bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I/II Trial of Erlotinib and Cisplatin in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: A Princess Margaret Hospital Phase II Consortium and National Cancer Institute of Canada Clinical Trials Group Study
Authors: Siu Lillian L. , Soulieres Denis , Chen Eric X. , Pond Gregory R. , Chin Soo F. , Francis Peggy , Harvey Luc , Klein Meri , Zhang Wenjiang , Dancey Janet , Eisenhauer Elizabeth A. , Winquist Eric 
Published: May 2007

PurposeTo determine the phase II dose and objective response rate of erlotinib, a selective epidermal growth factor receptor tyrosine kinase inhibitor, in combination with cisplatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC).Patients and MethodsHNSCC patients with no prior chemotherapy and measurable disease were treated in three escalating-dose cohorts of daily continuous oral (PO) erlotinib and intermittent intravenous (IV) cisplatin given every 21 days. The recommended phase II dose (RPTD) was then evaluated in a two-stage trial with a primary end point of objective response rate.ResultsA total of 51 patients were enrolled. The RPTD was identified as erlotinib 100 mg PO daily and cisplatin 75 mg/m2IV every 21 days. Forty-five patients were treated at the RPTD, of which 44 and 43 were eligible for toxicity and efficacy evaluations, respectively. The intention-to-treat response rate was 21%, with one complete and eight partial responses (95% CI, 10% to 36%), and disease stabilization was achieved in 21 patients (49%; 95% CI, 33% to 65%). Median progression-free survival was 3.3 months (95% CI, 2.7 to 4.8 months) and median overall survival was 7.9 (95% CI, 5.6 to 9.5) months. The combination was well tolerated, with minimal grade 3 or higher toxicity. Subgroup analysis suggested that patients who developed higher grade skin rashes during cycle 1 had better survival outcomes (P = .034).ConclusionThis schedule of erlotinib and cisplatin has a favorable toxicity profile and has antitumor activity in HNSCC comparable to standard combination chemotherapy regimens.
Predictive and Pharmacodynamic Biomarker Studies in Tumor and Skin Tissue Samples of Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck Treated With Erlotinib
Authors: Agulnik Mark , da Cunha Santos Gilda , Hedley David , Nicklee Trudey , dos Reis Patricia Pintor , Ho James , Pond Gregory R. , Chen Heidi , Chen Shuo , Shyr Yu , Winquist Eric , Soulieres Denis , Chen Eric X. , Squire Jeremy A. , Marrano Paula , Kamel-Reid Suzanne , Dancey Janet , Siu Lillian L. , Tsao Ming S. 
Published: May 2007

PurposePharmacodynamic tissue studies were conducted on a phase I/II trial of erlotinib and cisplatin in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Levels of epidermal growth factor receptor (EGFR), downstream signaling components, and markers of angiogenesis and apoptosis were evaluated to determine the relationship between correlative end points and clinical outcomes.Patients and MethodsPretreatment and during-treatment tumor and skin biopsies, and archival tumor specimens were evaluated for EGFR, phosphorylated (p) -EGFR, extracellular signal-regulated kinase (ERK), p-ERK, Akt, p-Akt, Ki67, p27, p-nuclear factor kappa B (NFκB), p-signal transducer and activator of transcription 3 (STAT3), and EGFR gene copy number.ResultsOn 37 archival samples, response to therapy was evident in two of four (50%) patients with high EGFR gene copy number tumors and in four of 27 (15%) patients with low gene copy number tumors. On nine paired tumor biopsies, elevated pretreatment levels of p27 and p-STAT3 predicted for prolonged time to progression (TTP) and overall survival (OS; P ≤ .03). With treatment, a decrease in p-EGFR, p-NFκB, and p27 correlated with increased TTP, OS, or both TTP and OS, respectively (P ≤ .04). Multidimensional scaling (MDS) models revealed clustering profiles of tumor markers by immunofluorescence could predict response. On 32 paired skin biopsies, suppression of p-EGFR with therapy correlated with increased OS (P = .045).ConclusionHigh EGFR gene copy in tumor specimens may predict which patients have an increased likelihood of response to erlotinib, and decreased p-EGFR level in skin biopsies during therapy may represent a potential surrogate marker for improved clinical outcome. MDS represents a novel way to evaluate the relationships between molecular markers and clinical outcome. Additional biomarker studies with larger sample sizes are required to elucidate HNSCC patients who may benefit from this targeted therapy.
Assessment of Care by Breast Cancer Patients Participating or Not Participating in a Randomized Controlled Trial: A Report With the Patients' Committee for Clinical Trials of the Ligue Nationale Contre le Cancer
Authors: Julian-Reynier Claire , Genève Jean , Dalenc Florence , Genre Dominique , Monnier Alain , Kerbrat Pierre , Largillier Rémy , Serin Daniel , Rios Maria , Roché Henri , Jimenez Marta , Tarpin Carole , Maraninchi Dominique 
Published: May 2007

Purpose Cancer patients participating in randomized controlled trials (RCTs) have not been found to have better clinical outcomes than other patients. Our objective was to assess the impact of RCTs on patients' satisfaction with care. Patients and Methods A prospective study was carried out in a cohort of women with breast cancer (N = 455) divided into those invited to participate in an RCT (201 acceptances, 66 refusals) and a comparable control group not invited to participate (n = 188). All the patients underwent the same treatment (fluorouracil, epirubicin, and cyclophosphamide 100 mg/m2 for six cycles). One and 7 months after the beginning of chemotherapy, self-administered satisfaction scores were used to compare the women's assessment of their care (Comprehensive Assessment of Satisfaction with Care validated scale). Results At the beginning of chemotherapy, women to whom RCT had been proposed rated the doctors' availability (average ± standard deviation [SD]: RCT acceptance group, 3.60 ± 0.78; RCT refusal group, 3.68 ± 0.87; control group, 3.41 ± 0.82; P ≤ .02) and the doctors' communication (average ± SD: RCT acceptance group, 3.56 ± 0.88; RCT refusal group, 3.67 ± 0.88; control group, 3.39 ± 0.84; P ≤ .05) higher than those to whom the trial was not proposed. After the treatment, participants in the RCT felt that their doctor was more supportive (average ± SD: RCT acceptance group, 3.04 ± 0.92; control group, 2.77 ± 0.85; P = .005) and more informative about their illness and treatment (average ± SD: RCT acceptance group, 3.34 ± 0.88; control group, 3.08 ± 0.92; P = .006) than those in the control group. The general level of satisfaction was also higher in the RCT acceptance group. Conclusion Women participating in an RCT have a more positive picture of their doctors' care than others, probably because of the structural effects of the informed consent and data collection processes.
Economic Analysis of NCIC CTG JBR.10: A Randomized Trial of Adjuvant Vinorelbine Plus Cisplatin Compared With Observation in Early Stage Non–Small-Cell Lung Cancer—A Report of the Working Group on Economic Analysis, and the Lung Disease Site Group, National Cancer Institute of Canada Clinical Trials Group
Authors: Ng Raymond , Hasan Baktiar , Mittmann Nicole , Florescu Marie , Shepherd Frances A. , Ding Keyue , Butts Charles Andrew , Cormier Yvon , Darling Gail , Goss Glenwood D. , Inculet Richard , Seymour Lesley , Winton Timothy L. , Evans William K. , Leighl Natasha B. 
Published: May 2007

PurposeNational Cancer Institute of Canada Clinical Trials Group JBR.10 study is among the landmark trials that have established third generation platinum-based adjuvant chemotherapy as the standard of care after resection of stages IB-II NSCLC, improving absolute 5-year survival by 15% and median survival by 21 months. This cost-effectiveness analysis of adjuvant chemotherapy from the perspective of Canada's public health care system was undertaken based on the JBR.10 study population.Patients and MethodsThe primary outcome of the study was the incremental cost effectiveness ratio (ICER) expressed in dollars per life-year gained (LYG). Direct medical resource utilization data were collected retrospectively from trial data and medical records of patients enrolled in the JBR.10 study at the five largest accruing Canadian centers, from the time of random assignment until death or study closure (April 2004). Survival and available costs (2005 Canadian dollars [$CAD]) are presented both with and without discounting at 5% per year.ResultsUtilization data were collected from 172 Canadian patients (36% of the trial population), 85 randomly assigned to observation and 87 randomly assigned to chemotherapy. The mean costs of treatment per patient in the observation and adjuvant chemotherapy arms were $23,878 and $31,319, respectively, with an ICER of CAD$7,175/LYG discounted (95% CI, −$3,463 to $41,565), and $10,096/LYG undiscounted (95% CI, −$819 to $55,651).ConclusionAdjuvant vinorelbine plus cisplatin is a highly cost effective treatment that compares very favorably with other standard health care interventions.
Predominant Treatment Failure in Postprostatectomy Patients Is Local: Analysis of Patterns of Treatment Failure in SWOG 8794
Authors: Swanson Gregory P. , Hussey Michael A. , Tangen Catherine M. , Chin Joseph , Messing Edward , Canby-Hagino Edith , Forman Jeffrey D. , Thompson Ian M. , Crawford E. David 
Published: May 2007

Purpose Southwest Oncology Group (SWOG) trial 8794 demonstrated that adjuvant radiation reduces the risk of biochemical (prostate-specific antigen [PSA]) treatment failure by 50% over radical prostatectomy alone. In this analysis, we stratified patients as to their preradiation PSA levels and correlated it with outcomes such as PSA treatment failure, local recurrence, and distant failure, to serve as guidelines for future research. Patients and Methods Four hundred thirty-one subjects with pathologically advanced prostate cancer (extraprostatic extension, positive surgical margins, or seminal vesicle invasion) were randomly assigned to adjuvant radiotherapy or observation. Results Three hundred seventy-four eligible patients had immediate postprostatectomy and follow-up PSA data. Median follow-up was 10.2 years. For patients with a postsurgical PSA of ≤ 0.2 ng/mL, radiation was associated with reductions in the 10-year risk of biochemical treatment failure (72% to 42%), local failures (20% to 7%), and distant failures (12% to 4%). For patients with a postsurgical PSA between higher than 0.2 and ≤ 1.0 ng/mL, reductions in the 10-year risk of biochemical failure (80% to 73%), local failures (25% to 9%), and distant failures (16% to 12%) were realized. In patients with postsurgical PSA higher than 1.0, the respective findings were 94% versus 100%, 28% versus 9%, and 44% versus 18%. Conclusion The pattern of treatment failure in high-risk patients is predominantly local with a surprisingly low incidence of metastatic failure. Adjuvant radiation to the prostate bed reduces the risk of metastatic disease and biochemical failure at all postsurgical PSA levels. Further improvement in reducing local treatment failure is likely to have the greatest impact on outcome in high-risk patients after prostatectomy.
Chemotherapy Delivery Issues in Central Nervous System Malignancy: A Reality Check
Authors: Muldoon Leslie L. , Soussain Carole , Jahnke Kristoph , Johanson Conrad , Siegal Tali , Smith Quentin R. , Hall Walter A. , Hynynen Kullervo , Senter Peter D. , Peereboom David M. , Neuwelt Edward A. 
Published: May 2007

PurposeThis review assesses the current state of knowledge regarding preclinical and clinical pharmacology for brain tumor chemotherapy and evaluates relevant brain tumor pharmacology studies before October 2006.ResultsChemotherapeutic regimens in brain tumor therapy have often emerged from empirical clinical studies with retrospective pharmacologic explanations, rather than prospective trials of rational chemotherapeutic approaches. Brain tumors are largely composed of CNS metastases of systemic cancers. Primary brain tumors, such as glioblastoma multiforme or primary CNS lymphomas, are less common. Few of these tumors have well-defined optimal treatment. Brain tumors are protected from systemic chemotherapy by the blood-brain barrier (BBB) and by intrinsic properties of the tumors. Pharmacologic studies of delivery of conventional chemotherapeutics and novel therapeutics showing actual tumor concentrations and biologic effect are lacking.ConclusionIn this article, we review drug delivery across the BBB, as well as blood-tumor and –cerebrospinal fluid (CSF) barriers, and mechanisms to increase drug delivery to CNS and CSF tumors. Because of the difficulty in treating CNS tumors, innovative treatments and alternative delivery techniques involving brain/cord capillaries, choroid plexus, and CSF are needed.
Brain White Matter Expansion in Human Obesity and the Recovering Effect of Dieting
Authors: Haltia Lauri T. , Viljanen Antti , Parkkola Riitta , Kemppainen Nina , Rinne Juha O. , Nuutila Pirjo , Kaasinen Valtteri 
Published: May 2007

Abstract
Context and Objective: Obesity is associated with several metabolic abnormalities. Recent studies suggest that obesity also affects brain function and is a risk factor for some degenerative brain diseases. The objective of this study was to examine the effects of weight gain and weight loss on brain gray and white matter structure. We hypothesized that possible differences seen in the brains of obese subjects would disappear or diminish after an intensive dieting period.
Methods: In part I of the study, we scanned with magnetic resonance imaging 16 lean (mean body mass index, 22 kg/m2) and 30 obese (mean body mass index, 33 kg/m2) healthy subjects. In part II, 16 obese subjects continued with a very low-calorie diet for 6 wk, after which they were scanned again. Regional brain white and gray matter volumes were calculated using voxel-based morphometry.
Results: White matter volumes were greater in obese subjects, compared with lean subjects in several basal brain regions, and obese individuals showed a positive correlation between white matter volume in basal brain structures and waist to hip ratio. The detected white matter expansion was partially reversed by dieting. Regional gray matter volumes did not differ significantly in obese and lean subjects, and dieting did not affect gray matter.
Conclusions: The precise mechanism for the discovered white matter changes remains unclear, but the present study demonstrates that obesity and dieting are associated with opposite changes in brain structure. It is not excluded that white matter expansion in obesity has a role in the neuropathogenesis of degenerative brain diseases.
Follicle-Stimulating Hormone Induces Multiple Signaling Cascades: Evidence that Activation of Rous Sarcoma Oncogene, RAS, and the Epidermal Growth Factor Receptor Are Critical for Granulosa Cell Differentiation
Authors: Wayne Chad M. , Fan Heng-Yu , Cheng Xiaodong , Richards JoAnne S. 
Published: May 2007

Abstract
FSH regulates ovarian granulosa cell differentiation not only by activating adenylyl cyclase and protein kinase A (PKA) but also by other complex mechanisms. Using primary rat granulosa cell cultures, we provide novel evidence that FSH rapidly activates two small GTP-binding proteins RAP1 and RAS. FSH activation of RAP1 requires cAMP-mediated activation of exchange factor activated by cAMP/RAPGEF3 whereas FSH activation of RAS and downstream signaling cascades involves multiple factors. Specifically, FSH activation of RAS required Rous sarcoma oncogene (SRC) family tyrosine kinase (SFK) and epidermal growth factor receptor (EGFR) tyrosine kinase activities but not PKA. FSH-induced phosphorylation of ERK1/2 was blocked by dominant-negative RAS as well as by inhibitors of EGFR tyrosine kinase, metalloproteinases involved in growth factor shedding, and SFKs. In contrast, FSH-induced phosphorylation of protein kinase B (PKB/AKT) and the Forkhead transcription factor, FOXO1a occurred by SFK-dependent but RAS-independent mechanisms. The SFKs, c-SRC and FYN, and the SRC-related tyrosine kinase ABL were present and phosphorylated rapidly in response to FSH. Lastly, the EGF-like factor amphiregulin (AREG) activated RAS and ERK1/2 phosphorylation in granulosa cells by mechanisms that were selectively blocked by an EGFR antagonist but not by an SFK antagonist. However, AREG-mediated phosphorylation of PKB and FOXO1a required both EGFR and SFK activation. Moreover, we show that FSH induces AREG and that activation of the EGFR impacts granulosa cell differentiation and the expression of genes characteristic of the luteal cell phenotype. Thus, FSH orchestrates the coordinate activation of three diverse membrane-associated signaling cascades (adenylyl cyclase, RAS, and SFKs) that converge downstream to activate specific kinases (PKA, ERK1/2, and PKB/FOXO1a) that control granulosa cell function and differentiation.
Uterine involvement in guineapig salmonellosis
Authors: Okewole P. A. , Uche E. M. I. , Oyetunde I. L. , Odeyemi P. S. , Dawul P. B. 
Published: May 2007

Of 334 mature breeding guineapigs, 53 (15·9%) died in a disease outbreak involving Salmonella typhimurium serotypes 1, 4, 5 and 12 : i : 1,2. The uterus was consistently involved. Nine other Salmonella-free mature female guineapigs when inoculated with a pure isolate from the outbreak, using the subcutaneous, intramuscular or per os route, succumbed to salmonellosis, reproducing signs and lesions observed during the outbreak. Abortion was not recorded during the outbreak despite many pregnant sows being affected. The isolate was sensitive to gentamicin, tetracycline, ampicillin and cefuroxime but resistant to co-trimoxazole, erythromycin and penicillin.
Preemptive Therapy in Nonneutropenic Patients with Candida Infection Using the Japanese Guidelines
Authors: Tsuruta Ryosuke , Mizuno Hidekazu , Kaneko Tadashi , Oda Yasutaka , Kaneda Kotaro , Fujita Motoki , Inoue Takeshi , Kasaoka Shunji , Maekawa Tsuyoshi 
Published: May 2007

Background: The Japanese Guidelines for the Diagnosis and Treatment of Deep-Seated Mycosis were established in 2003. Proven Candida infection (CI) is defined as at least one positive blood culture yielding a Candida species. Clinically documented CI requires documentation of more than 2 sites of colonization and a positive plasma β-O-glucan test. Possible CI is diagnosed by one of the above criteria in febrile, nonneutropenic critically ill patients. Objective: To assess the use of definitions of clinically documented and possible CI for guiding preemptive antifungal therapy in critically ill patients. Methods: The patients treated in our intensive care unit (ICU) for at least 48 hours between 2000 and 2004 were investigated. The administration of antifungal agents and ICU mortality were compared among proven, clinically documented, and possible CI groups for age, sex, APACHE II score, diagnosis, length of ICU stay, treatment, number of colonization sites, and plasma β-D-glucan level. Results: Six patients were diagnosed with proven CI, 25 were diagnosed with clinically documented CI, and 104 with possible CI. The patients with clinically documented CI were compared with those with possible CI, and statistically significant differences were found in the following variables: APACHE II score (p = 0.018), length of ICU stay (p < 0.01), use of ventilator (p = 0.027), tracheotomy (p = 0.027), number of colonization sites (p < 0.001), plasma β-D-glucan level (p < 0.001), and administration of antifungal agents (p < 0.001); incidence of mortality was not statistically significant (p = 0.33). The shorter length of ICU stay, use of ventilator, and continuous hemodiafiltration were risk factors for death after adjusting for APACHE II score, admission before/after 2003, antifungal therapy, and other factors. Although the frequency of the administration of preemptive antifungal therapy was higher after 2003 than before, the mortality rate did not differ significantly, Conclusions: The use of the definitions of clinically documented and possible CI may be beneficial for determining when it is appropriate to initiate preemptive antifungal therapy. However, use of the guidelines did not lead to prevention of possible CI proceeding to clinically documented CI or to improved mortality.
Radiolanthanides in endoradiotherapy: an overview
Authors: Rösch Frank 
Published: May 2007

Endoradiotherapy (targeted radionuclide therapy) is a systemic approach, involving a radiolabeled targeting vector with a well characterized biochemical strategy to selectively deliver a cytotoxic level of radiation to a disease site on a cellular/molecular level. The group of radiolanthanides has been considered both for imaging and therapy over many years. Some radiolanthanides have been and are increasingly applied for therapeutic purposes.
However, the clinical use of endoradiotherapeuticals containing radiolanthanides requires a complex and interdisciplinary approach. It involves, among other factors, the choice of the most suitable lanthanide radionuclide (in terms of nuclear decay parameters such as type and energy of the particles emitted, half-life, decay products etc.); the identification of the most promising production route; the determination of the relevant production parameters such as excitation functions, nuclear reaction yields, radionuclidic purities, specific activities etc.; the chemical isolation of the radiolanthanide produced from the target material (except the (n, γ) production route); the synthesis of the labelling precursor, and labelling of the precursor and the chemical purification and isolation of the labelled radiotherapeutical, ready for i.v. injection; and finally the investigation of pharmacological targeting parameters of the labelled radiotherapeutical in vitro and in vivo (animal experiments).
Preclinical evaluation of somatostatin analogs bearing two macrocyclic chelators for high specific activity labeling with radiometals
Authors: Storch Daniel , Schmitt Joerg S. , Waldherr Christian , Waser Beatrice , Reubi Jean-Claude , Maecke Helmut R. 
Published: May 2007

Radiometallated analogues of the regulatory peptide somatostatin are of interest in thein vivolocalization and targeted radiotherapy of somatostatin receptor-overexpressing tumors. An important aspect of their usein vivois a fast and efficient labeling (complexation) protocol for radiometals along with a high specific activity.We describe in this manuscript synthetic methods for the coupling of two chelators (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid=DOTA) to the bioactive peptide [Tyr3, Thr8]-octreotide (TATE) in order to increase the specific activity (radioactivity in Bq per mole peptide). The full chelator-linker-peptide conjugate was assembled on solid support using standard Fmoc chemistry. Two DOTA-chelators were linked to the peptide using lysine or N,N′-bis(3-aminopropyl)-glycine (Apg); in addition, pentasarcosine (Sar5) was used as a spacer between the chelators and the peptide to probe its influence on biology and pharmacology. Complexation rates with In3+and Y3+salts and the corresponding radiometals were high, the bis-DOTA-derivatives showed higher complexation rates and gave higher specific activity than DOTA-TATE.Pharmacological and biological data of the complexed molecules did not show significant differences if compared to the parent peptide [111/natIn-DOTA]-TATE except for [(111/natIn-DOTA)2-Apg]-TATE which showed a lower binding affinity and rate of internalization into tumor cells. The biodistribution of [(111/natIn-DOTA)-Lys(111/natIn-DOTA)]-TATE in the rat tumor model (AR4-2J) showed a high and specific (as shown by a blocking experiment) tracer uptake in somatostatin receptor-positive tissue but a lower tumor uptake compared to [111/natIn-DOTA]-TATE.