bluuebunny/crossref_metadata_2025 huggingface dataset:
Spasmodic Torticollis—A Multicentre Study on Behavioural Aspects IV: Psychopathology
Authors: Scheidt C. E. , Heinen F. , Nickel T. , Rayki O. , Wissel J. , Poewe W. , Benecke R. , Arnold G. , Oertel W. , Dengler R. , Deuschl G.
Published: March 2014

The GSI (General Symptom Index) of the Symptom Checklist 90 R (SCL 90 R) (as a global indicator of the severity of psychiatric symptoms) of 27% of the spasmodic torticollis (ST) sample fell outside the 95% range of the normal control group (two standard deviations). Patients with a higher GSI were younger, more functionally disabled and subject to higher psychosocial stress due to the illness. The highest scores were reached on the subscales of somatization, interpersonal sensitivity and depression. On the depression scale, 23% of the patients' scores were abnormal. This scale correlated significantly with the neurological signs, particularly the TSUI-index and laterocollis. A statistically significant correlation also existed between psychiatric morbidity and a family history of mental disorder. More than 50% of the patients reported that stressful life events had triggered their illness. In order of frequency, a death came first, followed by marital strife, changes in employment and family arguments. The data suggest that psychopathology in ST should generally be considered as a result of a variety of interacting factors, biological, psychological and social.
Autobiographical Memory for Emotional Events in Amnesia
Authors: Daum Irene , Flor Herta , Brodbeck Susann , Birbaumer Niels
Published: March 2014

This study investigated autobiographical memory for emotionally flavoured experiences in amnesia. Ten amnesic patients and 10 matched control subjects completed the Autobiographical Memory Interview and three semi-structured interviews which assessed memory for personal events associated with pain, happiness and fear. Despite retrograde amnesia for autobiographical facts and incidents, amnesics remembered a similar number of emotionally significant personal experiences as control subjects. Their recollections generally lacked elaboration and detail, but pain-related memories appeared to be more mildly impaired than memories associated with happiness and fear. The findings are discussed in relation to recent views on the relationship between affect and memory.
Neuropsychological Investigation of Anterior and Posterior Cortical Function in Early-Stage Probable Alzheimer’s Disease
Authors: Broks P. , Lines C. , Atchison L. , Challenor J. , Traub M. , Foster C. , Sagar H.
Published: March 2014

In vivo neuroimaging studies have generally indicated a greater involvement of posterior cortical areas in early-stage dementia of the Alzheimer type (DAT) relative to frontal involvement. By contrast, some recent neuropsychological studies have shown that DAT patients perform poorly in frontal lobe tasks even in the early stages of the disease, although there is disagreement as to whether this necessarily implicates frontal pathology. The main aim of this study was to examine the hypothesis prompted by both neuroimaging studies and the traditional clinical conception of the disease, that, compared with the functioning of posterior association cortex, executive functions (thought to depend on frontal lobe integrity) are relatively spared in the early stages of DAT. A group of patients with a diagnosis of early-stage, probable DAT (n= 17) was compared with age- and IQ-matched controls (n= 17) across a range of neuropsychological tasks presumed to exercise frontal or temporoparietal functions. A profile of strengths and weaknesses was observed across ‘anterior’ and ‘posterior’ cognitive tests, including dissociations among some tests of temporoparietal function, in particular visual object perception (impaired) and spatial analysis skills (intact). Thus there was little support for the notion that the disease progresses cortically in a posterior-to-anterior direction. Possible reasons for the discrepancy between neurophysiological and neuropsychological observations are discussed, including the possibility that neuropsychological tests do not provide a valid indication of regional brain function when used in the context of DAT. Caution is urged in the clinical application of ‘frontal lobe tests’ for the differential diagnosis of DAT.
Event Related Potentials and Serial List Picture Memory in Parkinson’s Patients
Authors: Korsnes M. S. , Reinvang I.
Published: March 2014

Two experiments examined short-term memory for order information in six patients diagnosed with Parkinson's disease (PD) and six control subjects while event related potentials (ERPs) were recorded. The subjects were tested for recognition of abstract spatial designs and words after a 5 s retention interval. The PD patients failed to respond in 29% of all trials, but the overall accuracy was similar to that in the control group when these trials were excluded. The corresponding ERP results show serial position variations both after presentation of the probe items, and after presentation of the memory set items. The amplitudes were generally lower at all positions for the PD patients at the parietal midline electrode, and the amplitudes were similar for both groups at the frontal electrode. Also, the ERP latencies were significantly slower for the PD patients than for the control group at all conditions. Indirectly the data are consistent with an interpretation of cognitive deficit in PD stressing attention resources.
Spasmodic Torticollis—A Multicentre Study on Behavioural Aspects III: Psychosocial Changes and Coping
Authors: Nickel T. , Heinen F. , Scheidt C. E. , Rayki O. , Wissel J. , Poewe W. , Benecke R. , Gasser T. , Oertel W. , Dengler R. , Deuschl G.
Published: March 2014

Psychosocial changes in spasmodic torticollis (ST) affect predominantly social life, professional life and psychological well-being. Concerning social life, 84.6% of the patients felt that they attracted considerable public attention due to their neurological illness and 65% had reduced participation in social events. A substantial number of patients had retired from professional activities; others felt severely impaired in their working capacity. The psychosocial sequelae in ST, however, seemed to depend less on the neurological signs per se than on the physical symptoms and on coping. Depressive coping in particular emerged as a predictor of psychosocial distress.
Crossed Aphasia. II: Why Are Deep Lesions Overrepresented with Respect to Standard Aphasia?
Authors: Laiacona M. , Capitani E. , Stangalino C. , Lorenzi L.
Published: March 2014

In this paper we have reviewed the cases of vascular crossed aphasia reported in the literature, in order to check whether deep lesions are really overrepresented in crossed aphasia with respect to standard aphasia. The comparison with a large sample of standard left-hemisphere-damaged aphasics revealed a significantly higher incidence of purely deep lesions in crossed aphasics than in standard aphasics. The overrepresentation of deep lesions in crossed aphasia appears to be contingent on the co-occurrence of aphasia and Unilateral Neglect after right-hemisphere lesion. This suggests an interaction between language and attentional mechanisms in the case of reversed language lateralisation: the overcrowding of these functions in the right hemisphere could make language more vulnerable after right deep lesions.
PET Study in a Patient with Spinocerebellar Degeneration before and after Long-Term Administration of Thyrotropin Releasing Hormone
Authors: Tanji H. , Nagasawa H. , Hayashi T. , Onodera H. , Fujiwara T. , Itoh M. , Ido T. , Itoyama Y.
Published: March 2014

We studied the chronic effect of thyrotropin releasing hormone (TRH) in a patient with spinocerebellar degeneration by measuring cerebral metabolic rate for glucose (CMRG1c) using 2-[18F]fluoro-2-deoxy-D-glucose (18FDG) and positron emission tomography (PET). A 56-year-old female, who had suffered from progressive ataxia for 2 years, was treated by intravenous administration of 2 mg TRH for 3 weeks, and CMRG1c of the brain was measured before and after treatment. CMRG1c was markedly decreased in the cerebellum and there was no significant difference before and after the treatment, i.e. mean CMRG1c values were 4.92 and 4.90 mg/100 g/min, and the ratios of the cerebellum versus the frontal cortex were 0.50 and 0.51, respectively. The degree of disequilibrium of her body examined with stabilography became better by the 19th day and further improved by the 26th day after the start of TRH treatment. Based on the present study we conclude that long-term administration of TRH did not improve CMRG1c in the cerebellum, but evidently improved the sway of gravity center by stabilography. We speculate that the chronic effect of TRH was not necessarily due to an improvement of cerebellar function, because TRH receptors are widely distributed throughout the central nervous system.
Procedural Memory: Computer Learning in Control Subjects and in Parkinson’s Disease Patients
Authors: Thomas-Antérion C. , Laurent B. , Foyatier-Michel N. , Laporte S. , Michel D.
Published: March 2014

We used perceptual motor tasks involving the learning of mouse control by looking at a Macintosh computer screen. We studied 90 control subjects aged between sixteen and seventy-five years. There was a significant time difference between the scales of age but improvement was the same for all subjects. We also studied 24 patients with Parkinson's disease (PD). We observed an influence of age and also of educational levels. The PD patients had difficulties of learning in all tests but they did not show differences in time when compared to the control group in the first learning session (Student's t-test). They learned two or four and a half times less well than the control group. In the first test, they had some difficulty in initiating the procedure and learned eight times less well than the control group. Performances seemed to be heterogeneous: patients with only tremor (seven) and patients without treatment (five) performed better than others but learned less. Success in procedural tasks for the PD group seemed to depend on the capacity to initiate the response and not on the development of an accurate strategy. Many questions still remain unanswered, and we have to study different kinds of implicit memory tasks to differentiate performance in control and basal ganglia groups.
Spasmodic Torticollis—A Multicentre Study on Behavioural Aspects II: Signs, Symptoms and Course
Authors: Heinen F. , Scheidt C. E. , Nickel T. , Rayki O. , Wissel J. , Poewe W. , Benecke R. , Arnold G. , Oertel W. , Dengler R. , Deuschl G.
Published: March 2014

This paper deals with signs, symptoms and course in spasmodic torticollis (ST). Two hundred and fifty-six patients were included in the study, 59.3% women, 40.7% men. The mean age was 49.1 years. Rotating torticollis out-numbered latero- and antero-retrocollis. A family history of ST occurred in 3.1% of the total sample. First degree relatives were affected in 2.3%. Thirty-four per cent of the patients had additional dystonic symptoms. Most frequently these affected the upper extremities (13%), and less often the legs. Of the patients 19.1% had experienced a period of complete remission. The correlations between the severity of the signs and the neurological symptoms are surprisingly weak.
Somatosensory Evoked Potentials and Dopaminergic Responsiveness to Apomorphine and Levodopa in Parkinsonian Patients
Authors: Miranda M. , Castillo J. L. , Araya F.
Published: March 2014

Short-latency somatosensory evoked potentials (SSEPs) were recorded from 10 parkinsonian patients in ‘off’ and ‘on’ states induced by apomorphine and levodopa. The effects of apomorphine and long-term levodopa treatment on the frontal N30 component were assessed and compared with healthy controls. Nine of 10 patients tested with apomorphine showed a significant improvement (p
Mirror-Reversal of a Face is Perceived as Expressing Emotions More Intensely
Authors: Asthana H. S. , Mandal M. K.
Published: March 2014

This study examined hemispatial bias in a free-viewing condition of the judgement of facial expressions of emotions. Right-handed male subjects were asked to judge the intensity, in terms of expressiveness, of facial emotion in normal and mirror-reversed orientations. Expressions in mirror-reversed orientation were perceived as more intense than in normal orientation.
Commonalities and Discrepancies in the Relationships between Behavioural Outcome and the Results of Neuroimaging in Brain-Damaged Patients
Authors: Markowitsch Hans J. , Calabrese Pasquale
Published: March 2014

Variables which are of influence in establishing clear predictions of neuropsychological alterations from neuroradiological data (and vice versa) are documented and discussed. It is concluded that personality factors and the kind and locus of brain lesions are the most crucial determinants. The locus of the brain damage may have cumulative effects either when it is situated in a strategic place (usually within the white matter, affecting interneuronal communication) or when various types of lesions appear superimposed (combination of focal and diffuse lesions). Consequently, the consideration of the patient's personality background and of as many neuropsychological facts as possible may considerably increase the validity of outcome predictions. When static or dynamic neuroimaging fails to show abnormalities in spite of obvious psychological alterations, an intensive neuropsychological documentation may even replace neuroradiology.
Synthesis of N-Alkyl-2-thiomethyl Benzimidazoles: A Green Approach
Authors: Rao S. Srinivas , Reddy Ch. Venkata Ramana , Dubey P. K.
Published: March 2014

A green approach for the synthesis of N-alkyl-2-thiomethyl benzimidazoles 2 (R=CH3, C2H5, CH2Ph) under different conditions has been developed from N-alkyl-2-chloromethyl benzimidazole (i.e., CH3, C2H5, CH2Ph) 1 by reaction with thiourea by physical grinding, or by using green solvents like ethanol and PEG-600, or by using microwave irradiation technique.
Global Behaviors of a Class of Discrete SIRS Epidemic Models with Nonlinear Incidence Rate
Authors: Wang Lei , Teng Zhidong , Zhang Long
Published: March 2014

We study a class of discrete SIRS epidemic models with nonlinear incidence rateF(S)G(I)and disease-induced mortality. By using analytic techniques and constructing discrete Lyapunov functions, the global stability of disease-free equilibrium and endemic equilibrium is obtained. That is, if basic reproduction numberℛ0<1, then the disease-free equilibrium is globally asymptotically stable, and ifℛ0>1, then the model has a unique endemic equilibrium and when some additional conditions hold the endemic equilibrium also is globally asymptotically stable. By using the theory of persistence in dynamical systems, we further obtain that only whenℛ0>1, the disease in the model is permanent. Some special cases ofF(S)G(I)are discussed. Particularly, whenF(S)G(I)=βSI/(1+λI), it is obtained that the endemic equilibrium is globally asymptotically stable if and only ifℛ0>1. Furthermore, the numerical simulations show that for general incidence rateF(S)G(I)the endemic equilibrium may be globally asymptotically stable only asℛ0>1.
Management of the Large Upper Eyelid Defects with Cutler-Beard Flap
Authors: Rahmi Duman , Mehmet Balcı , Ceyda Başkan , Sibel Özdoğan
Published: March 2014

Background.To assess Cutler-Beard procedure results in patients after wide excision of malignant eyelid tumours.Materials and Methods.The records of two women and two men (four patients) referred to our clinic with eyelid mass complaints and malign eyelid tumour diagnosis according to the histopathological examination were examined retrospectively.Results.The patients were 60–73 years old and their average age was66±11.10. The follow-up period of the cases was 16 (6–25) months. Total excisional biopsy was applied to all patients and then Cutler-Beard full thickness lid reconstruction was done because of the wide localization of the tumour. The patients’ diagnoses were consistent with basal cell carcinoma, sebaceous gland carcinoma, eyelid lymphoma, and squamous cell carcinoma. The patients’ eyelids were separated from each other 1 month postoperatively with a second operation. Superior eyelid entropium and blepharochalasis were seen in one patient during followup.Conclusions.Cutler-Beard flap is a successful procedure for superior eyelid tumours accompanied by wide tissue loss. The long-time closure of the eyelids and the need for secondary surgery are the major disadvantages of this procedure. Our experience with this procedure will reveal better results with large case series.
Delay-Dependent Robust Exponential Stability andH∞Analysis for a Class of Uncertain Markovian Jumping System with Multiple Delays
Authors: Xia Jianwei
Published: March 2014

This paper deals with the problem of robust exponential stability andH∞performance analysis for a class of uncertain Markovian jumping system with multiple delays. Based on the reciprocally convex approach, some novel delay-dependent stability criteria for the addressed system are derived. At last, numerical examples is given presented to show the effectiveness of the proposed results.
Phytochemistry and Preliminary Assessment of the Antibacterial Activity of Chloroform Extract of Amburana cearensis (Allemão) A.C. Sm. against Klebsiella pneumoniae Carbapenemase‐Producing Strains
Authors: Sá Mirivaldo Barros , Ralph Maria Taciana , Nascimento Danielle Cristina Oliveira , Ramos Clécio Souza , Barbosa Isvânia Maria Serafin , Sá Fabrício Bezerra , Lima-Filho J. V.
Published: March 2014

The chloroform extract of the stem bark of Amburana cearensis was chemically characterized and tested for antibacterial activity.The extract was analyzed by gas chromatography and mass spectrometry. The main compounds identified were 4‐methoxy‐3‐methylphenol (76.7%), triciclene (3.9%), α‐pinene (1.0%), β‐pinene (2.2%), and 4‐hydroxybenzoic acid (3.1%). Preliminary antibacterial tests were carried out against species of distinct morphophysiological characteristics: Escherichia coli, Salmonella enterica Serotype Typhimurium, Pseudomonas aeruginosa, Staphylococcus aureus, Listeria monocytogenes, and Bacillus cereus. The minimum inhibitory concentration (MIC) was determinate in 96‐well microplates for the chloroform extract and an analogue of themain compound identified, which was purchased commercially.We have shown that plant’s extract was only inhibitory (but not bactericidal) at the maximum concentration of 6900 μg/mL against Pseudomonas aeruginosa and Bacillus cereus. Conversely, the analogue 2‐methoxy‐4‐methylphenol produced MICs ranging from215 to 431 μg/mL against all bacterial species.New antibacterial assays conducted with such chemical compound against Klebsiella pneumoniae carbapenemase‐producing strains have shown similarMICresults and minimumbactericidal concentration (MBC) of 431 μg/mL.We conclude that A. cearensis is a good source of methoxy‐methylphenol compounds,which could be screened for antibacterial activity againstmultiresistant bacteria fromdifferent species
Linguatula serrata(Porocephalida: Linguatulidae) Infection among Client-Owned Dogs in Jalingo, North Eastern Nigeria: Prevalence and Public Health Implications
Authors: Oluwasina Oseni Saheed , ThankGod Onyiche Emmanuel , Augustine Omonuwa Omojefe , Gimba Fufa Ido
Published: March 2014

Pentastomiasis is a parasitic zoonosis endemic to western and central Africa. This study was undertaken to determine the prevalence and public health implications of Linguatulosis in client-owned dogs in Jalingo, North Eastern Nigeria. Seven hundred and seventy seven (777) dogs brought for treatment at the hospital were subjected to buccal (sublingual) examination for pentastomiasis. Parameters such as age, sex, and breeds were determined. Also, the months of the year were taken into consideration. An overall prevalence of 37.45% was recorded. Of the 477 dogs examined in 2010, 184 were positive representing prevalence of 38.57% and in 2011 107 were positive representing prevalence of 35.67%. The infection was higher in the male than in the female which does not differ significantly (P>0.05). There was no significant difference between sexes (P>0.05). However, significant difference (P<0.05) was observed between breeds and age of dogs examined. Season did not have much influence on the prevalence of Linguatulosis. The high prevalence of Linguatulosis in dogs and other animals found in this study highlights the need of improving preventative measures to reduce the rate of infection, which may pose a hazard to human health.
Physical Activity in Relation to Risk of Hematologic Cancers: A Systematic Review and Meta-analysis
Authors: Jochem Carmen , Leitzmann Michael F. , Keimling Marlen , Schmid Daniela , Behrens Gundula
Published: March 2014

Background: Despite the existence of numerous biologic pathways potentially linking increased physical activity to decreased risk of hematologic cancers, the associations between physical activity and subtype-specific hematologic cancers have not been comprehensively quantified.

Methods: We conducted a systematic review and meta-analysis of physical activity in relation to subtype-specific hematologic cancers. We summarized the data from 23 eligible studies (15 cohort and eight case–control studies) and estimated summary relative risks (RR) and 95% confidence intervals (CI) using random-effects models.

Results: When comparing high versus low physical activity levels, the RR for non-Hodgkin lymphoma was 0.91 (95% CI, 0.82–1.00), for Hodgkin lymphoma it was 0.86 (95% CI, 0.58–1.26), for leukemia it was 0.97 (95% CI, 0.84–1.13), and for multiple myeloma it was 0.86 (95% CI, 0.68–1.09). When focusing on subtypes of non-Hodgkin lymphoma, the RR for diffuse large B-cell lymphoma was 0.95 (95% CI, 0.80–1.14) and for follicular lymphoma it was 1.01 (95% CI, 0.83–1.22). In an exploratory analysis combining all hematologic cancers, high versus low physical activity levels yielded a statistically significant RR of 0.93 (95% CI, 0.88–0.99).

Conclusions: Physical activity showed statistically nonsignificant associations with risks of non-Hodgkin lymphoma, Hodgkin lymphoma, multiple myeloma, and leukemia. These findings may not represent a true lack of associations given the variation in high versus low physical activity definitions, the quality of physical activity assessments, and the variability in hematologic cancer classification schemes in individual studies.

Impact: Physical activity is unrelated to risks of subtype-specific hematologic cancers. Cancer Epidemiol Biomarkers Prev; 23(5); 833–46. ©2014 AACR.
Provider-Verified HPV Vaccine Coverage among a National Sample of Hispanic Adolescent Females
Authors: Reiter Paul L. , Gupta Kunal , Brewer Noel T. , Gilkey Melissa B. , Katz Mira L. , Paskett Electra D. , Smith Jennifer S.
Published: March 2014

Background: Hispanic females have the highest cervical cancer incidence rate of any racial or ethnic group in the United States, yet relatively little research has examined human papillomavirus (HPV) vaccination among this fast-growing population. We examined HPV vaccination among a national sample of Hispanic adolescent females.

Methods: We analyzed provider-verified vaccination data from the 2010–2011 National Immunization Survey-Teen for Hispanic females ages 13 to 17 years (n = 2,786). We used weighted logistic regression to identify correlates of HPV vaccine initiation (receipt of one or more doses), completion (receipt of three doses), and follow-through (receipt of three doses among those who initiated the series).

Results: HPV vaccine initiation was 60.9%, completion was 36.0%, and follow-through was 59.1%. Initiation and completion were more common among older daughters and those whose parents had received a provider recommendation to vaccinate (all P < 0.05). Completion was less common among daughters who had moved from their birth state (P < 0.05). All vaccination outcomes were less common among daughters without health insurance (all P < 0.05). Vaccination did not differ by parents' preferred language (all P > 0.05), although intent to vaccinate was higher among Spanish-speaking parents (P < 0.01). Spanish-speaking parents were more likely to indicate lack of provider recommendation (20.2% vs. 5.3%) and cost (10.9% vs. 1.8%) as main reasons for not intending to vaccinate (both P < 0.05).

Conclusions: Many Hispanic females have not received HPV vaccine. Several factors, including provider recommendation and health insurance, are key correlates of vaccination.

Impact: HPV vaccination programs targeting Hispanics are needed and should consider how potential barriers to vaccination may differ by preferred language. Cancer Epidemiol Biomarkers Prev; 23(5); 742–54. ©2014 AACR.
EZH2 Mutations in Follicular Lymphoma from Different Ethnic Groups and Associated Gene Expression Alterations
Authors: Guo Shuangping , Chan John K.C. , Iqbal Javeed , McKeithan Timothy , Fu Kai , Meng Bin , Pan Yi , Cheuk Wah , Luo Donglan , Wang Ruian , Zhang Weiwei , Greiner Timothy C. , Chan Wing C.
Published: March 2014

Purpose: Gain-of-function mutations of enhancer of Zeste homolog 2 (EZH2) occur frequently in diffuse large B-cell lymphomas and in follicular lymphomas. However, the frequency of EZH2 mutation in Chinese follicular lymphomas and the potential targets affected by this mutation are unknown.

Experimental Design: We determined EZH2 codon 641 mutations in Chinese follicular lymphomas (n = 124) and compared them with Western follicular lymphomas (n = 70) using a sensitive pyrosequencing assay. Gene expression profiling (GEP) was performed to determine differential gene expression between the mutated versus unmutated subgroups, and selected genes were validated using immunohistochemistry.

Results: Our results showed similar frequencies of EZH2 codon 641 mutations in Chinese and Western follicular lymphoma cohorts (16.9% vs. 18.6%, χ2 test, P = 0.773), including all five reported mutation variants. We observed significant association of EZH2 mutation with low morphologic grade follicular lymphomas (grade 1–2, 23.6% vs. grade 3, 7.7%, χ2 test, P = 0.02). EZH2 mutations also showed significant association with BCL2 rearrangement in the Chinese cohort (26.8% vs. 8.8%, χ2 test, P = 0.008) and combined cohorts (26.3% vs. 9.1%, χ2 test, P = 0.002). GEP analysis identified several genes, including TCF4, FOXP1, TCL1A, BIK, and RASSF6P, with significantly lower mRNA expression (P < 0.01) in mutated cases, and the potential target TCL1A showed consistent results at the protein level.

Conclusion: Similar prevalence of EZH2 mutation in two ethnic groups suggests shared pathogenetic mechanisms. The much lower frequency of EZH2 mutation in cases without BCL2 translocation suggests a different pattern of evolution of this subtype of follicular lymphoma. GEP studies showed a set of differentially expressed genes and suggested that EZH2 mutation may help to lock the tumor cells at the germinal center stage of differentiation. Clin Cancer Res; 20(12); 3078–86. ©2014 AACR.
A Pharmacodynamic/Pharmacokinetic Study of Ficlatuzumab in Patients with Advanced Solid Tumors and Liver Metastases
Authors: Tabernero Josep , Elez Maria Elena , Herranz Maria , Rico Isabel , Prudkin Ludmila , Andreu Jordi , Mateos Jose , Carreras Maria Josep , Han May , Gifford James , Credi Marc , Yin Wei , Agarwal Shefali , Komarnitsky Philip , Baselga Jose
Published: March 2014

Purpose: This study evaluated the safety, tolerability, pharmacodynamics, pharmacokinetics, and antitumor activity of ficlatuzumab, a humanized hepatocyte growth factor (HGF) inhibitory monoclonal antibody, as monotherapy in patients with advanced solid tumors and liver metastases.

Patients and Methods: Patients with p-Met (phosphorylated c-Met)–positive tumors enrolled in three dose-escalation cohorts, receiving ficlatuzumab 2, 10, or 20 mg/kg once per 14-day cycle. Pharmacodynamic changes in liver tumor biopsies and serum, pharmacokinetics, safety, and clinical activity were assessed.

Results: No dose-limiting toxicities occurred in the 19 patients enrolled (n = 6, 2 mg/kg; n = 7, 10 mg/kg; n = 6, 20 mg/kg). The most frequent diagnosis was colorectal cancer (n = 15; 79%). The most common treatment-emergent adverse events were asthenia, peripheral edema, hepatic pain (32% each), and cough (26%). Laboratory abnormalities of decreased serum albumin were present in all patients. Ficlatuzumab at 20 mg/kg lowered median levels of tumor p-Met (−53%), p-ERK (−43%), p-Akt (−2%), and increased median HGF levels (+33%), at the last on-study time point relative to baseline. Mean serum HGF levels increased with ficlatuzumab dose and number of treatment cycles. Ficlatuzumab exhibited linear pharmacokinetics and long terminal half-life (7.4–10 days). Best overall response was stable disease in 28% of patients, including 1 patient with pancreatic cancer with stable disease >1 year.

Conclusions: Ficlatuzumab exhibited good safety/tolerability and demonstrated ability to modulate the HGF/c-Met pathway and downstream signaling in the tumor in patients with advanced solid tumors. Safety, pharmacodynamic, and pharmacokinetic data for ficlatuzumab confirmed the recommended phase II dose of 20 mg/kg once per 14-day cycle. Clin Cancer Res; 20(10); 2793–804. ©2014 AACR.
PI3K Pathway Activation in High-Grade Ductal CarcinomaIn Situ—Implications for Progression to Invasive Breast Carcinoma
Authors: Sakr Rita A. , Weigelt Britta , Chandarlapaty Sarat , Andrade Victor P. , Guerini-Rocco Elena , Giri Dilip , Ng Charlotte K.Y. , Cowell Catherine F. , Rosen Neal , Reis-Filho Jorge S. , King Tari A.
Published: March 2014

Purpose: To assess the prevalence of phosphoinositide 3-kinase (PI3K) pathway alterations in pure high-grade ductal carcinoma in situ (DCIS) and DCIS associated with invasive breast cancer (IBC), and to determine whether DCIS and adjacent IBCs harbor distinct PI3K pathway aberrations.

Experimental Design: Eighty-nine cases of pure high-grade DCIS and 119 cases of high-grade DCIS associated with IBC were characterized according to estrogen receptor (ER) and HER2 status, subjected to immunohistochemical analysis of PTEN, INPP4B, phosphorylated (p)AKT and pS6 expression, and to microdissection followed by Sequenom genotyping of PIK3CA and AKT1 hotspot mutations.

Results: Alterations affecting the PI3K pathway were found in a subset of pure DCIS and DCIS adjacent to IBC. A subtype-matched comparison of pure DCIS and DCIS adjacent to IBC revealed that PIK3CA hotspot mutations and pAKT expression were significantly more prevalent in ER-positive/HER2-negative DCIS adjacent to IBC (P values, 0.005 and 0.043, respectively), and that in ER-negative/HER2-positive cases INPP4B loss of expression was more frequently observed in pure DCIS (a P value of 0.013). No differences in the parameters analyzed were observed in a pairwise comparison of the in situ and invasive components of cases of DCIS and adjacent IBC. Analysis of the PIK3CA-mutant allelic frequencies in DCIS and synchronous IBC revealed cases in which PIK3CA mutations were either restricted to the DCIS or to the invasive components.

Conclusion: Molecular aberrations affecting the PI3K pathway may play a role in the progression from high-grade DCIS to IBC in a subset of cases (e.g., a subgroup of ER-positive/HER2-negative lesions). Clin Cancer Res; 20(9); 2326–37. ©2014 AACR.
FOXM1 Promotes the Warburg Effect and Pancreatic Cancer Progression via Transactivation of LDHA Expression
Authors: Cui Jiujie , Shi Min , Xie Dacheng , Wei Daoyan , Jia Zhiliang , Zheng Shaojiang , Gao Yong , Huang Suyun , Xie Keping
Published: March 2014

Purpose: The transcription factor Forkhead box protein M1 (FOXM1) plays critical roles in cancer development and progression. However, the regulatory role and underlying mechanisms of FOXM1 in cancer metabolism are unknown. In this study, we characterized the regulation of aerobic glycolysis by FOXM1 and its impact on pancreatic cancer metabolism.

Experimental Design: The effect of altered expression of FOXM1 on expression of glycolytic enzymes and tumor development and progression was examined using animal models of pancreatic cancer. Also, the underlying mechanisms of altered pancreatic cancer glycolysis were analyzed using in vitro molecular biology. The clinical relevance of aberrant metabolism caused by dysregulated FOXM1 signaling was determined using pancreatic tumor and normal pancreatic tissue specimens.

Results: We found that FOXM1 did not markedly change the expression of most glycolytic enzymes except for phosphoglycerate kinase 1 (PGK-1) and lactate dehydrogenase A (LDHA). FOXM1 and LDHA were overexpressed concomitantly in pancreatic tumors and cancer cell lines. Increased expression of FOXM1 upregulated the expression of LDHA at both the mRNA and protein level and elevated LDH activity, lactate production, and glucose utilization, whereas reduced expression of FOXM1 did the opposite. Further studies demonstrated that FOXM1 bound directly to the LDHA promoter region and regulated the expression of the LDHA gene at the transcriptional level. Also, elevated FOXM1–LDHA signaling increased the pancreatic cancer cell growth and metastasis.

Conclusions: Dysregulated expression and activation of FOXM1 play important roles in aerobic glycolysis and tumorigenesis in patients with pancreatic cancer via transcriptional regulation of LDHA expression. Clin Cancer Res; 20(10); 2595–606. ©2014 AACR.
Biologic Effects of Platelet-Derived Growth Factor Receptor α Blockade in Uterine Cancer
Authors: Roh Ju-Won , Huang Jie , Hu Wei , Yang XiaoYun , Jennings Nicholas B. , Sehgal Vasudha , Sohn Bo Hwa , Han Hee Dong , Lee Sun Joo , Thanapprapasr Duangmani , Bottsford-Miller Justin , Zand Behrouz , Dalton Heather J. , Previs Rebecca A. , Davis Ashley N. , Matsuo Koji , Lee Ju-Seog , Ram Prahlad , Coleman Robert L. , Sood Anil K.
Published: March 2014

Purpose: Platelet-derived growth factor receptor α (PDGFRα) expression is frequently observed in many kinds of cancer and is a candidate for therapeutic targeting. This preclinical study evaluated the biologic significance of PDGFRα and PDGFRα blockade (using a fully humanized monoclonal antibody, 3G3) in uterine cancer.

Experimental Design: Expression of PDGFRα was examined in uterine cancer clinical samples and cell lines, and biologic effects of PDGFRα inhibition were evaluated using in vitro (cell viability, apoptosis, and invasion) and in vivo (orthotopic) models of uterine cancer.

Results: PDGFRα was highly expressed and activated in uterine cancer samples and cell lines. Treatment with 3G3 resulted in substantial inhibition of PDGFRα phosphorylation and of downstream signaling molecules AKT and mitogen-activated protein kinase (MAPK). Cell viability and invasive potential of uterine cancer cells were also inhibited by 3G3 treatment. In orthotopic mouse models of uterine cancer, 3G3 monotherapy had significant antitumor effects in the PDGFRα-positive models (Hec-1A, Ishikawa, Spec-2) but not in the PDGFRα-negative model (OVCA432). Greater therapeutic effects were observed for 3G3 in combination with chemotherapy than for either drug alone in the PDGFRα-positive models. The antitumor effects of therapy were related to increased apoptosis and decreased proliferation and angiogenesis.

Conclusions: These findings identify PDGFRα as an attractive target for therapeutic development in uterine cancer. Clin Cancer Res; 20(10); 2740–50. ©2014 AACR.
Profound Prevention of Experimental Brain Metastases of Breast Cancer by Temozolomide in an MGMT-Dependent Manner
Authors: Palmieri Diane , Duchnowska Renata , Woditschka Stephan , Hua Emily , Qian Yongzhen , Biernat Wojciech , Sosińska-Mielcarek Katarzyna , Gril Brunilde , Stark Andreas M. , Hewitt Stephen M. , Liewehr David J. , Steinberg Seth M. , Jassem Jacek , Steeg Patricia S.
Published: March 2014

Purpose: Brain metastases of breast cancer cause neurocognitive damage and are incurable. We evaluated a role for temozolomide in the prevention of brain metastases of breast cancer in experimental brain metastasis models.

Experimental Design: Temozolomide was administered in mice following earlier injection of brain-tropic HER2–positive JIMT-1-BR3 and triple-negative 231-BR-EGFP sublines, the latter with and without expression of O6-methylguanine-DNA methyltransferase (MGMT). In addition, the percentage of MGMT-positive tumor cells in 62 patient-matched sets of breast cancer primary tumors and resected brain metastases was determined immunohistochemically.

Results: Temozolomide, when dosed at 50, 25, 10, or 5 mg/kg, 5 days per week, beginning 3 days after inoculation, completely prevented the formation of experimental brain metastases from MGMT-negative 231-BR-EGFP cells. At a 1 mg/kg dose, temozolomide prevented 68% of large brain metastases, and was ineffective at a dose of 0.5 mg/kg. When the 50 mg/kg dose was administered beginning on days 18 or 24, temozolomide efficacy was reduced or absent. Temozolomide was ineffective at preventing brain metastases in MGMT-transduced 231-BR-EGFP and MGMT-expressing JIMT-1-BR3 sublines. In 62 patient-matched sets of primary breast tumors and resected brain metastases, 43.5% of the specimens had concordant low MGMT expression, whereas in another 14.5% of sets high MGMT staining in the primary tumor corresponded with low staining in the brain metastasis.

Conclusions: Temozolomide profoundly prevented the outgrowth of experimental brain metastases of breast cancer in an MGMT-dependent manner. These data provide compelling rationale for investigating the preventive efficacy of temozolomide in a clinical setting. Clin Cancer Res; 20(10); 2727–39. ©2014 AACR.
Effect of Aromatase Inhibition on Functional Gene Modules in Estrogen Receptor–Positive Breast Cancer and Their Relationship with Antiproliferative Response
Authors: Gao Qiong , Patani Neill , Dunbier Anita K. , Ghazoui Zara , Zvelebil Marketa , Martin Lesley-Ann , Dowsett Mitch
Published: March 2014

Purpose: To investigate potential associations between gene modules representing key biologic processes and response to aromatase inhibitors (AI) in estrogen receptor–positive (ER+) breast cancer.

Patients and Methods: Paired gene expression and Ki67 protein expression were available from 69 postmenopausal women with ER+ early breast cancer, at baseline and 2 weeks post-anastrozole treatment, in the presurgical setting. Functional gene modules (n = 26) were retrieved from published studies and their module scores were computed before and after elimination of proliferation-associated genes (PAG). Ki67 and module scores were assessed at baseline and 2 weeks post-anastrozole. Unsupervised clustering was used to assess associations between modules and Ki67.

Results: Proliferation-based modules were highly correlated with Ki67 expression both pretreatment and on-treatment. At baseline with and without PAGs, Ki67 expression was significantly inversely correlated with ERG, ESR1.2, SET, and PIK3CA modules. Modules measuring estrogen signaling strongly predicted antiproliferative response to therapy with and without PAGs. Baseline expression of insulin-like growth factor-1 (IGF-I) module predicted a poor change in Ki67-implicating genes within the module as involved in de novo resistance to AIs. High expression of Immune.2.STAT1 module pretreatment predicted poor antiproliferative response to therapy. A significant association between estrogen-regulated genes modules (ESR1, ESR1-2, SET, and ERG) was evident post AI.

Conclusions: Multiple processes and pathways are affected by AI treatment in ER+ breast cancer. Modules closely associated with ESR1 expression were predictive of good antiproliferative response to AIs, but modules representing immune activity and IGF-I/MAPK were predictive of poor Ki67 response, supporting their therapeutic targeting in combination with AIs. Clin Cancer Res; 20(9); 2485–94. ©2014 AACR.
Circulating Tumor Cells in Patients with Testicular Germ Cell Tumors
Authors: Nastały Paulina , Ruf Christian , Becker Pascal , Bednarz-Knoll Natalia , Stoupiec Małgorzata , Kavsur Refik , Isbarn Hendrik , Matthies Cord , Wagner Walter , Höppner Dirk , Fisch Margit , Bokemeyer Carsten , Ahyai Sascha , Honecker Friedemann , Riethdorf Sabine , Pantel Klaus
Published: March 2014

Purpose: Germ cell tumors (GCTs) represent the most frequent malignancies among young men, but little is known about circulating tumor cells (CTCs) in these tumors. Considering their heterogeneity, CTCs were investigated using two independent assays targeting germ cell tumor and epithelial cell–specific markers, and results were correlated with disease stage, histology, and serum tumor markers.

Experimental Design: CTCs were enriched from peripheral blood (n = 143 patients) and testicular vein blood (TVB, n = 19 patients) using Ficoll density gradient centrifugation. For CTC detection, a combination of germ cell tumor (anti-SALL4, anti-OCT3/4) and epithelial cell–specific (anti-keratin, anti-EpCAM) antibodies was used. In parallel, 122 corresponding peripheral blood samples were analyzed using the CellSearch system.

Results: In total, CTCs were detected in 25 of 143 (17.5%) peripheral blood samples, whereas only 11.5% of patients were CTC-positive when considering exclusively the CellSearch assay. The presence of CTCs in peripheral blood correlated with clinical stage (P < 0.001) with 41% of CTC positivity in patients with metastasized tumors and 100% in patients with relapsed and chemotherapy-refractory disease. Histologically, CTC-positive patients suffered more frequently from nonseminomatous primary tumors (P < 0.001), with higher percentage of yolk sac (P < 0.001) and teratoma (P = 0.004) components. Furthermore, CTC detection was associated with elevated serum levels of α-fetoprotein (AFP; P = 0.025), β-human chorionic gonadotropin (βHCG; P = 0.002), and lactate dehydrogenase (LDH; P = 0.002). Incidence and numbers of CTCs in TVB were much higher than in peripheral blood.

Conclusions: The inclusion of germ cell tumor–specific markers improves CTC detection in GCTs. CTCs occur frequently in patients with more aggressive disease, and there is a gradient of CTCs with decreasing numbers from the tumor-draining vein to the periphery. Clin Cancer Res; 20(14); 3830–41. ©2014 AACR.
CD133+ Tumor Initiating Cells in a Syngenic Murine Model of Pancreatic Cancer Respond to Minnelide
Authors: Banerjee Sulagna , Nomura Alice , Sangwan Veena , Chugh Rohit , Dudeja Vikas , Vickers Selwyn M. , Saluja Ashok
Published: March 2014

Purpose: Pancreatic adenocarcinoma is the fourth leading cause for cancer-related mortality with a survival rate of less than 5%. Late diagnosis and lack of effective chemotherapeutic regimen contribute to these grim survival statistics. Relapse of any tumor is largely attributed to the presence of tumor-initiating cells (TIC) or cancer stem cells (CSC). These cells are considered as hurdles to cancer therapy as no known chemotherapeutic compound is reported to target them. Thus, there is an urgent need to develop a TIC-targeted therapy for pancreatic cancer.

Experimental Design: We isolated CD133+ cells from a spontaneous pancreatic ductal adenocarcinoma mouse model and studied both surface expression, molecular markers of pancreatic TICs. We also studied tumor initiation properties by implanting low numbers of CD133+ cells in immune competent mice. Effect of Minnelide, a drug currently under phase I clinical trial, was studied on the tumors derived from the CD133+ cells.

Results: Our study showed for the first time that CD133+ population demonstrated all the molecular markers for pancreatic TIC. These cells initiated tumors in immunocompetent mouse models and showed increased expression of prosurvival and proinvasive proteins compared to the CD133− non-TIC population. Our study further showed that Minnelide was very efficient in downregulating both CD133− and CD133+ population in the tumors, resulting in a 60% decrease in tumor volume compared with the untreated ones.

Conclusion: As Minnelide is currently under phase I clinical trial, its evaluation in reducing tumor burden by decreasing TIC as well as non-TIC population suggests its potential as an effective therapy. Clin Cancer Res; 20(9); 2388–99. ©2014 AACR.
Adoptive Transfer of MART-1 T-Cell Receptor Transgenic Lymphocytes and Dendritic Cell Vaccination in Patients with Metastatic Melanoma
Authors: Chodon Thinle , Comin-Anduix Begoña , Chmielowski Bartosz , Koya Richard C. , Wu Zhongqi , Auerbach Martin , Ng Charles , Avramis Earl , Seja Elizabeth , Villanueva Arturo , McCannel Tara A. , Ishiyama Akira , Czernin Johannes , Radu Caius G. , Wang Xiaoyan , Gjertson David W. , Cochran Alistair J. , Cornetta Kenneth , Wong Deborah J.L. , Kaplan-Lefko Paula , Hamid Omid , Samlowski Wolfram , Cohen Peter A. , Daniels Gregory A. , Mukherji Bijay , Yang Lili , Zack Jerome A. , Kohn Donald B. , Heath James R. , Glaspy John A. , Witte Owen N. , Baltimore David , Economou James S. , Ribas Antoni
Published: March 2014

Purpose: It has been demonstrated that large numbers of tumor-specific T cells for adoptive cell transfer (ACT) can be manufactured by retroviral genetic engineering of autologous peripheral blood lymphocytes and expanding them over several weeks. In mouse models, this therapy is optimized when administered with dendritic cell (DC) vaccination. We developed a short 1-week manufacture protocol to determine the feasibility, safety, and antitumor efficacy of this double cell therapy.

Experimental Design: A clinical trial (NCT00910650) adoptively transferring MART-1 T-cell receptor (TCR) transgenic lymphocytes together with MART-1 peptide-pulsed DC vaccination in HLA-A2.1 patients with metastatic melanoma. Autologous TCR transgenic cells were manufactured in 6 to 7 days using retroviral vector gene transfer, and reinfused with (n = 10) or without (n = 3) prior cryopreservation.

Results: A total of 14 patients with metastatic melanoma were enrolled and 9 of 13 treated patients (69%) showed evidence of tumor regression. Peripheral blood reconstitution with MART-1–specific T cells peaked within 2 weeks of ACT, indicating rapid in vivo expansion. Administration of freshly manufactured TCR transgenic T cells resulted in a higher persistence of MART-1–specific T cells in the blood as compared with cryopreserved. Evidence that DC vaccination could cause further in vivo expansion was only observed with ACT using noncryopreserved T cells.

Conclusion: Double cell therapy with ACT of TCR-engineered T cells with a very short ex vivo manipulation and DC vaccines is feasible and results in antitumor activity, but improvements are needed to maintain tumor responses. Clin Cancer Res; 20(9); 2457–65. ©2014 AACR.