bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of TBCD and its regulatory interactor Arl2 on tubulin and microtubule integrity
Authors: Tian Guoling , Thomas Simi , Cowan Nicholas J.
Published: August 2010

Assembly of the α/β tubulin heterodimer requires the participation of a series of chaperone proteins (TBCA‐E) that function downstream of the cytosolic chaperonin (CCT) as a heterodimer assembly machine. TBCD and TBCE are also capable of acting in a reverse reaction in which they disrupt native heterodimers. Homologs of TBCA‐E exist in all eukaryotes, and the amino acid sequences of α‐ and β‐tubulin isotypes are rigidly conserved among vertebrates. However, the efficiency with which TBCD effects tubulin disruption in vivo depends on its origin: bovine (but not human) TBCD efficiently destroys tubulin and microtubules upon overexpression in cultured cells. Here we show that recombinant bovine TBCD is produced in HeLa cells as a stoichiometric cocomplex with β‐tubulin, consistent with its behavior in vitro and in vivo. In contrast, expression of human TBCD using the same host/vector system results in the generation of TBCD that is not complexed with β‐tubulin. We show that recombinant human TBCD functions indistinguishably from its nonrecombinant bovine counterpart in in vitro CCT‐driven folding reactions, in tubulin disruption reactions, and in tubulin GTPase activating protein assays in which TBCD and TBCC stimulate GTP hydrolysis by β‐tubulin at a heterodimer concentration far below that required for polymerization into microtubules. We conclude that bovine and human TBCD have functionally identical roles in de novo tubulin heterodimer assembly, and show that the inability of human TBCD to disrupt microtubule integrity upon overexpression in vivo can be overcome by siRNA‐mediated suppression of expression of the TBCD regulator Arl2 (ADP ribosylation factor‐like protein). © 2010 Wiley‐Liss, Inc.
Structure–Activity Relationships and Molecular Docking of Novel Dihydropyrimidine‐Based Mitotic Eg5 Inhibitors
Authors: Prokopcová Hana , Dallinger Doris , Uray Georg , Kaan Hung Yi Kristal , Ulaganathan Venkatasubramanian , Kozielski Frank , Laggner Christian , Kappe C. Oliver
Published: August 2010

Dihydropyrimidine‐based compounds belong to the first discovered inhibitors of the human mitotic kinesin Eg5. Although they are used by many research groups as model compounds for chemical genetics, considerably less emphasis has been placed on the improvement of this type of inhibitor, with the exception of two recent studies. Dihydropyrimidines can be divided into class I (analogues that bind in the S configuration) and class II type inhibitors, which bind in the R configuration. Herein we report the synthesis and optimization of novel class II type dihydropyrimidines using a combination of in vitro and docking techniques.
α‐Ketoheterocycles as Inhibitors of Leishmania mexicana Cysteine Protease CPB
Authors: Steert Koen , Berg Maya , Mottram Jeremy C. , Westrop Gareth D. , Coombs Graham H. , Cos Paul , Maes Louis , Joossens Jurgen , Van der Veken Pieter , Haemers Achiel , Augustyns Koen
Published: August 2010

Cysteine proteases of the papain superfamily are present in nearly all eukaryotes and also play pivotal roles in the biology of parasites. Inhibition of cysteine proteases is emerging as an important strategy to combat parasitic diseases such as sleeping sickness, Chagas disease, and leishmaniasis. Inspired by the in vivo antiparasitic activity of the vinylsulfone‐based cysteine protease inhibitors, a series of α‐ketoheterocycles were developed as reversible inhibitors of a recombinant L. mexicana cysteine protease, CPB2.8. Three isoxazoles and especially one oxadiazole compound are potent reversible inhibitors of CPB2.8; however, in vitro whole‐organism screening against a panel of protozoan parasites did not fully correlate with the observed inhibition of the cysteine protease.
Prevalence, predictors, and characteristics of off‐treatment fatigue in breast cancer survivors
Authors: Andrykowski Michael A. , Donovan Kristine A. , Laronga Christine , Jacobsen Paul B.
Published: August 2010

BACKGROUND:

Lack of consensus regarding how to identify cancer patients with significant fatigue has hampered research regarding cancer‐related fatigue (CRF).

METHODS:

Specific criteria were used to identify CRF cases in women with stage 0‐II breast cancer (BC group, n = 304). Women completed assessments before adjuvant therapy (baseline), end of adjuvant therapy (Post‐Tx), and 6 and 42 months after end of adjuvant therapy (6 and 42 Month Post‐Tx). At each, women completed a clinical interview and questionnaires assessing physical and mental health. A healthy control (HC) group with no history of BC (n = 337) completed 2 similar assessments 36 months apart.

RESULTS:

Off‐treatment CRF prevalence was 9% and 13% at the 6 and 42 Month Post‐Tx assessments, respectively. Thus, 15% of the sample evidenced off‐treatment CRF with 7% evidencing delayed onset CRF. CRF at the 6 Month Post‐Tx assessment was associated only with CRF at baseline (OR = 3.2) and Post‐Tx assessments (OR = 3.9). CRF at the 42 Month Post‐Tx assessment was associated with CRF at the Post‐Tx assessment (OR = 6.1), obesity at baseline, and several baseline measures of coping in response to fatigue. Off‐treatment CRF cases differed markedly from CRF noncases and healthy controls on a spectrum of health status indices (mean effect size >1.0 SD).

CONCLUSIONS:

Results document the prevalence of off‐treatment and delayed onset CRF, suggest the utility of a cognitive‐behavioral model of CRF, and support NCCN guidelines recommending monitoring fatigue across the cancer trajectory. Cancer 2010. © 2010 American Cancer Society.
Cognitive impairment in men with testicular cancer prior to adjuvant therapy
Authors: Wefel Jeffrey S. , Vidrine Damon J. , Veramonti Tracy L. , Meyers Christina A. , Marani Salma K. , Hoekstra Harald J. , Hoekstra‐Weebers Josette E. H. M. , Shahani Lokesh , Gritz Ellen R.
Published: August 2010

BACKGROUND:

Cognitive dysfunction experienced by individuals with cancer represents an important survivorship issue because of its potential to affect occupational, scholastic, and social activities. Whereas early efforts to characterize cognitive dysfunction primarily focused on the effects of chemotherapy, more recent evidence indicates that impairment may exist before systemic treatment. This study characterized cognitive dysfunction before adjuvant chemotherapy in a sample of men diagnosed with nonseminomatous germ cell tumors (NSGCT) of the testis.

METHODS:

Men with newly diagnosed NSGCT were recruited after orchiectomy but before adjuvant chemotherapy. Patients completed neuropsychological tests to assess attention, learning, language, executive function, and motor function. Self‐report measures of depression and anxiety were also administered. An overall cognitive function index was computed for participants. Cognitive impairment was defined as a z‐score of less than or equal to −1.5 on 2 or more tests, or a z‐score of less than or equal to −2.0 on a single test.

RESULTS:

Approximately 46% of patients exhibited cognitive impairment at the time of assessment, which is significantly greater than would be expected considering healthy population norms (binomial test: P < .0001). Patients exhibited impairments in motor function, verbal learning, and executive function much more frequently relative to normative expectations (binomial test: P < .0001).

CONCLUSIONS:

The prevalence of cognitive impairment in men with newly diagnosed NSGCT is unexpectedly high before the receipt of adjuvant chemotherapy. Efforts to track cognitive function over time and to develop effective interventions are warranted. Cancer 2011. © 2010 American Cancer Society.
Association of PAI‐1 gene polymorphism with survival and chemotherapy‐related vascular toxicity in testicular cancer
Authors: de Haas Esther C. , Zwart Nynke , Meijer Coby , Suurmeijer Albert J.H. , Meijer Karina , Guchelaar Henk‐Jan , Hoekstra Harald J. , van Leeuwen Flora E. , Sleijfer Dirk Th. , Boezen H. Marike , Gietema Jourik A.
Published: August 2010

BACKGROUND:

High Plasminogen‐Activator Inhibitor 1 (PAI‐1) expression by tumors has been associated with poor prognosis in several cancer types, and high systemic PAI‐1 levels with increased thrombosis risk. The authors investigated whether the germline 4G/5G deletion/insertion polymorphism in the PAI‐1 promoter (rs1799889), which may influence PAI‐1 expression, is associated with survival and chemotherapy‐related vascular toxicity in testicular cancer (TC).

METHODS:

Data were collected on PAI‐1 4G/5G polymorphism, survival, venous thromboembolism (VTE), and coronary heart disease (CHD) for 324 non‐seminomatous TC patients treated with platinum‐based chemotherapy. Genotypes were compared regarding survival and disease outcome. VTE and CHD incidence were compared with adjustment for cardiovascular risk factors and prothrombotic gene polymorphisms of coagulation factors II/prothrombin (G20210A) and V (G1691A).

RESULTS:

The 4G/4G variant of PAI‐1 4G/5G polymorphism shows a higher prevalence of International Germ Cell Cancer Classification (IGCCC) poor prognosis compared with 4G/5G and 5G/5G (24% vs 8% and 15%; chi‐square P = .003). In addition, the 4G/4G variant shows reduced TC‐related survival with a hazard ratio of 2.69 (95% CI, 1.26‐5.73; P = .010) for TC‐related death (adjusted for IGCCC). This is related to an increased risk for refractory disease and early relapses (odds ratio, 3.35; 95% CI, 1.48‐7.59; P = .004). PAI‐1 4G/5G polymorphism is not associated with VTE and CHD risk.

CONCLUSIONS:

The 4G/4G variant of PAI‐1 4G/5G polymorphism may be an unfavorable prognostic as well as predictive factor for response to chemotherapy in TC patients. If confirmed, it may contribute to the identification of patients with increased risk for refractory disease. Cancer 2010. © 2010 American Cancer Society.
Genetic variants in one‐carbon metabolism‐related genes contribute to NSCLC prognosis in a Chinese population
Authors: Jin Guangfu , Huang Jinlin , Hu Zhibin , Dai Juncheng , Tang Rong , Chen Yijiang , Xu Lin , Huang Xinen , Shu Yongqian , Shen Hongbing
Published: August 2010

BACKGROUND:

One‐carbon metabolism plays a critical role in DNA methylation and DNA synthesis. Variants of genes involved in one‐carbon metabolism may result in aberrant methylation and/or DNA synthesis inhibition, and ultimately modulate the initiation and progression of tumors. In this study, the authors hypothesized that polymorphisms in one‐carbon metabolism‐related genes may contribute to the prognosis of nonsmall cell lung cancer (NSCLC).

METHODS:

The authors screened 57 potentially functional single nucleotide polymorphisms (SNPs) from 11 candidate genes involved in one‐carbon metabolism and genotyped them in a cohort of 568 NSCLC patients by using Illumina Golden Gate platform. The Kaplan‐Meier method with log‐rank test and Cox proportional hazards model were used for survival analyses.

RESULTS:

Variant alleles were significantly associated with favorable survivals of NSCLC for MTR rs3768160 A>G (allelic hazards ratio [HR], 0.78; 95% confidence interval [CI], 0.62‐0.98), MTRR rs2966952 G>A (allelic HR, 0.84; 95% CI, 0.71‐0.99) and DHFR rs1650697 G>A (allelic HR, 0.83; 95% CI, 0.70‐0.99) and with unfavorable prognosis for MTHFD1 rs1950902 G>A with borderline significance (allelic HR, 1.18; 95% CI, 0.99‐1.40). In addition, the combined genotypes of these four SNPs showed a locus‐dosage effect on NSCLC survival (Ptrend = 6.9 × 10−5). In the final multivariate Cox regression model, combined genotypes based on 3 categories may be an independent prognostic factor for NSCLC with adjusted trend HR of 0.78 (95% CI, 0.66‐0.92).

CONCLUSION:

Genetic variants in one‐carbon metabolism pathway may be candidate biomarkers for NSCLC prognosis. Cancer 2010. © 2010 American Cancer Society.
Immunophenotype and intermediate‐high international prognostic index score are prognostic factors for therapy in diffuse large B‐cell lymphoma patients
Authors: Zinzani Pier Luigi , Broccoli Alessandro , Stefoni Vittorio , Musuraca Gerardo , Abruzzese Elisabetta , De Renzo Amalia , Cantonetti Maria , Bacci Francesco , Baccarani Michele , Pileri Stefano A.
Published: August 2010

BACKGROUND.

The development of gene expression profiling and tissue microarray techniques have provided more information about the heterogeneity of diffuse large B‐cell lymphoma (DLBCL), enabling categorization of DLBCL patients into 3 prognostic groups according to cell origin (but independently from the International Prognostic Index [IPI] score): germinal center (GCB), activated B‐cell (ABC), and not classified (NC) diffuse large B‐cell lymphoma. This study investigated the role of immunohistochemical discrimination between GCB and ABC&NC‐DLBCL subtypes in identifying those high‐risk patients who may benefit from a more aggressive first‐line therapeutic approach.

METHODS.

From February 2003 to August 2006, 45 newly diagnosed DLBCL patients, with IPI≥2, were considered eligible for this study: 13 had a GCB, 8 an ABC, and 24 a NC‐DLBCL. GCB patients received 6 courses of rituximab, cyclophophosphamide, doxorubicin, vinicristine, and prednisone (R‐CHOP) chemotherapy, with a subsequent, autologous stem cell transplantation in case of partial response. All ABC and NC‐DLBCL patients received 6 R‐CHOP cycles and autologous stem cell transplantation.

RESULTS.

Complete response rate for each treatment arm was 84.6% for GCB and 89.7% for ABC&NC‐DLBCL (P = .50), with a continuous complete response rate of 81.8% and 84.6%, respectively (P = .59). Projected 4‐year overall survival is 100% for GCB and 82% for ABC&NC patients (P = .12). Progression‐free survival is 77% and 79% (P = .7), respectively.

CONCLUSIONS.

The autologous stem cell transplantation consolidation in the ABC&NC‐DLBCL subtypes induced the same rate of complete response (and similar progression‐free survival rate) compared with GCB‐DLBCL. In ABC&NC‐DLBCL patients the authors observed a complete response rate of 89.7% vs. 84.6% in the GCB‐DLBCL subset, without any significant difference in progression‐free survival rate. Cancer 2010. © 2010 American Cancer Society.
Quality of surgical resection for nonsmall cell lung cancer in a US metropolitan area
Authors: Allen Jeffrey W. , Farooq Aamer , O'Brien Thomas F. , Osarogiagbon Raymond U.
Published: August 2010

BACKGROUND:

Curative treatment of early stage nonsmall cell lung cancer (NSCLC) requires good quality surgical resection (GQR). The degree of compliance with national recommendations for GQR is poorly defined. We sought to quantitatively define the degree of compliance in a consecutive series of NSCLC resections.

METHODS:

Medical records of patients who underwent curative‐intent resection for NSCLC in the Memphis, TN metropolitan area from January 1, 2004 to December 31, 2007 were retrospectively reviewed (N = 746 patients). GQR criteria were obtained from the National Comprehensive Cancer Network (NCCN), the RADIANT adjuvant study of erlotinib, and the American College of Surgeons Oncology Group (ACOSOG) Z0030 study. Factors associated with or without achievement of GQR were evaluated. Categorical variables were compared using chi‐square or Fisher exact test, and survival curves by the log‐rank test.

RESULTS:

Twenty‐three and one‐half percent of patients met GQR criteria as established by RADIANT, 8.2% by NCCN, and 0.9% by ACOSOG. The most common limiting factor in achieving GQR was inadequate lymph node sampling. The only patient factor associated with GQR was race (African‐Americans were more likely than Caucasians to have GQR per RADIANT and NCCN criteria [P = .022 and P = .0489, respectively]). There was no significant survival difference between GQR and non‐GQR patients.

CONCLUSIONS:

The vast majority of curative‐intent resections did not achieve GQR standards. The greatest deficit is in surgical sampling of mediastinal (Level 2) lymph nodes, but evaluation of Level 1 lymph nodes is also suboptimal. Interventions are needed to improve current surgical practices and achieve minimum standards for accurate staging, prognostication, and eligibility for clinical trials. Cancer 2011. © 2010 American Cancer Society.
Phase 1 clinical trials in 83 patients with pancreatic cancer
Authors: Vaklavas Christos , Tsimberidou Apostolia‐Maria , Wen Sijin , Hong David , Wheler Jennifer , Ng Chaan S. , Naing Aung , Uehara Cynthia , Wolff Robert A. , Kurzrock Razelle
Published: August 2010

BACKGROUND:

The outcomes of patients with pancreatic cancer treated on early phase clinical trials have not been systematically analyzed. The purpose of this study was to report the presenting characteristics and outcomes of patients with locally advanced or metastatic pancreatic cancer treated on phase 1 clinical trials at a single institution.

METHODS:

The authors reviewed the records of consecutive patients with metastatic pancreatic cancer who were treated in the Phase I Clinical Trials Program at The University of Texas M. D. Anderson Cancer Center from November 2004 to March 2009. Data recorded and analyzed included survival, response, and disease characteristics.

RESULTS:

Eighty‐three patients were identified. The median age was 62 years (range, 39‐81 years). Of 78 patients evaluable for response, 2 (3%) had a partial response (PR), and 10 (13%) had stable disease (SD) for ≥4 months. With a median follow‐up for survivors of 3.7 months, the median survival from presentation in the phase 1 clinic was 5.0 months (95% confidence interval [CI], 3.3‐6.2). The median overall survival from diagnosis was 22.1 months (95% CI, 17.9‐26.5). The median time to treatment failure was 1.5 months (95% CI, 1.3‐1.8). Independent factors associated with lower rates of PR/SD were liver metastases (P = .001) and performance status >0 (P = .01). Independent factors associated with shorter survival were liver metastases (P = .007), low calcium level (P = .015), and elevated CEA level (>6 ng/mL) (P = .005).

CONCLUSIONS:

Our results suggest that phase 1 clinical trials offer a reasonable therapeutic approach for patients with advanced pancreatic cancer. Cancer 2011. © 2010 American Cancer Society.
Estimating recurrences prevented from using trastuzumab in HER‐2/neu–positive adjuvant breast cancer in the United States
Authors: Danese Mark D. , Lalla Deepa , Brammer Melissa , Doan Quan , Knopf Kevin
Published: August 2010

BACKGROUND.

Breast cancer recurrence is associated with significant morbidity, mortality, and cost. Patients with early stage HER2+ tumors are at increased risk of recurrence. The use of trastuzumab for these patients has been shown to reduce recurrences and improve overall survival.

METHODS.

A Monte Carlo simulation was conducted based on Surveillance, Epidemiology, and End Results incidence rates for 2005, United States Census data for 2005, and the results of key trials of the adjuvant use of trastuzumab. Patients included in this analysis had incident, HER2+, stage I to III breast cancer. The number of recurrences that could be prevented with trastuzumab, the cardiac adverse events that might occur, and the associated cost savings were estimated.

RESULTS.

Approximately 31,200 women had HER2+ breast cancer in 2005, of whom 7298 would have had a recurrence over the subsequent 5 years despite standard of care adjuvant treatment. If trastuzumab were added to their regimen, 2791 women might have avoided recurrence, and 948 may have had an asymptomatic or symptomatic cardiac adverse event, for a ratio of expected recurrences to cardiac adverse events of 3.2 (95% confidence interval, 1.5‐5.9). In economic terms, avoidance of future breast cancer recurrences was associated with lifetime reduction in future direct and indirect costs on the order of $240 million to $1.7 billion.

CONCLUSIONS.

On the basis of the simulation results, targeting HER2+ tumors with trastuzumab in the adjuvant setting should prevent a significant number of women from recurrence events, with important outcomes for patients, physicians, payers, and society. Cancer 2010. © 2010 American Cancer Society.
Defining the course and prognosis of adults with acute lymphocytic leukemia in first salvage after induction failure or short first remission duration
Authors: Kantarjian Hagop M. , Thomas Deborah , Ravandi Farhad , Faderl Stefan , Jabbour Elias , Garcia‐Manero Guillermo , Pierce Sherry , Shan Jianquin , Cortes Jorge , O'Brien Susan
Published: August 2010

BACKGROUND:

Results from salvage therapy in adult patients with acute lymphocytic leukemia (ALL) are wide‐ranging and depend on several disease and patient characteristics. The objectives of this study were to define the prognosis for adult patients with ALL after first salvage through multivariate analyses of patient and disease characteristics.

METHODS:

Adults with ALL who had primary resistance to frontline therapy or who had a disease recurrence after a first complete response (CR) duration <1 year were analyzed. Multivariate analyses for subsequent CR and survival were conducted.

RESULTS:

Seventy‐five of 245 patients (31%) achieved CR. The median CR duration was 5 months, the median survival was 4.7 months. In multivariate analysis, independent poor prognostic factors for not achieving CR were age >55 years, bone marrow blasts ≥20%, and platelet count <75 × 109/L. Variables that were associated independently with shorter survival were age >55 years, bone marrow blasts ≥20%, platelet count <75 × 109/L, albumin level <3 g/L, and lactic dehydrogenase level ≥1000 IU/L. Patients who had ≥3 of the 5 adverse factors (45%) had a median survival of 2 to 3 months and CR rates of 8% to 15%. Achieving CR was associated independently with improved survival in a landmark multivariate analysis (P< .0001; hazard ratio, 0.40; 95% confidence interval, 0.03‐0.72).

CONCLUSIONS:

The current analyses identified a subset of adults patients ALL in first salvage for whom standard therapies were associated with an extremely poor outcome. The results also confirmed the importance of achieving CR to attain improved survival. Cancer 2010. © 2010 American Cancer Society.
The expanding melanoma burden in California hispanics
Authors: Pollitt Ricardo A. , Clarke Christina A. , Swetter Susan M. , Peng David H. , Zadnick John , Cockburn Myles
Published: August 2010

BACKGROUND:

The incidence patterns and socioeconomic distribution of cutaneous melanoma among Hispanics are poorly understood.

METHODS:

The authors obtained population‐based incidence data for all Hispanic and non‐Hispanic white (NHW) patients who were diagnosed with invasive cutaneous melanoma from 1988 to 2007 in California. By using a neighborhood‐level measure of socioeconomic status (SES), the variables investigated included incidence, thickness at diagnosis, histologic subtype, anatomic site, and the relative risk (RR) for thicker (>2 mm) versus thinner (≤2 mm) tumors at diagnosis for groups categorized by SES.

RESULTS:

Age‐adjusted melanoma incidence rates per million were higher in NHWs (P < .0001), and tumor thickness at diagnosis was greater in Hispanics (P < .0001). Sixty‐one percent of melanomas in NHWs occurred in the High SES group. Among Hispanics, only 35% occurred in the High SES group; and 22% occurred in the Low SES group. Lower SES was associated with thicker tumors (P < .0001); this association was stronger in Hispanics. The RR of thicker tumors versus thinner tumors (≤2 mm) in the Low SES group versus the High SES group was 1.48 (95% confidence interval [CI], 1.37‐1.61) for NHW men and 2.18 (95% CI, 1.73‐2.74) for Hispanic men. Patients with lower SES had less of the superficial spreading melanoma subtype (especially among Hispanic men) and more of the nodular melanoma subtype. Leg/hip melanomas were associated with higher SES in NHW men but with lower SES in Hispanic men.

CONCLUSIONS:

The socioeconomic distribution of melanoma incidence and tumor thickness differed substantially between Hispanic and NHW Californians, particularly among men. Melanoma prevention efforts targeted to lower SES Hispanics and increased physician awareness of melanoma patterns among Hispanics are needed. Cancer 2011. © 2010 American Cancer Society.
Toward curative treatment of peritoneal carcinomatosis from nonovarian origin by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy
Authors: Glehen Olivier , Gilly François N. , Boutitie Florent , Bereder Jean M. , Quenet François , Sideris Lucas , Mansvelt Baudouin , Lorimier Gérard , Msika Simon , Elias Dominique
Published: August 2010

BACKGROUND:

Peritoneal carcinomatosis (PC) from nonovarian malignancies long has been regarded as a terminal disease. Over the past decade, new locoregional therapeutic approaches combining cytoreductive surgery with perioperative intraperitoneal chemotherapy (PIC) have evolved that have demonstrated improved survival.

METHODS:

A retrospective, multicenter cohort study was performed in French‐speaking institutions to evaluate toxicity and principal prognostic factors after cytoreductive surgery and PIC (hyperthermic intraperitoneal chemotherapy [HIPEC] and/or early postoperative intraperitoneal chemotherapy [EPIC]) for PC from nongynecologic malignancies.

RESULTS:

The study included 1290 patients from 25 institutions who underwent 1344 procedures between February 1989 and December 2007. HIPEC was performed in 1154 procedures. The principal origins of PC were colorectal adenocarcinoma (N = 523), pseudomyxoma peritonei (N = 301), gastric adenocarcinoma (N = 159), peritoneal mesothelioma (N = 88), and appendiceal adenocarcinoma (N = 50). The overall morbidity and mortality rates were 33.6% and 4.1%, respectively. In multivariate analysis, patient age, the extent of PC, and institutional experience had a significant influence on toxicity. The overall median survival was 34 months; and the median survival was 30 months for patients with colorectal PC, not reached for patients with pseudomyxoma peritonei, 9 months for patients with gastric PC, 41 months for patients with peritoneal mesothelioma, and 77 months for patients with PC from appendiceal adenocarcinoma. Independent prognostic indicators in multivariate analysis were institution, origin of PC, completeness of cytoreductive surgery, extent of carcinomatosis, and lymph node involvement.

CONCLUSIONS:

A therapeutic approach that combined cytoreductive surgery with PIC was able to achieve long‐term survival in a selected group of patients who had PC of nonovarian origin and had acceptable morbidity and mortality. The current results indicated that this treatment should be centralized to institutions with expertise in the management of PC. Cancer 2010. © 2010 American Cancer Society.
Predictors of competing mortality in early breast cancer
Authors: Mell Loren K. , Jeong Jong‐Hyeon , Nichols Michael A. , Polite Blase N. , Weichselbaum Ralph R. , Chmura Steven J.
Published: August 2010

BACKGROUND:

Death in the absence of disease recurrence (competing mortality) is an important determinant of disease‐free survival (DFS) in early breast cancer. The authors sought to identify predictors of this event using competing risks modeling.

METHODS:

A cohort study was made of 1231 consecutive women with stage I to II invasive breast cancer diagnosed between 1986 and 2004, treated with breast conservation therapy. Median follow‐up was 82 months. The authors used a parametric competing risks regression model to analyze factors associated with the cumulative incidence of competing mortality. They generated a risk score from the model coefficient estimates and stratified patients according to low and high risk score for analysis.

RESULTS:

Ten‐year DFS was 69.7% (95% confidence interval [CI], 66.2%‐72.9%). The 10‐year cumulative incidence of locoregional recurrence (LRR) was 4.4% (95% CI, 3.0%‐5.8%), distant recurrence was 7.1% (95% CI, 5.4%‐8.9%), and competing mortality was 18.7% (95% CI, 15.9%‐21.6%). On multivariate analysis, competing mortality was associated with increasing age (hazard ratio [HR], 1.83 per 10 years; 95% CI, 1.58‐2.12), black race (HR, 1.71; 95% CI, 1.17‐2.51), and comorbid disease (HR, 1.93, 95% CI, 1.40‐2.65). Ten‐year cumulative incidences of competing mortality, locoregional recurrence, and distant recurrence for patients at low (n = 638) versus high (n = 593) risk of competing mortality were 7.2% versus 30.6% (P< .001), 4.4% versus 4.4% (P= .97), and 8.6% versus 5.6% (P= .12), respectively.

CONCLUSIONS:

Competing mortality is an important event influencing 10‐year DFS in early breast cancer and is associated with increasing age, black race, and comorbid disease. Stratifying patients according to competing mortality risk may be useful in designing clinical trials. Cancer 2010. © 2010 American Cancer Society.
Clinical significance of regulatory T cells and CD8+ effector populations in patients with human endometrial carcinoma
Authors: Chang Wen‐Chun , Li Chao‐Hsu , Huang Su‐Cheng , Chang Daw‐Yuan , Chou Li‐Yun , Sheu Bor‐Ching
Published: August 2010

BACKGROUND:

A study was carried out to determine the functional attributes of CD4+ CD25+ regulatory T cells in cancer progression by suppressing antitumor immunity.

METHODS:

Triple‐color flow cytometry was used to study the phenotype expression of CD4+ CD25+ regulatory T cells and CD8+ T cells in the peripheral blood lymphocytes (PBLs) and tumor‐infiltrating lymphocytes (TILs) of 57 cases of stage I to IV endometrial carcinoma. The expression of T cell subsets was correlated with clinical prognostic parameters.

RESULTS:

The prevalence of CD4+ CD25+ T cells was significantly higher in the TILs than PBLs. The expression of CD4+ CD25+ regulatory T cells in cancer milieu correlated with the tumor grade, stage, and myometrium invasion. The expression of FOXP3 and GITR in CD4+ CD25+ regulatory T cells was lower in PBLs than TILs. Most tumor‐infiltrating CD8+ T cells were CD28− CD45RA− CD45RO+ CCR7−, suggesting good terminal differentiation. Most of them had an activated role with CD69+ CD103+ CD152+. Functionally, both granzyme B and perforin were scarcely expressed in peripheral regulatory T cells but were highly expressed in peripheral regulatory T cells in the tumor microenvironment. In contrast, CD8+ cytotoxic T cells derived from PBLs expressed both granzyme B and perforin, and at significantly higher levels than in TILs. Further functional assays demonstrated that Th1 cytokines and cytotoxic molecules can be synchronously up‐regulated in CD8+ cytotoxic T cells.

CONCLUSIONS:

Regulatory T cells in the tumor microenvironment may abrogate CD8+ T cell cytotoxicity in a granzyme B‐ and perforin‐dependent conduit. Decreases in both Th1 cytokines and cytotoxic enzymes are relevant for regulatory T cell‐mediated restraint of tumor clearance in vivo. Of clinical significance, the expression of regulatory T cells in TILs may mediate T cell immune repression within cancer milieu and thus greatly correlate with cancer progression. Cancer 2010. © 2010 American Cancer Society.
Prognostic factors and long‐term outcomes of childhood nasopharyngeal carcinoma
Authors: Cheuk Daniel Ka Leung , Billups Catherine A. , Martin Michael G. , Roland Cynthia R. , Ribeiro Raul C. , Krasin Matthew J. , Rodriguez‐Galindo Carlos
Published: August 2010

BACKGROUND:

The authors studied the survival and long‐term morbidities of children with nasopharyngeal carcinoma (NPC).

METHODS:

This was a retrospective review of children with NPC who were treated at St. Jude Children's Research Hospital between 1961 and 2004. Prognostic factors and long term effects of therapy were analyzed.

RESULTS:

Fifty‐nine patients (median age, 14.1 years) were identified. Most were male (66.1%) and black (54.2%) and had lymphoepithelioma (93.2%). Thirty‐five patients had stage IV disease (59.3%), 20 patients had stage III disease (33.9%), and 4 patients had stage II disease (6.8%). All patients received radiotherapy (RT) to the primary tumor, and most received cervical RT (98.3%) and chemotherapy (88.1%). The 15‐year survival and event‐free survival (EFS) rates were 67.2% ± 7.5% and 63.5% ± 7.8%, respectively. Five patients (8.5%) developed subsequent malignancies 8.6 to 27 years after NPC diagnosis. EFS was improved in patients who were diagnosed after 1980 (74.8% ± 10% vs 45.5% ± 10.1%; P = .031), in patients who had stage III disease compared with patients who had stage IV disease (79.3% ± 9.6% vs 56.2% ± 11.8%; P = .049), in patients who received cisplatin (81% ± 10.7% vs 45.8% ± 9.7%; P = .013), and in patients who received ≥50 grays of RT (71.4% ± 9.3% vs 43.8% ± 11.6%; P = .048). White patients had higher distant failure rates than black patients (41.7% ± 10.4% vs 15.6 ± 6.5%; P = .045). The 15‐year cumulative incidence (CI) of any morbidity was 83.7% ± 5.4%, the CI of sensorineural hearing loss was 52.9% ± 6.7%, the CI of primary hypothyroidism was 42.7% ± 6.6%, and the CI of growth hormone deficiency (GHD) was 14.1% ± 4.7%. Dose‐response relations were observed between the RT dose and primary hypothyroidism and GHD.

CONCLUSIONS:

The outcome of children with NPC improved over the past 4 decades with the use of cisplatin‐based chemotherapy and higher RT doses. However, many survivors had long‐term treatment‐related morbidities. Cancer 2011. © 2010 American Cancer Society.
Biologic and immunologic effects of preoperative trastuzumab for ductal carcinoma in situ of the breast
Authors: Kuerer Henry M. , Buzdar Aman U. , Mittendorf Elizabeth A. , Esteva Francisco J. , Lucci Anthony , Vence Luis M. , Radvanyi Laszlo , Meric‐Bernstam Funda , Hunt Kelly K. , Symmans William Fraser
Published: August 2010

BACKGROUND:

Through this study, the authors sought to investigate the biologic and immunologic effects of preoperative trastuzumab in patients with ductal carcinoma in situ (DCIS) of the breast.

METHODS:

Patients with DCIS were enrolled in this open‐label phase 2 trial and tested for HER2. Trastuzumab was given by intravenous infusion (8 mg/kg). The patients then had surgery 14 to 28 days after treatment. Tissue and peripheral blood samples were obtained before therapy and at the time of surgery to examine residual disease and immunologic response.

RESULTS:

Median age of the 69 enrolled patients was 53 years, mean mammographic size of the DCIS lesions was 5.2 ± 1.2 cm, and 24 patients (35%) were found to have HER2 overexpression/amplification (12 received trastuzumab and 12 untreated patients provided tissue for blinded, controlled biomarker analyses). No overt histologic evidence of response was noted. No significant change in mean pretherapy staining for Ki‐67 (44.3 ± 3.4%) and cleaved caspase‐3 (2.6 ± 0.8%) was noted when surgical specimens from drug‐treated patient samples were compared with those not treated. Trastuzumab significantly augmented antibody‐dependent cell mediated cytotoxicity (ADCC) in 100% of patients; this was demonstrated to be mediated through CD56+ degranulating natural killer cells (P < .01). One patient developed a significant anti‐HER2 humoral CD4 T‐cell response.

CONCLUSIONS:

Single‐dose monotherapy with trastuzumab for patients with HER2‐positive DCIS does not result in significant, clinically overt, histologic, antiproliferative, or apoptotic changes, but does result in the ability to mount ADCC mediated through natural killer cells and may also induce T‐cell dependent humoral immunity. Further studies of trastuzumab for DCIS appear warranted. Cancer 2011. © 2010 American Cancer Society.
Increasing incidence of rectal cancer in patients aged younger than 40 years
Authors: Meyer Joshua E. , Narang Tarun , Schnoll‐Sussman Felice H. , Pochapin Mark B. , Christos Paul J. , Sherr David L.
Published: August 2010

BACKGROUND:

The incidence of rectal cancer in the United States in young patients is considered to be low. Underestimating this incidence may result in a failure to diagnose younger patients with rectal cancer in a timely manner.

METHODS:

The authors conducted a retrospective cohort study using Surveillance, Epidemiology, and End Results (SEER) cancer registry data. A total of 7661 patients with colon, rectal, and rectosigmoid cancer who were diagnosed at age <40 years were identified between 1973 and 2005. The change in incidence over time for colon and rectal/rectosigmoid cancer was calculated and the annual percent change for anatomic subsites of colorectal cancer compared.

RESULTS:

SEER data demonstrated an increase in the incidence of rectal cancer without any increase in colon cancer (annual percent change of 2.6% vs −0.2%). The difference was statistically significant and extended to rectosigmoid cancer, but not cancer of the sigmoid colon or descending colon (annual percent change of 2.2% vs 0.4% and −2.8%, respectively). Joinpoint analysis of the slope of the curve of rectal and rectosigmoid cancer incidence identified the beginning of the increase to be 1984. All races and both sexes demonstrated similar statistically significant increases in the incidence of rectal and rectosigmoid cancer.

CONCLUSIONS:

The incidence of rectal and rectosigmoid cancer appears to be increasing in patients aged <40 years. Patients presenting with rectal bleeding or other alarming signs or symptoms should be evaluated with this finding in mind. Cancer 2010. © 2010 American Cancer Society.
Does the progression‐free interval after primary chemotherapy predict survival after salvage chemotherapy in advanced and recurrent endometrial cancer?
Authors: Moore Kathleen N. , Tian Chunqiao , McMeekin D. Scott , Thigpen J. Tate , Randall Marcus E. , Gallion Holly H.
Published: August 2010

BACKGROUND:

This study evaluated whether progression‐free interval (PFI) following primary chemotherapy (PCT) was predictive of overall survival (OS) after second‐line chemotherapy in advanced/recurrent endometrial cancer (EC).

METHODS:

This is a pooled analysis of patients who recurred after PCT and were treated with second‐line chemotherapy on Gynecologic Oncology Group trials. PFI‐1 measured from initiation of PCT to recurrence or treatment‐free interval (TFI) measured from completion of PCT to initiation of second‐line chemotherapy was evaluated in relation to clinical outcomes.

RESULTS:

A total of 586 patients treated on 5 phase 3 PCT protocols were included. Baseline factors in primary setting associated with clinical outcome after PCT were also predictive of OS after second‐line chemotherapy, including race, Gynecologic Oncology Group performance status, grade, and prior radiation therapy (P< .01). PFI‐1 was the most significant factor predictive of survival after second‐line chemotherapy, with a 30% reduction in the risk of death for PFI‐1 >6 months compared with ≤6 months (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.59‐0.84 [P< .0001]) and median OS after second‐line chemotherapy of 10 versus 5 months. A total of 275 patients treated on 9 phase 2 second‐line chemotherapy protocols were also evaluated, and TFI >3 months was associated with a 25% reduction in the risk of death (HR, 0.75; 95% CI, 0.57‐0.97 [P= .030]) and median OS after second‐line chemotherapy of 10 versus 7 months compared with TFI ≤3 months. The tumor response to second‐line chemotherapy was 9.6% versus 5.8%; the difference was not statistically significant.

CONCLUSIONS:

Time to recurrence after PCT is predictive of survival after recurrence in advanced/recurrent EC. However, there is no evidence that this variable can be used in selecting salvage chemotherapy. Cancer 2010. © 2010 American Cancer Society.
MicroRNA‐205–directed transcriptional activation of tumor suppressor genes in prostate cancer
Authors: Majid Shahana , Dar Altaf A. , Saini Sharanjot , Yamamura Soichiro , Hirata Hiroshi , Tanaka Yuichiro , Deng Guoren , Dahiya Rajvir
Published: August 2010

BACKGROUND:

MicroRNAs (miRNAs) are small noncoding RNAs that regulate the expression of approximately 60% of all human genes. They play important roles in numerous cellular processes, including development, proliferation, and apoptosis. Currently, it is believed that miRNAs elicit their effect by silencing the expression of target genes. In this study, the authors demonstrated that miRNA‐205 (miR‐205) induced the expression the interleukin (IL) tumor suppressor genes IL24 and IL32 by targeting specific sites in their promoters.

METHODS:

The methods used in this study included transfection of small RNAs; quantitative real‐time polymerase chain reaction; in situ hybridization; fluorescence‐labeled in situ hybridization; cell cycle, apoptosis, cell viability, migratory, clonability, and invasion assays; immunoblotting; and luciferase reporter, nuclear run‐on, and chromatin immunoprecipitation assays.

RESULTS:

The results revealed that miR‐205 was silenced in prostate cancer. Its re‐expression induced apoptosis and cell cycle arrest. It also impaired cell growth, migration, clonability, and invasiveness of prostate cancer cells. Micro‐RNA‐205 induced the expression of tumor suppressor genes IL24 and IL32 at both the messenger RNA and protein levels. The induction of in vitro transcription and enrichment of markers for transcriptionally active promoters in the IL24 and IL32 genes was observed in response to miR‐205.

CONCLUSIONS:

In this study, a new function for miR‐205 was identified that specifically activated tumor suppressor genes by targeting specific sites in their promoters. These results corroborate a newly identified function that miRNAs have in regulating gene expression at the transcriptional level. The specific activation of tumor suppressor genes (eg, IL24, IL32) or other dysregulated genes by miRNA may contribute to a novel therapeutic approach for the treatment of prostate cancer. Cancer 2010. © 2010 American Cancer Society.
Screening for major depression in cancer outpatients
Authors: Thekkumpurath Parvez , Walker Jane , Butcher Isabella , Hodges Laura , Kleiboer Annet , O'Connor Mark , Wall Lucy , Murray Gordon , Kroenke Kurt , Sharpe Michael
Published: August 2010

BACKGROUND:

Systematic screening for depression has been recommended for patients who have medical conditions like cancer. The 9‐item Patient Health Questionnaire (PHQ‐9) is becoming widely used, but its diagnostic accuracy has not yet been tested in a cancer patient population. In this article, the authors report on the performance of the PHQ‐9 as a screening instrument for major depressive disorder (MDD) in patients with cancer.

METHODS:

Data obtained from a depression screening service for patients who were attending clinics of a Regional Cancer Centre in Edinburgh, United Kingdom were used. Patients had completed both the PHQ‐9 and a 2‐stage procedure to identify cases of MDD. Performance of the PHQ‐9 in identifying cases of MDD was determined using receiver operating characteristic (ROC) analysis.

RESULTS:

Data were available on 4264 patients. When scored as a continuous measure, the PHQ‐9 performed well with an area under the ROC curve of 0.94 (95% confidence interval [CI], 0.93‐0.95). A cutoff score of ≥8 provided a sensitivity of 93% (95% CI, 89%‐95%), a specificity of 81% (95% CI, 80%‐82%), a positive predictive value (PPV) of 25%, and a negative predictive value (NPV) of 99% and could be considered optimum in a screening context. The PHQ‐9 did not perform as well when it was scored using an algorithm with a sensitivity of 56% (95% CI, 55%‐57%), a specificity of 96% (95% CI, 95%‐97%), a PPV of 52%, and an NPV of 97%.

CONCLUSIONS:

The PHQ‐9 scored as a continuous measure with a cutoff score of ≥8 performed well in identifying MDD in cancer patients and should be considered as a screening instrument in this population. Cancer 2011. © 2010 American Cancer Society.
How does initial treatment choice affect short‐term and long‐term costs for clinically localized prostate cancer?
Authors: Snyder Claire F. , Frick Kevin D. , Blackford Amanda L. , Herbert Robert J. , Neville Bridget A. , Carducci Michael A. , Earle Craig C.
Published: August 2010

BACKGROUND.

Data regarding costs of prostate cancer treatment are scarce. This study investigates how initial treatment choice affects short‐term and long‐term costs.

METHODS.

This retrospective, longitudinal cohort study followed prostate‐cancer cases diagnosed in 2000 for 5 years using the Surveillance, Epidemiology, and End Results (SEER)‐Medicare database. Men age ≥66 years, in Medicare fee for service, diagnosed with clinically localized prostate cancer in 2000 while residing in a SEER region, were matched to noncancer controls using age, sex, race, region, comorbidity, and survival. On the basis of treatment received during the first 9 months postdiagnosis, patients were assigned to watchful waiting, radiation, hormonal therapy, hormonal + radiation, and surgery (may have received other treatments). Incremental costs for prostate cancer were the difference in costs for prostate cancer cases versus matched controls. Costs were divided into initial treatment (months −1 to 12), long‐term (each 12 months thereafter), and total (months −1 to 60). Sensitivity analyses excluded the last 12 months of life.

RESULTS.

A total of 13,769 prostate‐cancer cases were matched to 13,769 noncancer controls. Watchful waiting had the lowest initial treatment ($4270) and 5‐year total costs ($9130). Initial treatment costs were highest for hormonal + radiation ($17,474) and surgery ($15,197). At $26,896, 5‐year total costs were highest for hormonal therapy only followed by hormonal + radiation ($25,097) and surgery ($19,214). After excluding the last 12 months of life, total costs were highest for hormonal + radiation ($23,488) and hormonal therapy ($23,199).

CONCLUSIONS.

Patterns of costs vary widely based on initial treatment. These data can inform patients and clinicians considering treatment options and policy makers interested in patterns of costs. Cancer 2010. © 2010 American Cancer Society.
Putative tumor suppressor miR‐145 inhibits colon cancer cell growth by targeting oncogene friend leukemia virus integration 1 gene
Authors: Zhang Jianjun , Guo Haiyan , Zhang He , Wang Haibo , Qian Guanxiang , Fan Xianqun , Hoffman Andrew R. , Hu Ji‐Fan , Ge Shengfang
Published: August 2010

BACKGROUND:

Tumor suppressor microRNA miR‐145 is commonly down‐regulated in colon carcinoma tissues, but its specific role in tumors remains unknown.

METHODS:

In this study, the authors identified the Friend leukemia virus integration 1 gene (FLI1) as a novel target of miR‐145. FLI1 is involved in t(11;22)(q24:q12) reciprocal chromosomal translocation in Ewing sarcoma, and its expression appears to be associated with biologically more aggressive tumors.

RESULTS:

The authors demonstrated that miR‐145 targets a putative microRNA regulatory element in the 3′‐untranslated region (UTR) of FLI1, and its abundance is reversely associated with FLI1 expression in colon cancer tissues and cell lines. By using a luciferase/FLI1 3′‐UTR reporter system, they found that miR‐145 down‐regulated the reporter activity, and this down‐regulation was reversed by anti–miR‐145. Mutation of the miR‐145 microRNA regulatory element sequence in the FLI1 3′‐UTR abolished the activity of miR‐145. miR‐145 decreased FLI1 protein but not FLI1 mRNA, suggesting a mechanism of translational regulation. Furthermore, the authors demonstrated that miR‐145 inhibited cell proliferation and sensitized LS174T cells to 5‐fluorouracil–induced apoptosis.

CONCLUSIONS:

Taken together, these results suggest that miR‐145 functions as a tumor suppressor by down‐regulating oncogenic FLI1 in colon cancer. Cancer 2011. © 2010 American Cancer Society.