bluuebunny/crossref_metadata_2025 huggingface dataset:
A polymorphism at the 3'-UTR region of the aromatase gene defines a subgroup of postmenopausal breast cancer patients with poor response to neoadjuvant letrozole
Authors: Garcia-Casado Zaida , Guerrero-Zotano Angel , Llombart-Cussac Antonio , Calatrava Ana , Fernandez-Serra Antonio , Ruiz-Simon Amparo , Gavila Joaquin , Climent Miguel A , Almenar Sergio , Cervera-Deval Jose , Campos Josefina , Albaladejo Carlos Vazquez , Llombart-Bosch Antonio , Guillem Vicente , Lopez-Guerrero Jose A
Published: February 2010

Background

Aromatase (CYP19A1) regulates estrogen biosynthesis. Polymorphisms inCYP19A1have been related to the pathogenesis of breast cancer (BC). Inhibition of aromatase with letrozole constitutes the best option for treating estrogen-dependent BC in postmenopausal women. We evaluate a series of polymorphisms ofCYP19A1and their effect on response to neoadjuvant letrozole in early BC.

Methods

We analyzed 95 consecutive postmenopausal women with stage II-III ER/PgR [+] BC treated with neoadjuvant letrozole. Response to treatment was measured by radiology at 4thmonth by World Health Organization (WHO) criteria. Three polymorphisms ofCYP19A1, one in exon 7 (rs700519) and two in the 3'-UTR region (rs10046 and rs4646) were evaluated on DNA obtained from peripheral blood.

Results

Thirty-five women (36.8%) achieved a radiological response to letrozole. The histopathological and immunohistochemical parameters, including hormonal receptor status, were not associated with the response to letrozole. Only the genetic variants (AC/AA) of the rs4646 polymorphism were associated with poor response to letrozole (p = 0.03). Eighteen patients (18.9%) reported a progression of the disease. Those patients carrying the genetic variants (AC/AA) of rs4646 presented a lower progression-free survival than the patients homozygous for the reference variant (p = 0.0686). This effect was especially significant in the group of elderly patients not operated after letrozole induction (p = 0.009).

Conclusions

Our study reveals that the rs4646 polymorphism identifies a subgroup of stage II-III ER/PgR [+] BC patients with poor response to neoadjuvant letrozole and poor prognosis. Testing for the rs4646 polymorphism could be a useful tool in order to orientate the treatment in elderly BC patients.
Newly diagnosed exudative age-related macular degeneration treated with pegaptanib sodium monotherapy in US community-based practices: medical chart review study
Authors: Weber Pamela A , Wirostko Barbara M , Xu Xiao , Goss Thomas F , Zlateva Gergana
Published: February 2010

Background

Studies have shown that early detection and treatment of neovascular age-related macular degeneration (NV-AMD) can delay vision loss and blindness. The objective of this study was to evaluate the efficacy/safety of intravitreal pegaptanib sodium monotherapy in treatment-naïve subjects with newly diagnosed NV-AMD and to gain insight into characteristics of lesions treated in community-based practices.

Methods

From seven private US practices, charts were retrospectively reviewed on 73 subjects with previously untreated subfoveal choroidal NV-AMD treated with their first dose of pegaptanib monotherapy on/after 4/1/2005 through 6/5/2006, receiving ≥4 treatments at 6-week intervals over 21 weeks. Primary endpoint: mean visual acuity (VA) change from baseline to month 6.

Results

75% of lesions were occult, and 82% were subfoveal. From baseline to month 6, mean VA change was -0.68 lines; 58% and 16% gained ≥0 and ≥3 lines of VA, and 70% were responders (<3 lines lost). In 35 subjects with early disease, 80% were responders with a mean gain of 0.46 lines.

Conclusion

Pegaptanib is effective in real-world patients with treatment-naïve NV-AMD in uncontrolled community-based retina practices.
Warburg effect in chemosensitivity: Targeting lactate dehydrogenase-A re-sensitizes Taxol-resistant cancer cells to Taxol
Authors: Zhou Ming , Zhao Yuhua , Ding Yan , Liu Hao , Liu Zixing , Fodstad Oystein , Riker Adam I , Kamarajugadda Sushama , Lu Jianrong , Owen Laurie B , Ledoux Susan P , Tan Ming
Published: February 2010

Background

Taxol is one of the most effective chemotherapeutic agents for the treatment of patients with breast cancer. Despite impressive clinical responses initially, the majority of patients eventually develop resistance to Taxol. Lactate dehydrogenase-A (LDH-A) is one of the predominant isoforms of LDH expressed in breast tissue, which controls the conversion of pyruvate to lactate and plays an important role in glucose metabolism. In this study we investigated the role of LDH-A in mediating Taxol resistance in human breast cancer cells.

Results

Taxol-resistant subclones, derived from the cancer cell line MDA-MB-435, sustained continuous growth in high concentrations of Taxol while the Taxol-sensitive cells could not. The increased expression and activity of LDH-A were detected in Taxol-resistant cells when compared with their parental cells. The downregulation of LDH-A by siRNA significantly increased the sensitivity of Taxol-resistant cells to Taxol. A higher sensitivity to the specific LDH inhibitor, oxamate, was found in the Taxol-resistant cells. Furthermore, treating cells with the combination of Taxol and oxamate showed a synergistical inhibitory effect on Taxol-resistant breast cancer cells by promoting apoptosis in these cells.

Conclusion

LDH-A plays an important role in Taxol resistance and inhibition of LDH-A re-sensitizes Taxol-resistant cells to Taxol. This supports that Warburg effect is a property of Taxol resistant cancer cells and may play an important role in the development of Taxol resistance. To our knowledge, this is the first report showing that the increased expression of LDH-A plays an important role in Taxol resistance of human breast cancer cells. This study provides valuable information for the future development and use of targeted therapies, such as oxamate, for the treatment of patients with Taxol-resistant breast cancer.
Decreased NPC1L1 expression in the liver from Chinese female gallstone patients
Authors: Cui Wei , Jiang Zhao-Yan , Cai Qu , Zhang Ru-Yuan , Wu Wei-Ze , Wang Jian-Cheng , Fei Jian , Zhang Sheng-Dao , Han Tian-Quan
Published: February 2010

Background

Cholesterol gallstone disease is a very common disease in both industrialized and developing countries. Many studies have found that cholesterol gallstones are more common in women than men. The molecular mechanisms underlying the relationship between female gallstone disease and hepatic sterol transporters are still undergoing definition and have not been evaluated in humans.

Aims

The aim of this study is to probe for underlying hepatic molecular defects associated with development of gallstones in female.

Methods/Results

Fifty-seven nonobese, normolipidemic Chinese female gallstone patients (GS) were investigated with 12 age- and body mass index-matched female gallstone-free controls (GSF). The bile from the female GS had higher cholesterol saturation than that from the female GSF. The hepatic NPC1L1 mRNA levels were lower in female GS, correlated with SREBP2 mRNA. NPC1L1 downregulation was confirmed at protein levels. Consistently, immunohistochemistry showed decreased NPC1L1 expression in female GS.

Conclusions

The decreased hepatic NPC1L1 levels in female GS might indicate a downregulated reabsorption of biliary cholesterol in the liver, which, in turn, leads to the cholesterol supersaturation of bile. Our data are consistent with the possibility that hepatic NPC1L1 may be mediated by SREBP2.
Effect of chronic treatment with Rosiglitazone on Leydig cell steroidogenesis in rats: In vivo and ex vivo studies
Authors: Couto Janaína A , Saraiva Karina LA , Barros Cleiton D , Udrisar Daniel P , Peixoto Christina A , Vieira Juliany SB César , Lima Maria C , Galdino Suely L , Pitta Ivan R , Wanderley Maria I
Published: February 2010

Background

The present study was designed to examine the effect of chronic treatment with rosiglitazone - thiazolidinedione used in the treatment of type 2 diabetes mellitus for its insulin sensitizing effects - on the Leydig cell steroidogenic capacity and expression of the steroidogenic acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (P450scc) in normal adult rats.

Methods

Twelve adult male Wistar rats were treated with rosiglitazone (5 mg/kg) administered by gavage for 15 days. Twelve control animals were treated with the vehicle. The ability of rosiglitazone to directly affect the production of testosterone by Leydig cells ex vivo was evaluated using isolated Leydig cells from rosiglitazone-treated rats. Testosterone production was induced either by activators of the cAMP/PKA pathway (hCG and dbcAMP) or substrates of steroidogenesis [22(R)-hydroxy-cholesterol (22(R)-OH-C), which is a substrate for the P450scc enzyme, and pregnenolone, which is the product of the P450scc-catalyzed step]. Testosterone in plasma and in incubation medium was measured by radioimmunoassay. The StAR and P450scc expression was detected by immunocytochemistry.

Results

The levels of total circulating testosterone were not altered by rosiglitazone treatment. A decrease in basal or induced testosterone production occurred in the Leydig cells of rosiglitazone-treated rats. The ultrastructural and immunocytochemical analysis of Leydig cells from rosiglitazone-treated rats revealed cells with characteristics of increased activity as well as increased StAR and P450scc expression, which are key proteins in androgen biosynthesis. However, a number of rosiglitazone-treated cells exhibited significant mitochondrial damage.

Conclusion

The results revealed that the Leydig cells from rosiglitazone-treated rats showed significant reduction in testosterone production under basal, hCG/dbcAMP- or 22 (R)-OH-C/pregnenolone-induced conditions, although increased labeling of StAR and P450scc was detected in these cells by immunocytochemistry. The ultrastructural study suggested that the lower levels of testosterone produced by these cells could be due to mitochondrial damage induced by rosiglitazone.
Complete genome sequence of human astrovirus genotype 6
Authors: Guo Li , Gonzalez Richard , Wang Wei , Li Yongjun , Paranhos-Baccalà Gláucia , Vernet Guy , Wang Jianwei
Published: February 2010

Background

Human astroviruses (HAstVs) are one of the important causes of acute gastroenteritis in children. Currently, eight HAstV genotypes have been identified and all but two (HAstV-6 and HAstV-7) have been fully sequenced. We here sequenced and analyzed the complete genome of a HAstV-6 strain (192-BJ07), which was identified in Beijing, China.

Results

The genome of 192-BJ07 consists of 6745 nucleotides. The 192-BJ07 strain displays a 77.2-78.0% nucleotide sequence identity with other HAstV genotypes and exhibits amino acid sequence identities of 86.5-87.4%, 94.2-95.1%, and 65.5-74.8% in the ORF1a, ORF1b, and ORF2 regions, respectively. Homological analysis of ORF2 shows that 192-BJ07 is 96.3% identical to the documented HAstV-6 strain. Further, phylogenetic analysis indicates that different genomic regions are likely undergoing different evolutionary and selective pressures. No recombination event was observed in HAstV-6 in this study.

Conclusion

The completely sequenced and characterized genome of HAstV-6 (192-BJ07) provides further insight into the genetics of astroviruses and aids in the surveillance and control of HAstV gastroenteritis.
The prevalence of atypical scrapie in sheep from positive flocks is not higher than in the general sheep population in 11 European countries
Authors: Fediaevsky Alexandre , Maurella Cristiana , Nöremark Maria , Ingravalle Francesco , Thorgeirsdottir Stefania , Orge Leonor , Poizat Renaud , Hautaniemi Maria , Liam Barry , Calavas Didier , Ru Giuseppe , Hopp Petter
Published: February 2010

Background

During the last decade, active surveillance for transmissible spongiform encephalopathies in small ruminants has been intensive in Europe. In many countries this has led to the detection of cases of atypical scrapie which, unlike classical scrapie, might not be contagious. EU legislation requires, that following detection of a scrapie case, control measures including further testing take place in affected flocks, including the culling of genotype susceptible to classical scrapie. This might result in the detection of additional cases. The aim of this study was to investigate the occurrence of additional cases in flocks affected by atypical scrapie using surveillance data collected in Europe in order to ascertain whether atypical scrapie, is contagious.

Results

Questionnaires were used to collect, at national level, the results of active surveillance and testing associated with flock outbreaks in 12 European countries. The mean prevalence of atypical scrapie was 5.5 (5.0-6.0) cases per ten thousand in abattoir surveillance and 8.1 (7.3-9.0) cases per ten thousand in fallen stock. By using meta-analysis, on 11 out of the 12 countries, we found that the probability of detecting additional cases of atypical scrapie in positive flocks was similar to the probability observed in animals slaughtered for human consumption (odds ratio, OR = 1.07, CI95%: 0.70-1.63) or among fallen stock (OR = 0.78, CI95%: 0.51-1.2). In contrast, when comparing the two scrapie types, the probability of detecting additional cases in classical scrapie positive flocks was significantly higher than the probability of detecting additional cases in atypical scrapie positive flocks (OR = 32.4, CI95%: 20.7-50.7).

Conclusions

These results suggest that atypical scrapie is not contagious or has a very low transmissibility under natural conditions compared with classical scrapie. Furthermore this study stressed the importance of standardised data collection to make good use of the analyses undertaken by European countries in their efforts to control atypical and classical scrapie.
Dynamic transport and localization of alpha-synuclein in primary hippocampal neurons
Authors: Yang Mong-Lin , Hasadsri Linda , Woods Wendy S , George Julia M
Published: February 2010

Background

Alpha-synuclein is a presynaptic protein with a proposed role in neurotransmission and dopamine homeostasis. Abnormal accumulation of α-synuclein aggregates in dopaminergic neurons of the substantia nigra is diagnostic of sporadic Parkinson's disease, and mutations in the protein are linked to early onset forms of the disease. The folded conformation of the protein varies depending upon its environment and other factors that are poorly understood. When bound to phospholipid membranes, α-synuclein adopts a helical conformation that mediates specific interactions with other proteins.

Results

To investigate the role of the helical domain in transport and localization of α-synuclein, eGFP-tagged constructs were transfected into rat primary hippocampal neurons at 7 DIV. A series of constructs were analyzed in which each individual exon was deleted, for comparison to previous studies of lipid affinity and α-helix content. A53T and A30P substitutions, representing Parkinson's disease-associated variants, were analyzed as well. Single exon deletions within the lipid-binding N-terminal domain of α-synuclein (exons 2, 3, and 4) partially disrupted its presynaptic localization at 17-21 DIV, resulting in increased diffuse labeling of axons. Similar results were obtained for A30P, which exhibits decreased lipid binding, but not A53T. To examine whether differences in presynaptic enrichment were related to deficiencies in transport velocity, transport was visualized via live cell microscopy. Tagged α-synuclein migrated at a rate of 1.85 ± 0.09 μm/s, consistent with previous reports, and single exon deletion mutants migrated at similar rates, as did A30P. Deletion of the entire N-terminal lipid-binding domain (Δ234GFP) did not significantly alter rates of particle movement, but decreased the number of moving particles. Only the A53TGFP mutant exhibited a significant decrease in transport velocity as compared to ASGFP.

Conclusions

These results support the hypothesis that presynaptic localization involves a mechanism that requires helical conformation and lipid binding. Conversely, the rate of axonal transport is not determined by lipid affinity and is not sufficient to account for differences in presynaptic localization of α-synuclein-eGFP variants.
Mongolian and Japanese Joint Conference on "Echinococcosis: diagnosis, treatment and prevention in Mongolia" June 4, 2009
Authors: Gurbadam A , Nyamkhuu D , Nyamkhuu G , Tsendjav A , Sergelen O , Narantuya B , Batsukh Z , Battsetseg G , Oyun-Erdene B , Uranchimeg B , Otgonbaatar D , Temuulen D , Bayarmaa E , Abmed D , Tsogtsaikhan S , Usukhbayar A , Smirmaul K , Gereltuya J , Ito A
Published: February 2010

The first Mongolian-Japanese Joint Conference on "Echinococcosis: diagnosis, treatment and prevention in Mongolia" was held in Ulaanbaatar on June 4th, 2009. It was the first chance for Mongolian experts (clinicians, pathologists, parasitologists, biologists, epidemiologists, veterinarians and others working on echinococcosis) joined together. Increase in the number of cystic echinococcosis (CE) cases year by year was stressed. CE in children may be more than adult cases. Alveolar echinococcosis was suspected chronic malignant hepatic tumors or abscesses. Main discussion was as to how to introduce modern diagnostic tools for pre-surgical diagnosis, how to establish the national system for the data base of echinococcosis with the establishment of a network system by experts from different areas. The importance of molecular identification of the parasites in domestic and wild animals was also stressed.
Four different malignancies in one patient: a case report
Authors: Demirci Umut , Coşkun Ugur , Göçün Pinar Uyar , Gurlek Bahar , Saka Burcu , Öztürk Banu , Benekli Mustafa , Büyükberber Süleyman
Published: February 2010

Cancer survivors have a higher risk of new primary cancer, in the same or in another organ, than the general population. We report a 78-year-old women who has metachronous quadruple adenocarcinoma, includes bilateral breast cancer, ovarian cancer and retroperitoneal neuroendocrine carcinoma. The development of second cancer in cancer survivors can be expected but third or higher order malignancies are rare.
Local leptin production in osteoarthritis subchondral osteoblasts may be responsible for their abnormal phenotypic expression
Authors: Mutabaruka Marie-Solange , Aoulad Aissa Mohamed , Delalandre Aline , Lavigne Martin , Lajeunesse Daniel
Published: February 2010

Introduction

Leptin is a peptide hormone with a role in bone metabolism and rheumatic diseases. The subchondral bone tissue plays a prominent role in the pathophysiology of osteoarthritis (OA), related to abnormal osteoblast (Ob) differentiation. Although leptin promotes the differentiation of Ob under normal conditions, a role for leptin in OA Ob has not been demonstrated. Here we determined if endogenous leptin produced by OA Ob could be responsible for the expression of the abnormal phenotypic biomarkers observed in OA Ob.

Methods

We prepared primary normal and OA Ob from subchondral bone of tibial plateaus removed for knee surgery of OA patients or at autopsy. We determined the production of leptin and of the long, biologically active, leptin receptors (OB-Rb) using reverse transcriptase-polymerase chain reaction, ELISA and Western blot analysis. We determined the effect of leptin on cell proliferation by BrdU incorporation and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, and we determined by Western blot analysis phospho 42/44 MAPK (p42/44 Erk1/2) and phospho p38 levels. We then determined the effect of the addition of exogenous leptin, leptin receptor antagonists, inhibitors of leptin signaling or siRNA techniques on the phenotypic features of OA Ob. Phenotypic features of Ob were determined by measuring alkaline phosphatase activity (ALP), osteocalcin release (OC), collagen type 1 production (CICP) and of Transforming Growth Factor-β1 (TGF-β1).

Results

Leptin expression was increased approximately five-fold and protein levels approximately two-fold in OA Ob compared to normal. Leptin stimulated its own expression and the expression of OB-Rb in OA Ob. Leptin dose-dependently stimulated cell proliferation of OA Ob and also increased phosphorylated p42/44 Erk1/2 and p38 levels. Inactivating antibodies against leptin reduced ALP, OC, CICP and TGF-β1 levels in OA Ob. Tyrphostin (AG490) and piceatannol (Pce), inhibitors of leptin signaling, reproduced this effect. Inhibition of endogenous leptin levels using siRNA for leptin or inhibiting leptin signaling using siRNA for OB-Rb expression both reduced ALP and OC about 60%. Exogenous leptin addition stimulated ALP, yet this failed to further increase OC or CICP.

Conclusions

These results suggest that abnormal production of leptin by OA Ob could be responsible, in part, for the elevated levels of ALP, OC, collagen type 1 and TGF-β1 observed in these cells compared to normal. Leptin also stimulated cell proliferation, and Erk 1/2 and p38 signaling. Taken together, these data suggest leptin could contribute to abnormal osteoblast function in OA.
Brain metabolism is significantly impaired at blood glucose below 6 mM and brain glucose below 1 mM in patients with severe traumatic brain injury
Authors: Meierhans Roman , Béchir Markus , Ludwig Silke , Sommerfeld Jutta , Brandi Giovanna , Haberthür Christoph , Stocker Reto , Stover John F
Published: February 2010

Introduction

The optimal blood glucose target following severe traumatic brain injury (TBI) must be defined. Cerebral microdialysis was used to investigate the influence of arterial blood and brain glucose on cerebral glucose, lactate, pyruvate, glutamate, and calculated indices of downstream metabolism.

Methods

In twenty TBI patients, microdialysis catheters inserted in the edematous frontal lobe were dialyzed at 1 μl/min, collecting samples at 60 minute intervals. Occult metabolic alterations were determined by calculating the lactate- pyruvate (L/P), lactate- glucose (L/Glc), and lactate- glutamate (L/Glu) ratios.

Results

Brain glucose was influenced by arterial blood glucose. Elevated L/P and L/Glc were significantly reduced at brain glucose above 1 mM, reaching lowest values at blood and brain glucose levels between 6-9 mM (P < 0.001). Lowest cerebral glutamate was measured at brain glucose 3-5 mM with a significant increase at brain glucose below 3 mM and above 6 mM. While L/Glu was significantly increased at low brain glucose levels, it was significantly decreased at brain glucose above 5 mM (P < 0.001). Insulin administration increased brain glutamate at low brain glucose, but prevented increase in L/Glu.

Conclusions

Arterial blood glucose levels appear to be optimal at 6-9 mM. While low brain glucose levels below 1 mM are detrimental, elevated brain glucose are to be targeted despite increased brain glutamate at brain glucose >5 mM. Pathogenity of elevated glutamate appears to be relativized by L/Glu and suggests to exclude insulin- induced brain injury.
Posttraumatic stress, anxiety and depression symptoms in patients during the first year post intensive care unit discharge
Authors: Myhren Hilde , Ekeberg Øivind , Tøien Kirsti , Karlsson Susanne , Stokland Olav
Published: February 2010

Introduction

To study the level and predictors of posttraumatic stress, anxiety and depression symptoms in medical, surgical and trauma patients during the first year post intensive care unit (ICU) discharge.

Methods

Of 255 patients included, 194 participated at 12 months. Patients completed the Impact of Event Scale (IES), Hospital Anxiety and Depression Scale (HADS), Life Orientation Test (LOT) at 4 to 6 weeks, 3 and 12 months and ICU memory tool at the first assessment (baseline). Case level for posttraumatic stress symptoms with high probability of a posttraumatic stress disorder (PTSD) was ≥ 35. Case level of HADS-Anxiety or Depression was ≥ 11. Memory of pain during ICU stay was measured at baseline on a five-point Likert-scale (0-low to 4-high). Patient demographics and clinical variables were controlled for in logistic regression analyses.

Results

Mean IES score one year after ICU treatment was 22.5 (95%CI 20.0 to 25.1) and 27% (48/180) were above case level, IES ≥ 35. No significant differences in the IES mean scores across the three time points were found (P = 0.388). In a subgroup, 27/170 (16%), patients IES score increased from 11 to 32, P < 0.001. No differences in posttraumatic stress, anxiety or depression between medical, surgical and trauma patients were found. High educational level (OR 0.4, 95%CI 0.2 to 1.0), personality trait (optimism) OR 0.9, 95%CI 0.8 to 1.0), factual recall (OR 6.6, 95%CI 1.4 to 31.0) and memory of pain (OR 1.5, 95%CI 1.1 to 2.0) were independent predictors of posttraumatic stress symptoms at one year. Optimism was a strong predictor for less anxiety (OR 0.8, 0.8 to 0.9) and depression symptoms (OR 0.8, 0.8 to 0.9) after one year.

Conclusions

The mean level of posttraumatic stress symptoms in patients one year following ICU treatment was high and one of four were above case level Predictors of posttraumatic stress symptoms were mainly demographics and experiences during hospital stay whereas clinical injury related variables were insignificant. Pessimism was a predictor of posttraumatic stress, anxiety and depression symptoms. A subgroup of patients developed clinically significant distress symptoms during the follow-up period.
Effects of Tamoxifen and Exemestane on Cognitive Functioning of Postmenopausal Patients With Breast Cancer: Results From the Neuropsychological Side Study of the Tamoxifen and Exemestane Adjuvant Multinational Trial
Authors: Schilder Christina M. , Seynaeve Caroline , Beex Louk V. , Boogerd Willem , Linn Sabine C. , Gundy Chad M. , Huizenga Hilde M. , Nortier Johan W. , van de Velde Cornelis J. , van Dam Frits S. , Schagen Sanne B.
Published: February 2010

Purpose

To evaluate the influence of adjuvant tamoxifen and exemestane on cognitive functioning in postmenopausal patients with breast cancer (BC).

Patients and Methods

Neuropsychological assessments were performed before the start (T1) and after 1 year of adjuvant endocrine treatment (T2) in Dutch postmenopausal patients with BC, who did not receive chemotherapy. Patients participated in the international Tamoxifen and Exemestane Adjuvant Multinational trial, a prospective randomized study investigating tamoxifen versus exemestane as adjuvant therapy for hormone-sensitive BC.

Results

Participants included 80 tamoxifen users (mean age, 68.7 years; range 51 to 84), 99 exemestane users (mean age, 68.3 years; range, 50 to 82), and 120 healthy controls (mean age, 66.2 years; range, 49 to 86). At T2, after adjustment for T1 performance, exemestane users did not perform statistically significantly worse than healthy controls on any cognitive domain. In contrast, tamoxifen users performed statistically significantly worse than healthy controls on verbal memory (P < .01; Cohen's d = .43) and executive functioning (P = .01; Cohen's d = .40), and statistically significantly worse than exemestane users on information processing speed (P = .02; Cohen's d = .36). With respect to visual memory, working memory, verbal fluency, reaction speed, and motor speed, no significant differences between the three groups were found.

Conclusion

After 1 year of adjuvant therapy, tamoxifen use is associated with statistically significant lower functioning in verbal memory and executive functioning, whereas exemestane use is not associated with statistically significant lower cognitive functioning in postmenopausal patients with BC. Our results accentuate the need to include assessments of cognitive effects of adjuvant endocrine treatment in long-term safety studies.
Skin Toxicity Evaluation Protocol With Panitumumab (STEPP), a Phase II, Open-Label, Randomized Trial Evaluating the Impact of a Pre-Emptive Skin Treatment Regimen on Skin Toxicities and Quality of Life in Patients With Metastatic Colorectal Cancer
Authors: Lacouture Mario E. , Mitchell Edith P. , Piperdi Bilal , Pillai Madhavan V. , Shearer Heather , Iannotti Nicholas , Xu Feng , Yassine Mohamed
Published: February 2010

Purpose

Panitumumab, a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR), is approved in the United States and Europe for the treatment of refractory metastatic colorectal cancer (mCRC). Skin toxicities are the most common adverse events with EGFR inhibitors. This is the first study designed to examine differences between pre-emptive and reactive skin treatment for specific skin toxicities in patients with mCRC for any EGFR inhibitor.

Patients and Methods

Patients receiving panitumumab-containing therapy were randomly assigned 1:1 to pre-emptive or reactive treatment (after skin toxicity developed). Pre-emptive treatment included use of skin moisturizers, sunscreen, topical steroid, and doxycycline. The primary end point of the study was the incidence of protocol-specified ≥ grade 2 skin toxicities during the 6-week skin treatment period. Quality of life (QOL) was assessed with the Dermatology Life Quality Index (DLQI).

Results

Of 95 enrolled patients, 48 received pre-emptive treatment, and 47 received reactive treatment. The incidence of protocol-specified ≥ grade 2 skin toxicities during the 6-week skin treatment period was 29% and 62% for the pre-emptive and reactive groups, respectively. Mean DLQI score change from baseline to week 3 was 1.3 points and 4.2 points in the pre-emptive and reactive groups, respectively.

Conclusion

The pre-emptive skin treatment regimen was well tolerated. The incidence of specific ≥ grade 2 skin toxicities during the 6-week skin treatment period was reduced by more than 50% in the pre-emptive group compared with the reactive group. Patients in the pre-emptive group reported less QOL impairment than patients in the reactive group.
Phase II Trial of the Oral Mammalian Target of Rapamycin Inhibitor Everolimus in Relapsed or Refractory Waldenström Macroglobulinemia
Authors: Ghobrial Irene M. , Gertz Morie , LaPlant Betsy , Camoriano John , Hayman Suzanne , Lacy Martha , Chuma Stacey , Harris Brianna , Leduc Renee , Rourke Meghan , Ansell Stephen M. , DeAngelo Daniel , Dispenzieri Angela , Bergsagel Leif , Reeder Craig , Anderson Kenneth C. , Richardson Paul G. , Treon Steven P. , Witzig Thomas E.
Published: February 2010

Purpose

The phosphatidylinositol 3-kinase/mammalian target of rapamycin (mTOR) signal transduction pathway controls cell proliferation and survival. Everolimus is an oral agent targeting raptor mTOR (mTORC1). The trial's goal was to determine the antitumor activity and safety of single-agent everolimus in patients with relapsed/refractory Waldenström macroglobulinemia (WM).

Patients and Methods

Eligible patients had measurable disease (immunoglobulin M monoclonal protein > 1,000 mg/dL with > 10% marrow involvement or nodal masses > 2 cm), a platelet count more than 75,000 × 106/L, a neutrophil count more than 1,000 × 106/L, and a creatinine and bilirubin less than 2 × the laboratory upper limit of normal. Patients received everolimus 10 mg orally daily and were evaluated monthly. Tumor response was assessed after cycles 2 and 6 and then every three cycles until progression.

Results

Fifty patients were treated. The median age was 63 years (range, 43 to 85 years). The overall response rate (complete response plus partial remission [PR] plus minimal response [MR]) was 70% (95% CI, 55% to 82%), with a PR of 42% and 28% MR. The median duration of response and median progression-free survival (PFS) have not been reached. The estimated PFS at 6 and 12 months is 75% (95% CI, 64% to 89%) and 62% (95% CI, 48% to 80%), respectively. Grade 3 or higher related toxicities were observed in 56% of patients. The most common were hematologic toxicities with cytopenias. Pulmonary toxicity occurred in 10% of patients. Dose reductions due to toxicity occurred in 52% of patients.

Conclusion

Everolimus has high single-agent activity with an overall response rate of 70% and manageable toxicity in patients with relapsed WM and offers a potential new therapeutic strategy for this patient group.
Mature Results of an Individualized Radiation Dose Prescription Study Based on Normal Tissue Constraints in Stages I to III Non–Small-Cell Lung Cancer
Authors: van Baardwijk Angela , Wanders Stofferinus , Boersma Liesbeth , Borger Jacques , Öllers Michel , Dingemans Anne-Marie C. , Bootsma Gerben , Geraedts Wiel , Pitz Cordula , Lunde Ragnar , Lambin Philippe , De Ruysscher Dirk
Published: February 2010

Purpose

We previously showed that individualized radiation dose escalation based on normal tissue constraints would allow safe administration of high radiation doses with low complication rate. Here, we report the mature results of a prospective, single-arm study that used this individualized tolerable dose approach.

Patients and Methods

In total, 166 patients with stage III or medically inoperable stage I to II non–small-cell lung cancer, WHO performance status 0 to 2, a forced expiratory volume at 1 second and diffusing capacity of lungs for carbon monoxide ≥ 30% were included. Patients were irradiated using an individualized prescribed total tumor dose (TTD) based on normal tissue dose constraints (mean lung dose, 19 Gy; maximal spinal cord dose, 54 Gy) up to a maximal TTD of 79.2 Gy in 1.8 Gy fractions twice daily. Only sequential chemoradiation was administered. The primary end point was overall survival (OS), and the secondary end point was toxicity according to Common Terminology Criteria of Adverse Events (CTCAE) v3.0.

Results

The median prescribed TTD was 64.8 Gy (standard deviation, ± 11.4 Gy) delivered in 25 ± 5.8 days. With a median follow-up of 31.6 months, the median OS was 21.0 months with a 1-year OS of 68.7% and a 2-year OS of 45.0%. Multivariable analysis showed that only a large gross tumor volume significantly decreased OS (P < .001). Both acute (grade 3, 21.1%; grade 4, 2.4%) and late toxicity (grade 3, 4.2%; grade 4, 1.8%) were acceptable.

Conclusion

Individualized prescribed radical radiotherapy based on normal tissue constraints with sequential chemoradiation shows survival rates that come close to results of concurrent chemoradiation schedules, with acceptable acute and late toxicity. A prospective randomized study is warranted to further investigate its efficacy.
Phase II, Randomized, Open-Label Study of Pegfilgrastim-Supported VDC/IE Chemotherapy in Pediatric Sarcoma Patients
Authors: Spunt Sheri L. , Irving Helen , Frost Jami , Sender Leonard , Guo Matthew , Yang Bing-Bing , Dreiling Lyndah , Santana Victor M.
Published: February 2010

Purpose

This multicenter, randomized, open-label study evaluated the efficacy, safety, and pharmacokinetics of a single subcutaneous pegfilgrastim injection with daily subcutaneous filgrastim administration in pediatric patients receiving myelosuppressive chemotherapy for sarcoma.

Patients and Methods

Forty-four patients with previously untreated, biopsy-proven sarcoma stratified into three age groups (0-5, 6-11, and 12-21 years) were randomly assigned in a 6:1 randomization ratio to receive a single pegfilgrastim dose of 100 μg/kg (n = 38) or daily filgrastim doses of 5 μg/kg (n = 6) after chemotherapy (cycles 1 and 3: vincristine-doxorubicin-cyclophosphamide; cycles 2 and 4: ifosfamide-etoposide). The duration of grade 4 neutropenia, time to neutrophil recovery, incidence of febrile neutropenia, and adverse events were recorded.

Results

Pegfilgrastim and filgrastim were similar for all efficacy and safety end points, and their pharmacokinetic profiles were consistent with those in adults. Younger children experienced more protracted neutropenia and had higher median pegfilgrastim exposure than older children.

Conclusion

A single dose of pegfilgrastim at 100 μg/kg administered once per chemotherapy cycle is comparable to daily injections of filgrastim at 5 μg/kg for pediatric sarcoma patients receiving myelosuppressive chemotherapy.
Facilitating Informed Decisions Regarding Microsatellite Instability Testing Among High-Risk Individuals Diagnosed With Colorectal Cancer
Authors: Manne Sharon L. , Meropol Neal J. , Weinberg David S. , Vig Hetal , Ali-Khan Catts Zohra , Manning Cheri , Ross Eric , Shannon Kristen , Chung Daniel C.
Published: February 2010

Purpose

To evaluate the impact of a CD-ROM intervention in the education of patients with suspected Lynch syndrome (LS) about microsatellite instability (MSI) and immunohisochemistry (IHC) testing.

Patients and Methods

Two hundred thirteen patients meeting Bethesda criteria were randomly assigned to receive either a brief educational session with a health educator (n = 105) or a brief educational session plus a CD-ROM (n = 108). Assessments were administered at baseline and 2 weeks post-treatment. Primary outcomes included MSI and IHC knowledge and level of satisfaction with and completeness of the preparation to make the decision for MSI testing. Secondary outcomes included decisional conflict, difficulty making the decision, cancer-specific and global anxiety, and level of discussion about MSI testing with family and friends.

Results

Participants in the education plus CD-ROM condition reported significant increases in knowledge about the MSI and IHC tests, greater satisfaction with the preparation to make a decision for testing, lower decisional conflict, and greater decisional self-efficacy. The effects of the education plus CD-ROM on most outcomes were not moderated by preintervention levels of exposure to MSI testing, family support for MSI testing, or the family history of cancer.

Conclusion

Incorporation of new media education strategies for individuals at risk for LS may be a valuable component of the informed consent process. As clinical criteria for MSI and IHC testing continue to expand, the need for alternative educational approaches to meet this increased demand could be met by the self-administered computer-based strategy that we described.
Phase II Trial of Weekly Bortezomib in Combination With Rituximab in Relapsed or Relapsed and Refractory Waldenström Macroglobulinemia
Authors: Ghobrial Irene M. , Hong Fangxin , Padmanabhan Swaminathan , Badros Ashraf , Rourke Meghan , Leduc Renee , Chuma Stacey , Kunsman Janet , Warren Diane , Harris Brianna , Sam Amy , Anderson Kenneth C. , Richardson Paul G. , Treon Steven P. , Weller Edie , Matous Jeffrey
Published: February 2010

Purpose

This study aimed to determine activity and safety of weekly bortezomib and rituximab in patients with relapsed/refractory Waldenström macroglobulinemia (WM).

Patients and Methods

Patients who had at least one previous therapy were eligible. All patients received bortezomib intravenously weekly at 1.6 mg/m2 on days 1, 8, and 15, every 28 days for six cycles and rituximab 375 mg/m2 weekly on cycles 1 and 4. The primary end point was the percentage of patients with at least a minor response.

Results

Thirty-seven patients were treated. The majority of patients (78%) completed treatment per protocol. At least minimal response (MR) or better was observed in 81% (95% CI, 65% to 92%), with two patients (5%) in complete remission (CR)/near CR, 17 patients (46%) in partial response, and 11 patients (30%) in MR. The median time to progression was 16.4 months (95% CI, 11.4 to 21.1 months). Death occurred in one patient due to viral pneumonia. The most common grade 3 and 4 therapy-related adverse events included reversible neutropenia in 16%, anemia in 11%, and thrombocytopenia in 14%. Grade 3 peripheral neuropathy occurred in only two patients (5%). The median progression-free (PFS) is 15.6 months (95% CI, 11 to 21 months), with estimated 12-month and 18-month PFS of 57% (95% CI, 39% to 75%) and 45% (95% CI, 27% to 63%), respectively. The median overall survival has not been reached.

Conclusion

The combination of weekly bortezomib and rituximab showed significant activity and minimal neurologic toxicity in patients with relapsed WM.
Phase II Study of Sunitinib in Patients With Metastatic Urothelial Cancer
Authors: Gallagher David J. , Milowsky Matthew I. , Gerst Scott R. , Ishill Nicole , Riches Jamie , Regazzi Ashley , Boyle Mary G. , Trout Alisa , Flaherty Anne-Marie , Bajorin Dean F.
Published: February 2010

Purpose

No standard therapy exists for metastatic urothelial cancer (UC) that has progressed after initial chemotherapy. This trial was designed to assess the efficacy and tolerability of sunitinib in patients with advanced, previously treated UC.

Patients and Methods

In this phase II trial, 77 patients received sunitinib between September 2006 and January 2009 on one of two schedules (50 mg per day for 4 weeks on and 2 weeks off [cohort A], 37.5 mg per day continuously [cohort B]), using a Simon 2 stage design in each cohort separately.

Results

A partial response was seen in three of 45 patients (95% CI, 1% to 18%) in cohort A, and in one of 32 patients (95% CI, 0% to 16%) in cohort B. Clinical regression or stable disease was achieved in 33 of 77 patients (43%). Tumor regression lasted between 0.6 and 23.4 months with 29% of patients achieving response lasting longer than 3 months. The progression-free survival (2.4 v 2.3 months; P = .4) and overall survival (7.1 v 6.0 months; P = .4) were similar in both cohorts. There was one treatment-related death, and 47 patients (33 cohort A, 24 cohort B) experienced grade 3 or 4 toxicity.

Conclusion

Sunitinib did not achieve the predetermined threshold of ≥ 20% activity defined by Response Evaluation Criteria in Solid Tumors. However, antitumor responses were observed, identifying the vascular endothelial growth factor axis as a viable pathway for UC treatment. The reported clinical benefit in previously treated patients warrants further investigation in a disease for which there is no US Food and Drug Administration–approved treatment.
Phase I/II Study of the Src Inhibitor Dasatinib in Combination With Erlotinib in Advanced Non–Small-Cell Lung Cancer
Authors: Haura Eric B. , Tanvetyanon Tawee , Chiappori Alberto , Williams Charles , Simon George , Antonia Scott , Gray Jhanelle , Litschauer Sharon , Tetteh Leticia , Neuger Anthony , Song Lanxi , Rawal Bhupendra , Schell Michael J. , Bepler Gerold
Published: February 2010

Purpose

Src family kinase (SFK) proteins are frequently activated in cancer and can coordinate tumor cell growth, survival, invasion, and angiogenesis. Given the importance of SFK signaling in cancer, known cooperation between SFK and epidermal growth factor receptor (EGFR) signaling, and efficacy of EGFR inhibitors, we performed a phase I trial combining dasatinib, an SFK and multikinase inhibitor, with erlotinib, an EGFR inhibitor, in patients with advanced non–small-cell lung cancer.

Patients and Methods

Patients received erlotinib for 1 week before addition of dasatinib; pharmacokinetics were performed after weeks 1 and 2. Four cohorts were examined, including twice-daily and daily dasatinib dosing. Responses were assessed after 8 weeks. Plasma levels of angiogenic markers (vascular endothelial growth factor [VEGF], interleukin-8, and basic fibroblast growth factor [bFGF]) were determined before and during treatment.

Results

Thirty-four patients were enrolled. The average duration of treatment was 73 days. The main adverse events include GI (diarrhea, anorexia, and nausea), skin rash, cytopenias, pleural effusions, and fatigue. No effect of escalating doses of dasatinib was observed on erlotinib pharmacokinetics. Two partial responses and one bone response were observed, and the disease control rate was 63%. Reductions in plasma VEGF and bFGF were observed, and reductions in VEGF correlated with disease control.

Conclusion

The combination of erlotinib and dasatinib is tolerable, with adverse effects consistent with the two agents. Disease control and inhibition of plasma angiogenesis markers were observed. Personalized strategies for deployment of SFK should receive further attention.
Whole-Genome Profiling of Pediatric Diffuse Intrinsic Pontine Gliomas Highlights Platelet-Derived Growth Factor Receptor α and Poly (ADP-ribose) Polymerase As Potential Therapeutic Targets
Authors: Zarghooni Maryam , Bartels Ute , Lee Eric , Buczkowicz Pawel , Morrison Andrew , Huang Annie , Bouffet Eric , Hawkins Cynthia
Published: February 2010

Purpose

Diffuse intrinsic pontine glioma (DIPG) is one of the most devastating of pediatric malignancies and one for which no effective therapy exists. A major contributor to the failure of therapeutic trials is the assumption that biologic properties of brainstem tumors in children are identical to cerebral high-grade gliomas of adults. A better understanding of the biology of DIPG itself is needed in order to develop agents targeted more specifically to these children's disease. Herein, we address this lack of knowledge by performing the first high-resolution single nucleotide polymorphism (SNP) –based DNA microarray analysis of a series of DIPGs.

Patients and Methods

Eleven samples (nine postmortem and two pretreatment surgical samples), the largest series thus far examined, were hybridized to SNP arrays (250 k or 6.0). The study was approved by the research ethics board at our institution. All array findings were validated using quantitative polymerase chain reaction, fluorescence in situ hybridization, immunohistochemistry, and/or microsatellite analysis.

Results

Analysis of DIPG copy number alterations showed recurrent changes distinct from those of pediatric supratentorial high-grade astrocytomas. Thirty-six percent of DIPGs had gains in platelet-derived growth factor receptor alpha (PDGFRA; 4 to 18 copies) and all showed PDGFR-α expression. Low-level gains in poly (ADP-ribose) polymerase (PARP) -1 were identified in three cases. Pathway analysis revealed genes with loss of heterozygosity were enriched for DNA repair pathways.

Conclusion

To our knowledge, our data provides the first, comprehensive high-resolution genomic analysis of pediatric DIPG. Our findings of recurrent involvement of the PDGFR pathway as well as defects in DNA repair pathways coupled with gain of PARP-1 highlight two potential, biologically based, therapeutic targets directed specifically at this devastating disease.
Neratinib, an Irreversible ErbB Receptor Tyrosine Kinase Inhibitor, in Patients With Advanced ErbB2-Positive Breast Cancer
Authors: Burstein Harold J. , Sun Yan , Dirix Luc Y. , Jiang Zefei , Paridaens Robert , Tan Antoinette R. , Awada Ahmad , Ranade Anantbhushan , Jiao Shunchang , Schwartz Gary , Abbas Richat , Powell Christine , Turnbull Kathleen , Vermette Jennifer , Zacharchuk Charles , Badwe Rajendra
Published: February 2010

Purpose

Neratinib is an oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor. The efficacy and safety of neratinib were evaluated in two cohorts of patients with advanced ErbB2-positive breast cancer—those with and those without prior trastuzumab treatment—in an open-label, multicenter, phase II trial.

Patients and Methods

Patients in the two cohorts (prior trastuzumab, n = 66; no prior trastuzumab, n = 70) received oral neratinib 240 mg once daily. The primary end point was the 16-week progression-free survival (PFS) rate for the evaluable population (prior trastuzumab, n = 63; no prior trastuzumab, n = 64), as assessed by independent review.

Results

The 16-week PFS rates were 59% for patients with prior trastuzumab treatment and 78% for patients with no prior trastuzumab treatment. Median PFS was 22.3 and 39.6 weeks, respectively. Objective response rates were 24% among patients with prior trastuzumab treatment and 56% in the trastuzumab-naïve cohort. The most common adverse events were diarrhea, nausea, vomiting, and fatigue. Diarrhea was the most frequent grades 3 to 4 adverse event, occurring in 30% of patients with prior trastuzumab treatment and in 13% of patients with no prior trastuzumab treatment, which prompted dose reductions in 29% and 4% of patients, respectively, but treatment discontinuation in only one patient. No neratinib-related, grades 3 or 4 cardiotoxicity was reported.

Conclusion

Oral neratinib showed substantial clinical activity and was reasonably well tolerated among both heavily pretreated and trastuzumab-naïve patients who had advanced, ErbB2-positive breast cancer. Diarrhea was the most common adverse effect but was manageable with antidiarrheal agents and dose modification.