of at least 5 mmHg at 24 h postdose), trough‐to‐peak rations ranged from 50 to 81%, and the range indicates that fosinopril is efficacious when administered once daily. Adverse effects were mild to moderate, and no patient discontinued treatment. Changes in the laboratory test results, electrocardiograms, or the results of physical examinations were unremarkable. Once‐daily fosinopril 10, 20, or 40 mg effectively and safely controlled blood pressure in patients with mild to moderate essential hypertension.
The clinical distinction between regional postinfarction pericarditis and other causes of postinfarction chest pain: Ancillary observations regarding the effect of lytic therapy upon the frequency of postinfarction pericarditis, postinfarction angina, and reinfarction
Authors: Oliva Philip B. , Hammill Stephen C.
Published: August 2009

Recently two types of atypical T‐wave evolution were recognized as electrocardiographic (ECG) markers of regional postinfarction pericarditis. The sensitivity and specificity of these of these changes for this condition were 100 and 77%, respectively. The major purpose of this investigation is to show how these ECG changes can be used to differentiate among postinfarction pericarditis, postinfarction angina, and reinfarction. Even appropriately constructed serial monitor lead ECGs can be used to make this distinction. The ease of correctly distinguishing among the three causes of postinfarction chest pain utilizing a carefully elicited history and ECG criteria is discussed. In addition, a secondary objective was to assess the effect of lytic therapy on the incidence of postinfarction pericarditis. Among the 200 patients in this study, lytic therapy halved the incidence of postinfarction pericarditis, which is in accord with the larger Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI) study.
Pharmacologic treatment of congestive heart failure
Authors: Carson Peter
Published: August 2009

Congestive heart failure is a clinical syndrome producing symptomatic deterioration, functional impairment, and shortened life span. The syndrome is complex in that it includes both peripheral and cardiac effects which contribute to the progression of heart failure. In the periphery, elevations in thesympathetic nervous system and renin‐angiotensin system increase afterload and contribute to further salt and water retention. The central cardiac abnormalities include remodeling of the heart and downregulation of beta receptors. Traditional heart failure therapy has included treatment of fluid retention with diuretics, although their effect on mortality has never been addressed. The most proven therapy in heart failure is treatment with vasodilators, particularly angiotensin‐converting enzyme (ACE) inhibitors. Improved survival with ACE‐inhibitor therapy has been demonstrated in patients with severe heart failure (CONSENSUS), mild to moderate heart failure (SOLVD), and in comparison with vasodilator therapy with hydralazine isosorbide dinitrate (VHeFT II). Improved survival has also been noted in postmyocardial infarction when the ejection fraction is decreased (SAVE). The ACE inhibitors have now become standard therapy for heart failure regardless of severity. Additive vasodilator therapy with calcium‐channel antagonists is under investigation. Inotropic therapy is controversial at present because of disappointing mortality results. The clinical mainstay digitalis remains without convincing mortality reduction data. Other inotropic agents, particularly phosphodiesterase inhibitors, have shown uniformly negative survival results. However, the new mixed action agents vesnarinone and pimobenden have shown favorable data, with vesnarinone demonstrating a mortality reduction effect. Beta‐blocker therapy in heart failure has also found renewed interest, particularly with the new agents carvedolol and bucindolol which also have vasodilating properties.
Evaluation of left ventricular diastolic function from the pattern of left ventricular filling
Authors: Little William C. , Warner James G. , Rankin Kevin M. , Kitzman Dalane W. , Cheng Che‐Ping
Published: August 2009

The pattern of left ventricular (LV) filling can be determined by Doppler echocardiography. Normally most LV filling occurs early in diastole, with some additional filling occurring during atrial systole, late in diastole. In the absence of mitral stenosis, three patterns of LV filling indicate progressively greater diastolic dysfunction: (1) Reduced early diastolic filling with a compensatory increase in importance of atrial filling, termed a pattern of “impaired relaxation;” (2) “pseudo‐normalization” with most filling early in diastole but with rapid deceleration of mitral flow; and (3) “restricted filling” with almost all filling of the LV occurring very early in diastole in association with very rapid deceleration of mitral flow. A large, prolonged atrial regurgitant flow in the pulmonary veins also indicates impaired diastolic performance. The time for early filling deceleration is predominantly determined by LV stiffness: the shorter the deceleration time, the stiffer the LV. Patients with short deceleration time have a poor prognosis.
Angioplasty decreases prolonged QT dispersion in patients with angina pectoris but not in patients with prior myocardial infarction
Authors: Takase Bonpei , Tujimoto Tetuya , Hamabe Akira , Satomura Kimio , Ohsuzu Fumitaka , Kurita Akira , Kitamura Katuhiro , Uehata Akimi , Kazusige Isojima
Published: August 2009

Background and hypothesis: Prolonged QT dispersion (QTd) is shortened by successful percutaneous transluminal coronary angioplasty (PTCA) in patients with ischemic heart disease. Particularly, QTd plays an important role in the prognostication in patients with prior myocardial infarction (MI). However, whether the effect of PTCA on QTd differs in patients with and without prior MI is not clear, and this study sought to clarify this question.

Methods: In 41 consecutive patients with ischemic heart disease, we measured QTd from a routine 12‐lead electrocardiogram taken at 72 h before and after successful PTCA. Patients were divided into two groups based on the presence or absence of prior MI: Group 1 consisted of 24 patients with angina (61 ± 11 years old) without prior MI and Group 2 was comprised of 17 patients (69 ± 10 years old) with prior MI. QTd was calculated as the difference between the maximum and minimum QT and QT corrected for heart rate (QTc), using Bazett's formula for calculating QTcd. All measurements were obtained manually and blindly.

Results: In Group 1,15 of 24 patients (63%) demonstrated multivessel disease and 16 of 24 (67%) patients had high QTd > 60 ms. Percutaneous transluminal coronary angioplasty decreased QTd and QTcd in Group 1 (QTd, from 83 ± 35 to 57 ± 19 ms, p < 0.05; QTcd, from 89 ± 37 to 63 ± 33 ms, p < 0.05), whereas no changes were observed in Group 2 (QTd, from 73 ± 25 to 69 ± 22 ms, NS; QTcd, from 80 ± 30 to 79 ± 28 ms, NS). QTd is more sensitive to decrease by successful PTCA in patients with angina than in patients with prior MI.

Conclusions: The effect of successful PTCA on inhomogeneity of ventricular repolarization reflected by QTd in patients with prior MI is different from that in patients without prior MI.
Clinical characteristics of acute pulmonary thromboembolism in Japan: Results of a multicenter registry in the japanese society of pulmonary embolism research
Authors: Nakamura Mashio , Fujioka Hirofumi , Yamada Norikazu , Nakano Takeshi , Sakuma Masahito , Okada Osamu , Kuriyama Takayuki , Nakanishi Norifumi , Miyahara Yoshiyuki , Kunieda Takeyoshi , Sugimoto Tsuneaki
Published: August 2009

Background: Although the incidence of acute pulmonary thromboembolism (APTE) has been increasing in Japan, patient characteristics, management strategies, and outcome have not yet been assessed in large series.

Hypothesis: The present study was designed to investigate the current status of APTE in Japan.

Methods: Of a total of 533 registry patients with pulmonary thromboembolism, 309 with APTE were analyzed with respect to clinical symptoms and signs, predisposing factors, diagnostic procedures, estimation of deep venous thrombosis, treatment, and clinical course.

Results: Main risk factors were recent major surgery, cancer, prolonged immobilization, and obesity; only a few patients had coagulopathy and 36% were in cardiogenic shock at presentation. The majority of registry patients underwent lung scans or pulmonary angiography; 30% were diagnosed only by lung scanning. Venous ultrasonography was used in only 34 patients, while 188 patients underwent at least one diagnostic procedure for deep venous thrombosis. Thrombolysis was more frequently performed in patients with cardiogenic shock, and only a few patients received thromboembolectomy. In‐hospital mortality rate was 14%. In patients with cardiogenic shock, the mortality rate was reduced by thrombolysis. The predictors of in‐hospital mortality were male gender, cardiogenic shock, cancer, and prolonged immobilization.

Conclusions: The patients in this registry had almost the same findings as those in Western patients, except for some points that had the possibility of demonstrating a difference between Westerners and Japanese in the development of APTE. These results can prove especially helpful in planning prospective, randomized trials that will clarify the impact of widely used treatment modalities on the outcome of patients with APTE.
Native aortic valve tissue systemic embolization complicating bacterial endocarditis
Authors: Garg Mukesh , Quick Annette , Depond William , Schroder William , Chowdhry Shaheen , Spertus John
Published: August 2009

Systemic embolic events are known complications of bacterial endocarditis. Embolization of prosthetic valves has previously been reported in the literature. We report a case of embolization of native aortic valve tissue to the popliteal artery as the presenting event in a patient with subacute bacterial endocarditis. To our knowledge, this rare complication has not been previously reported.
Optimization of Thienopyrrole‐Based Finger‐Loop Inhibitors of the Hepatitis C Virus NS5B Polymerase
Authors: Martin Hernando Jose Ignacio , Ontoria Jesus Maria , Malancona Savina , Attenni Barbara , Fiore Fabrizio , Bonelli Fabio , Koch Uwe , Di Marco Stefania , Colarusso Stefania , Ponzi Simona , Gennari Nadia , Vignetti Sue Ellen , del Rosario Rico Ferreira Maria , Habermann Jörg , Rowley Michael , Narjes Frank
Published: August 2009

Infections caused by the hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The NS5B polymerase of HCV is responsible for the replication of viral RNA and has been a prime target in the search for novel treatment options. We had discovered allosteric finger‐loop inhibitors based on a thieno[3,2‐b]pyrrole scaffold as an alternative to the related indole inhibitors. Optimization of the thienopyrrole series led to several N‐acetamides with submicromolar potency in the cell‐based replicon assay, but they lacked oral bioavailability in rats. By linking the N4‐position to the ortho‐position of the C5‐aryl group, we were able to identify the tetracyclic thienopyrrole 40, which displayed a favorable pharmacokinetic profile in rats and dogs and is equipotent with recently disclosed finger‐loop inhibitors based on an indole scaffold.
Biliary intraepithelial neoplasia in patients without chronic biliary disease
Authors: Wu Tsung‐Teh , Levy Michael , Correa Arlene M. , Rosen Charles B. , Abraham Susan C.
Published: August 2009

BACKGROUND:

Biliary intraepithelial neoplasia (BilIN) represents a spectrum of proliferative and/or cytologically atypical lesions of the large intrahepatic bile ducts. BilIN is believed to be a major pathway leading to the development of intrahepatic cholangiocarcinoma (CCA) through a dysplasia‐carcinoma sequence. Recently, a large interobserver agreement study in patients with hepatolithiasis, choledochal cysts, and primary sclerosing cholangitis proposed diagnostic criteria for 3 categories of BilIN based on increasing grades of nuclear atypia and loss of nuclear polarity: BilIN‐1, BilIN‐2, and BilIN‐3. BilIN has not been systematically studied as a potential precursor lesion in patients with nonbiliary liver disease, despite the epidemiologic association between intrahepatic CCA, hepatitis C infection (HCV), and alcohol (EtOH) consumption.

METHODS:

We submitted 12 paraffin blocks targeted to the large intrahepatic and hilar ducts in each of 244 explanted livers with EtOH cirrhosis (n = 94), HCV cirrhosis (n = 44), EtOH + HCV (n = 26), and noncirrhotic controls (eg, livers removed for metabolic disorders, massive hepatic necrosis) (n = 80), and classified all bile duct profiles as normal/reactive, metaplastic, or BilIN‐1, ‐2, or ‐3 (flat or papillary).

RESULTS:

Livers transplanted for EtOH and EtOH + HCV cirrhosis had the highest prevalence of BilIN, greater numbers of ducts with BilIN, and a shift toward higher grades of BilIN as compared with HCV alone and with noncirrhotics. In EtOH, the highest grades of BilIN were 0 = 3%, BilIN‐1 = 35%, BilIN‐2 = 57%, BilIN‐3 = 4%; in EtOH + HCV: 4%, 38%, 54%, 4%; in HCV: 18%, 55%, 20%, 7%; and in noncirrhotics: 45%, 39%, 16%, 0%, respectively. In both univariate and multivariate analysis, EtOH (P < .001), EtOH + HCV (P < .001), and HCV cirrhosis (P < .001) were all significant predictors of BilIN grade. Multifocal BilIN (≥10 ducts) was present in 91% of EtOH, 92% of EtOH + HCV, and 61% of HCV cirrhosis, as compared with only 34% of noncirrhotics (P values of <.0001, <.001, and .002, respectively, in both univariate and multivariate analysis). Papillary or micropapillary architecture of BilIN was also more common in EtOH (47%) than in EtOH + HCV (19%), HCV (23%), or noncirrhotics (17%) (P < .001 in both univariate and multivariate analysis). BilIN‐3 occurred only in the setting of cirrhosis (8 of 164 cirrhotic livers, 5%) and was associated with CCA (2 cases) or mixed hepatocellular/CCA (1 case) elsewhere in the liver.

CONCLUSIONS:

In aggregate, these findings provide morphologic support for the epidemiologic role of alcohol and HCV in the development of CCA. Cancer 2009. © 2009 American Cancer Society.
Why cancer at the primary site and in the lymph nodes contributes to the risk of cancer death
Authors: Michaelson James S. , Chen L. Leon , Silverstein Melvin J. , Cheongsiatmoy Justin A. , Mihm Martin C. , Sober Arthur J. , Tanabe Kenneth K. , Smith Barbara L. , Younger Jerry
Published: August 2009

BACKGROUND:

Cancer at both the primary site and in the lymph nodes is associated with lethality, although the mechanism by which lethality arises from each site has been poorly understood. For breast carcinoma, each positive lymph node contributes an approximately 6% risk of death, and each millimeter of primary tumor greatest dimension contributes approximately 1%; whereas, for melanoma, each positive lymph node contributes an approximately 23% risk, and each millimeter of tumor thickness contributes approximately 8%: This is described by a pair of linked equations, the Size+Nodes method.

METHODS:

A simple expression, the ProbabilityEstimation equation, which was derived from the authors' binary‐biologic model of cancer metastasis, was used to calculate the probabilities of spread of cancer cells from data on tumor size, lymph node status, and death rate.

RESULTS:

In this report, the authors demonstrated, that when similar masses of cancer are compared, the chance of lethal spread of a cancer cell to the periphery is approximately the same whether the spread emerges from a lymph node or from the primary site. The greater the number of cells at the primary site (tumor size) or the greater the number of cells in the lymph nodes (number of positive lymph nodes), the greater is the aggregate chance that 1 or more cells has undergone a lethal event of spread, a process captured by the Size+Nodes equations.

CONCLUSIONS:

The lethal contributions of cancer at the primary site and lymph nodes can be explained by a simple mechanical process of the spread of cancer cells occurring with definable probabilities per cell. The presence of cancer in the lymph nodes does not indicate an intrinsic change in a malignancy but, rather, an increased mass of cancer from which spread can emerge. Cancer 2009. © 2009 American Cancer Society.
The efficacy for unresectable hepatocellular carcinoma may be improved by transcatheter arterial chemoembolization in combination with a traditional Chinese herbal medicine formula
Authors: Yu Yang , Lang Qingbo , Chen Zhe , Li Bai , Yu Chaoqin , Zhu Dezeng , Zhai Xiaofeng , Ling Changquan
Published: August 2009

Transcatheter arterial chemoembolization (TACE) is the most widely used primary treatment for unresectable hepatocellular carcinoma (HCC) because of its survival benefit, although its clinical effect is still far from satisfactory. In China, there has been a long history of using traditional Chinese medicine in the treatment of liver cancer and other malignancies. In this study, the authors evaluated the effect of combined therapy with TACE and JDF granule preparation (a traditional Chinese herbal medicine formula) in the treatment of patients with unresectable HCC on survival. Clinical data, including baseline, performance status change, and survival time of 165 patients with unresectable HCC seen between January 2002 and December 2007 were retrospectively analyzed. Among the 165 patients, 80 patients (study group) received combined therapy consisting of TACE and a long‐term maintenance treatment with oral JDF granule preparation, and 85 patients (control group) received TACE alone. The survival rate of both groups was calculated by the Kaplan‐Meier method. Factors possibly affecting survival were assessed by multivariate analysis in the Cox proportional hazard model. The median overall survival was 9.2 months (95% confidence interval [95% CI], 6.94‐1.46) in the study group versus 5.87 months (95% CI, 4.21‐7.52) in the control group. In the study group (TACE + JDF), 1‐year, 2‐year, and 3‐year survival rates were 41.2%, 18.4%, and 9.6%, respectively. The Cox regression analysis revealed the therapy model to be an independent predictor of patient prognosis. Current study data demonstrated that TACE combined with JDF granule preparation could improve the prognosis of patients. TACE combined with JDF granule preparation may prolong survival of patients with unresectable HCC. Cancer 2009. © 2009 American Cancer Society.
Combination therapy with rituximab and intravenous or oral fludarabine in the first‐line, systemic treatment of patients with extranodal marginal zone B‐cell lymphoma of the mucosa‐associated lymphoid tissue type
Authors: Salar Antonio , Domingo‐Domenech Eva , Estany Cristina , Canales Miguel A. , Gallardo Fernando , Servitje Octavio , Fraile Guadalupe , Montalbán Carlos
Published: August 2009

BACKGROUND:

Currently, there are no consensus guidelines regarding the best therapeutic option for patients with extranodal marginal zone lymphomas of the mucosa‐associated lymphoid tissue (MALT) type.

METHODS:

Patients with systemically untreated or de novo extranodal MALT lymphoma received rituximab 375 mg/m2 intravenously on Day 1 and fludarabine 25 mg/m2 intravenously on Days 1 through 5 (Days 1‐3 in patients aged >70 years) every 4 weeks, for 4 to 6 cycles. After the first cycle, oral fludarabine could be given orally at 40 mg/m2 on the same schedule. After 3 cycles, a workup was done. Patients who achieved a complete remission (CR) received an additional cycle, and patients who achieved a partial remission (PR) received a total of 6 cycles.

RESULTS:

Twenty‐two patients were studied, including 12 patients with gastric lymphoma and 10 patients with extragastric MALT lymphoma. Six patients (27%) had stage IV disease. In total, 101 cycles were administered (median, 4 cycles per patients). After the third cycle, 13 patients (62%) achieved a CR, and 8 patients (38%) achieved a PR. Primary extragastric disease was an adverse factor to achieve CR after 3 cycles of chemotherapy (hazard ratio, 23.3; 95% confidence interval, 2.0‐273.3). At the end of treatment, the overall response rate was 100%, and 90% of patients achieved a CR. The progression‐free survival rate at 2 years in patients with gastric and extragastric MALT lymphoma was 100% and 89%, respectively. Toxicities were mild and mainly were hematologic.

CONCLUSIONS:

Combination therapy with rituximab and fludarabine is a very active treatment with favorable safety profile as first‐line systemic treatment for patients with extranodal MALT lymphoma. Cancer 2009. © 2009 American Cancer Society.
Cuplike nuclei (prominent nuclear invaginations) in acute myeloid leukemia are highly associated with FLT3 internal tandem duplication and NPM1 mutation
Authors: Chen Weina , Konoplev Sergej , Medeiros L. Jeffrey , Koeppen Hartmut , Leventaki Vasiliki , Vadhan‐Raj Saroj , Jones Dan , Kantarjian Hagop M. , Falini Brunangelo , Bueso‐Ramos Carlos E.
Published: August 2009

BACKGROUND:

A small subset of patients with acute myeloid leukemia (AML) have cuplike nuclei. Other investigators have demonstrated that these neoplasms have distinctive clinicopathologic and molecular features.

METHODS:

The authors searched for patients who had AML with cuplike nuclei at their institution over a 10‐year interval. A strict definition for cuplike nuclei was used: ≥10% blasts with nuclear invaginations in ≥25% of the nuclear area. The relevant data were reviewed, and the results were compared with a control group of patients who had AML without cuplike nuclei.

RESULTS:

In total, 22 patients who had AML with cuplike nuclei were identified and were classified as AML without maturation (French‐American‐British classification M1) (AML M1). Compared with the control group (AML M1), patients who had AML with cuplike nuclei were associated significantly with fms‐like tyrosine kinase 3 (FLT3)‐internal tandem duplication (ITD) (86% vs 38%, respectively; P = .002); nucleophosmin 1 (NPM1) mutations (86% vs 19%; P < .0001); both mutations (77% vs 14%; P < .0001); normal karyotype (86% vs 40%; P = .003); bone marrow blast count (90% vs 84%; P = .016); myeloperoxidase positivity (95% vs 30% blasts; P = .001); higher D‐dimer levels (>5000 ng/mL vs 569 ng/mL; P = .001); and the absence of CD7 (91% vs 52%; P = .007), CD34 (82% vs 5%; P < .0001), and human leukocyte antigen, D‐related (59% vs 10%; P = .001). There were no differences in age, sex, or peripheral blood counts. The positive predictive value of recognizing AML with cuplike nuclei for FLT3‐ITD, NPM1, and both mutations was 81%, 86%, and 77%, respectively.

CONCLUSIONS:

Cuplike nuclei in AML were highly associated with the presence of NPM1 and FLT3‐ITD mutations and with several clinicopathologic and immunophenotypic features. Recognition of the distinctive morphologic features of AML with cuplike nuclei may be helpful in streamlining the workup of these neoplasms. Cancer 2009. © 2009 American Cancer Society.
Estimating breast cancer‐specific and other‐cause mortality in clinical trial and population‐based cancer registry cohorts
Authors: Dignam James J. , Huang Lan , Ries Lynn , Reichman Marsha , Mariotto Angela , Feuer Eric
Published: August 2009

BACKGROUND:

To compute net cancer‐specific survival rates using population data sources (eg, the National Cancer Institute's Surveillance, Epidemiology, and End Results [SEER] Program), 2 approaches primarily are used: relative survival (observed survival adjusted for life expectancy) and cause‐specific survival based on death certificates. The authors of this report evaluated the performance of these estimates relative to a third approach based on detailed clinical follow‐up history.

METHODS:

By using data from Cancer Cooperative Group clinical trials in breast cancer, the authors estimated 1) relative survival, 2) breast cancer‐specific survival (BCSS) determined from death certificates, and 3) BCSS obtained by attributing cause according to clinical events after diagnosis, which, for this analysis was considered the benchmark “true” estimate. Noncancer life expectancy also was compared between trial participants, SEER registry patients, and the general population.

RESULTS:

Among trial patients, relative survival overestimated true BCSS in patients with lymph node‐negative breast cancer; whereas, in patients with lymph node‐positive breast cancer, the 2 estimates were similar. For higher risk patients (younger age, larger tumors), relative survival accurately estimated true BCSS. In lower risk patients, death certificate BCSS was more accurate than relative survival. Noncancer life expectancy was more favorable among trial participants than in the general population and among SEER patients. Tumor size at diagnosis, which is a potential surrogate for screening use, partially accounted for this difference.

CONCLUSIONS:

In the clinical trials, relative survival accurately estimated BCSS in patients who had higher risk disease despite more favorable other‐cause mortality than the population at large. In patients with lower risk disease, the estimate using death certificate information was more accurate. For SEER data and other data sources where detailed postdiagnosis clinical history was unavailable, death certificate‐based estimates of cause‐specific survival may be a superior choice. Cancer 2009. © 2009 American Cancer Society.
Lymph node status after neoadjuvant radiotherapy for rectal cancer is a biologic predictor of outcome
Authors: Chang George J. , Rodriguez‐Bigas Miguel A. , Eng Cathy , Skibber John M.
Published: August 2009

BACKGROUND:

Lymph node (LN) status after surgery for rectal cancer is affected by preoperative radiotherapy. The purpose of this study was to perform a population‐based evaluation of the impact of pathologic LN status (ypN) after neoadjuvant radiotherapy on survival.

METHODS:

Patients undergoing radical resection for rectal adenocarcinoma were identified from the Surveillance Epidemiology and End Results registry (1991‐2004). Patient characteristics, overall survival, and cancer‐specific survival (CSS) by ypN stage after surgery and use of preoperative or postoperative radiotherapy were compared.

RESULTS:

Of the 23,809 patients identified, 12,513 received preoperative (n = 5367) or postoperative (n = 7146) radiotherapy and resection. Preoperative patients were more likely to be younger (P < .001) and histopathologically free of detectable nodal metastasis (ypN0) than postoperative (51.8% vs 31.7%, P < .001). Median total numbers of LNs (6 vs 10) and positive LNs (2 vs 3) were lower among preoperative than postoperative (P < .001 for both). OS and CSS were similar among pN0 patients. However, on proportional hazards regression, ypN+ stage was associated with an increase in relative risk for death by 21% overall (hazard ratio [HR] = 1.21; 95% confidence interval 1.09‐1.35, P < .001) and 23% cancer‐specific (HR = 1.23; P = .001) for preoperative compared with postoperative.

CONCLUSIONS:

Pathologic LN status after neoadjuvant radiotherapy for rectal cancer is a biologic marker of prognosis. Patients who are ypN+ after preoperative are a subgroup of LN positive patients with adverse outcome. These high‐risk patients should be targeted for studies of novel multidisciplinary approaches, including expanded chemo‐ and biologic therapies. Cancer 2009. © 2009 American Cancer Society.
Local recurrence after surgery for early stage lung cancer
Authors: Kelsey Chris R. , Marks Lawrence B. , Hollis Donna , Hubbs Jessica L. , Ready Neal E. , D'Amico Thomas A. , Boyd Jessamy A.
Published: August 2009

BACKGROUND:

The objective of the current study was to evaluate the actuarial risk of local failure (LF) after surgery for stage I to II nonsmall cell lung cancer (NSCLC) and assess surgical and pathologic factors affecting this risk.

METHODS:

The records, including pertinent radiologic studies, of all patients who underwent surgery for T1 to T2, N0 to N1 NSCLC at Duke University between 1995 and 2005 were reviewed. Risks of disease recurrence were estimated using the Kaplan‐Meier method. A multivariate Cox regression analysis assessed factors associated with LF in the entire cohort and a subgroup undergoing optimal surgery for stage IB to II disease.

RESULTS:

For all 975 consecutive patients, the 5‐year actuarial risk of local and/or distant disease recurrence was 36%. First sites of failure were local only (25%), local and distant (29%), and distant only (46%). The 5‐year actuarial risk of LF was 23%. On multivariate analysis, squamous/large cell histology (hazards ratio [HR], 1.98), stage > IA (HR, 2.02), and sublobar resections (HR, 1.99) were found to be independently associated with a higher risk of LF. For the subset of patients (n = 445) undergoing at least a lobectomy with negative surgical margins and currently considered for adjuvant chemotherapy (stage IB‐II disease), the 5‐year actuarial risk of LF was 27%. Within this subgroup, squamous/large cell histology (HR, 2.5) and lymphovascular space invasion (HR, 1.74) were associated with a higher risk of LF. The 5‐year rate of LF was 13%, 32%, and 47%, respectively, with 0, 1, or 2 risk factors.

CONCLUSIONS:

Greater than half of disease recurrences after surgery for early stage NSCLC involved local sites. Pathologic factors may help to distinguish those patients at highest risk. Cancer 2009. © 2009 American Cancer Society.
Expression and regulation of vitamin D3 upregulated protein 1 (VDUP1) is conserved in mammalian and insect brain
Authors: Levendusky Mark C. , Basle Jacilyn , Chang Solomon , Mandalaywala Neil V. , Voigt Jeffrey M. , Dearborn Richard E.
Published: August 2009

Originally characterized as a cell‐cycle inhibitor induced by vitamin D3, the tumor suppressor vitamin‐D3 upregulated protein 1 (VDUP1) has increasingly been shown to play major physiological roles in cell differentiation and glucose metabolism. Here we show evolutionarily conserved expression patterns of VDUP1 in Drosophila and rat nervous systems, including subcellular localization—cytoplasmic enrichment in neurons and nuclear expression in glia. These anatomical correlates suggested conservation of VDUP1 regulation, which was investigated both functionally and through promoter studies. Characterization of orthologous vdup1 cis‐regulatory regions identified evolutionarily conserved sequence blocks (CSBs) with similarities to neural enhancers, including basic helix‐loop‐helix (bHLH) transcription factor Neurogenin/Math/atonal and Mash/achaete‐scute family members. E‐boxes (CANNTG), the binding sites for bHLH proteins, were associated with these CSBs as well, including E‐boxes known to mediate glucose‐dependent upregulation of VDUP1 in nonneuronal cells. Hyperglycemia‐induced upregulation of VDUP1 was observed in brain tumor cells and in the Drosophila nervous system, which resulted in developmental arrest. Taken together, these data demonstrate evolutionary conservation of VDUP1 regulation and function, and suggest an expanding role for VDUP1 in nervous system development. J. Comp. Neurol. 517:581–600, 2009. © 2009 Wiley‐Liss, Inc.
An alternative procedure for simulating one‐dimensional transport phenomena with shock waves in a gas
Authors: Porto Eliane Maracajá , Martins‐Costa Maria Laura , Saldanha da Gama Rogério M.
Published: August 2009

This article employs an alternative procedure to treat a class of non‐linear hyperbolic systems, using a preliminary model to describe pollutants motion in an atmosphere, accounting for the production or destruction of pollutants, described, as a first approximation, by a source term. The mathematical description consists of a non‐linear hyperbolic system of m+2 partial differential equations representing mass and momentum conservation for the multicomponent mixture of air and gases and mass balance equations for the gases. After simplifying assumptions, the resulting one‐dimensional system of m+2 equations is simulated in such a way that the simultaneous problem is treated sequentially: the operator is splitted into a non‐homogeneous (time‐dependent) ordinary part and a homogeneous associated hyperbolic one. This latter is simulated by a Glimm's scheme for evolution in time, employing an approximate Riemann solver for each two consecutive steps. The employed Riemann solver approximates the solution of the associated Riemann problem by piecewise constant functions always satisfying the jump condition—giving rise to an approximation easier to implement with lower computational cost. Comparison with the standard procedure, employing the complete solution of the associated Riemann problem for implementing Glimm's scheme, has shown good agreement. Copyright © 2009 John Wiley & Sons, Ltd.
Posttranslational regulation of BCL2 levels in cerebellar granule cells: A mechanism of neuronal survival
Authors: Lossi Laura , Gambino Graziana , Ferrini Francesco , Alasia Silvia , Merighi Adalberto
Published: August 2009

Apoptosis can be modulated by K+ and Ca2+ inside the cell and/or in the extracellular milieu. In murine organotypic cultures, membrane potential‐regulated Ca2+ signaling through calcineurin phosphatase has a pivotal role in development and maturation of cerebellar granule cells (CGCs). P8 cultures were used to analyze the levels of expression of B cell lymphoma 2 (BCL2) protein, and, after particle‐mediated gene transfer in CGCs, to study the posttranslational modifications of BCL2 fused to a fluorescent tag in response to a perturbation of K+/Ca2+ homeostasis. There are no changes in Bcl2 mRNA after real time PCR, whereas the levels of the fusion protein (monitored by calculating the density of transfected CGCs under the fluorescence microscope) and of BCL2 (inWestern blotting) are increased. After using a series of agonists/antagonists for ion channels at the cell membrane or the endoplasmic reticulum (ER), and drugs affecting protein synthesis/degradation, accumulation of BCL2 was related to a reduction in posttranslational cleavage by macroautophagy. The ER functionally links the [K+]e and [Ca2+]i to the BCL2 content in CGCs along two different pathways. The first, triggered by elevated [K+]e under conditions of immaturity, is independent of extracellular Ca2+ and operates via IP3 channels. The second leads to influx of extracellular Ca2+ following activation of ryanodine channels in the presence of physiological [K+]e, when CGCs are maintained in mature status. This study identifies novel mechanisms of neuroprotection in immature and mature CGCs involving the posttranslational regulation of BCL2. © 2009 Wiley Periodicals, Inc. Develop Neurobiol, 2009
Membrane domain modulation by Spectrins in Drosophila photoreceptor morphogenesis
Authors: Chen Tony W. , Chen Geng , Funkhouser Lisa J. , Nam Sang‐Chul
Published: August 2009

Spectrins are major proteins in the cytoskeletal network of most cells. In Drosophila, βHeavy‐Spectrin encoded by the karst gene functions together with Crb during photoreceptor morphogenesis. However, the roles of two other Spectrins (α‐ and β‐Spectrins) in developing photoreceptor cells have not been studied. Here, we analyzed the effects of spectrin mutations on developing eyes to determine their roles in photoreceptor morphogenesis. We found that the Spectrins are dispensable for retinal differentiation in eye imaginal discs during larval stage. However, photoreceptors deficient in α‐ or β‐Spectrin display dramatic apical membrane expansions including Crb and show morphogenesis defects during pupal eye development, suggesting that α‐ and β‐Spectrins are specifically required for photoreceptor polarity during pupal eye development. Karst localizes apically, whereas β‐Spectrin is preferentially distributed in the basolateral region. We show that overexpression of β‐Spectrin causes a strong shrinkage of apical membrane domains, and loss of β‐Spectrin causes an expansion of apical domains, implying an antagonistic relationship between β‐Spectrin and Karst. These results indicate that Spectrins are required for controlling photoreceptor morphogenesis through the modulations of cell membrane domains. genesis 47:744–750, 2009. © 2009 Wiley‐Liss, Inc.
Ligation of the OX40 co‐stimulatory receptor reverses self‐Ag and tumor‐induced CD8 T‐cell anergy in vivo
Authors: Redmond William L. , Gough Michael J. , Weinberg Andrew D.
Published: August 2009

Tumor‐specific CD8 T‐cell peripheral tolerance occurs through clonal deletion, suppression, and the induction of anergy and can limit the generation of anti‐tumor immunity. Several groups have demonstrated that prostate cancer can render tumor‐specific CD8 T cells anergic, suggesting reversing tumor‐induced anergy may greatly augment anti‐tumor immunity. Recent work has demonstrated that signaling through the OX40 (CD134) co‐stimulatory receptor, a member of the TNFR super‐family, can augment CD4 and CD8 T‐cell expansion, differentiation, and the generation of memory cells. However, whether OX40 ligation can reverse CD8 T‐cell anergy, and more specifically, tumor‐induced CD8 T‐cell anergy, remains unclear. In the current study, we demonstrate that OX40 ligation can reverse CD8 T‐cell anergy to a prostate‐specific self‐Ag in non‐tumor‐bearing hosts. Furthermore, OX40 engagement reversed tumor‐specific CD8 T‐cell anergy and restored the proliferative capacity of tumor‐reactive CD8 T cells, which attenuated tumor growth and enhanced the survival of tumor‐bearing hosts. These data demonstrate that OX40 ligation can rescue the function of anergic self‐ or tumor‐reactive CD8 T cells in vivo and suggests that OX40‐mediated therapy may provide a novel means of boosting anti‐tumor immunity by restoring the responsiveness of previously anergic tumor‐specific CD8 T cells.
Overcoming the global crisis: “Yes, we can”, but also for TB … ?
Authors: Ottenhoff Tom H. M.
Published: August 2009

Tuberculosis (TB) poses formidable challenges to global health at the public health‐, scientific‐ and political level. Causing almost two million deaths every year, this ancient disease represents a continuing global crisis. The writing on the wall is that TB is resurging in more virulent and treatment‐resistant forms. Our tools to combat TB are dangerously out of date and ineffective. Besides new tools (TB drugs, vaccines, diagnostics), we also need new strategies to identify key Mycobacterium tuberculosis/human host interactions, since it is here that we can most likely find Mtb's Achilles' heel. Equally important is that we build high‐quality clinical trial capacity and biobanks for TB biomarker identification. But most important is a global commitment at all levels to roll back TB before it outwits us again.
Malaria vaccine development: Lessons from the field
Authors: Todryk Stephen , Bejon Philip
Published: August 2009

Studies and trials in the field are key to the development of a vaccine for malaria. Our limited knowledge of naturally acquired immunity and of transmission dynamics and disease causation in the field imposes limitations on our ability to predict the efficacy of candidate vaccinations, and the eventual outcome on deploying an efficacious vaccine at a population level.
Multiple sclerosis: Human model for EAE?
Authors: Hohlfeld Reinhard
Published: August 2009

Concepts of the pathogenesis of MS are based on evidence from the animal model, EAE. Yet, the relationship between human MS and EAE is far from being a one‐way road: many paths lead from the bedside back to animals in the laboratory.
25 years of HIV research! … and what about a vaccine?
Authors: Appay Victor
Published: August 2009

Over the past quarter century, colossal progress in our understanding of HIV pathogenesis has been achieved. Yet, we have no solution to the pandemic; the search for an HIV vaccine remains among the highest public health priorities. Identifying correlates of immune protection in humans, inducing effective immunity through immunization, and overcoming virus and host diversity represent the major obstacles in vaccine development. HIV vaccine research discovery may only be at its dawn.
What have we learnt from mouse models for the study of malaria?
Authors: Wykes Michelle N. , Good Michael F.
Published: August 2009

Malaria is a serious cause of morbidity and mortality and yet a vaccine is not available. Studies have used animal models to understand the pathogenesis of disease and a large amount of data on parasite biology, immune regulation and disease processes have been gained from these studies. Moreover, these models have been used for pre‐clinical testing of various drugs and vaccines. Here, we discuss the features of various mouse models used to study the immunobiology of malaria and test pre‐clinical vaccines and conclude that animal models have a role in the study of malaria but the experimental conditions used for testing must reflect the environment of infected individuals.
Update on animal models for HIV research
Authors: Haigwood Nancy L.
Published: August 2009

Animal models for HIV research have been indispensible in fulfilling Koch's postulate and in exploring issues of viral infectivity and pathogenesis, sequence divergence, route(s) of acquisition, tissue distribution and tropism, immunogenicity and protection capacity of vaccine candidates, escape from adaptive immunity, and more. Did they fail to predict the efficacy of T‐cell vaccines in humans? This article summarizes progress and status of models to inform and complement clinical work.
Animal models of rheumatoid arthritis
Authors: Asquith Darren L. , Miller Ashley M. , McInnes Iain B. , Liew Foo Y.
Published: August 2009

Animal models have been used extensively in studies of rheumatoid arthritis pathogenesis. Despite the inherent limitations of all animal models, several rodent models have significantly progressed our understanding of the fundamental mechanisms underpinning rheumatoid arthritis and contributed to several current major advances in treatment. These models include the induced arthritis models such as collagen‐induced arthritis, collagen‐antibody‐induced arthritis, zymosan‐induced arthritis, and the methylated BSA model, and the genetically manipulated or spontaneous arthritis models such as the TNF‐α‐transgenic mouse, K/BxN mouse, and the Skg mouse. Here, we describe these animal models and discuss their advantages and limitations.

Note added after publication: For an update on this topic, please see the latest review
Acid‐Free Synthesis of Carbazoles and Carbazolequinones by Intramolecular Pd‐Catalyzed, Microwave‐Assisted Oxidative Biaryl Coupling Reactions – Efficient Syntheses of Murrayafoline A, 2‐Methoxy‐3‐methylcarbazole, and Glycozolidine
Authors: Sridharan Vellaisamy , Martín M. Antonia , Menéndez J. Carlos
Published: August 2009

A mild and efficient methodology for the synthesis of oxygenated carbazoles from diarylamines under non‐acidic conditions was developed, based on a palladium‐catalyzed, microwave‐assisted double C–H bond activation process. This new protocol was successfully applied to the synthesis of three naturally occurring carbazoles, namely murrayafoline A, 2‐methoxy‐3‐methylcarbazole, and glycozolidine. The scope of the reaction was also expanded to include the synthesis of benzo fused carbazolequinones.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Synthesis and Biological Evaluation of Novel Gramicidin S Analogues (Eur. J. Org. Chem. 25/2009)
Authors: Tuin Adriaan Willem , Palachanis Dimitrios Konstantinos , Buizert Annelies , Grotenbreg Gijsbert Marnix , Spalburg Emile , de Neeling Albert J. , Mars‐Groenendijk Roos H. , Noort Daan , van der Marel Gijsbert A. , Overkleeft Herman S. , Overhand Mark
Published: August 2009

The cover picture shows the cationic antimicrobial peptide Gramicidin S (GS, left structure), which disrupts the bacterial membrane, however with little selectivity over the erythrocytic membrane. This mode of action is explained by the amphiphilic β‐sheet structure of GS. Three new analogues of GS were designed in which one DPhe‐Pro β‐turn motif has been replaced by different sugar amino acids (1, 2 and 3 in the right structures). The solution structures of these new analogues were assessed by 1D and 2D NMR spectroscopy, which shows a slightly altered backbone conformation. The antibacterial and hemolytic activities of all analogues were also determined in this study. Details are discussed in the article by M. Overhand et al. on p. 4231 ff.