bluuebunny/crossref_metadata_2025 huggingface dataset:
Intrinsic genetic characteristics determine tumor-modifying capacity of fibroblasts: matrix metalloproteinase-3 5A/5A genotype enhances breast cancer cell invasion
Authors: Holliday Deborah L , Hughes Simon , Shaw Jacqueline A , Walker Rosemary A , Jones J Louise
Published: October 2007

Background

Stromal fibroblasts can contribute to tumor invasion through the release of matrix metalloproteinases (MMPs). Population studies have suggested that single nucleotide polymorphisms (SNPs) in MMP genes influence levels of expression and may be associated with breast cancer risk and with disease progression. This study directly examined the impact of MMP SNP genotype on the ability of host fibroblasts to promote tumor cell invasion.

Methods

Primary breast fibroblasts were isolated from patients with (n = 13) or without (n = 19) breast cancer, and their ability to promote breast cancer cell invasion was measured in in vitro invasion assays. Fibroblast invasion-promoting capacity (IPC) was analyzed in relation to donor type (tumor or non-tumor patient), MMP-1, MMP-3, and MMP-9 SNP genotype and MMP activity using independent samples t test and analysis of variance. All statistical tests were two-sided.

Results

Tumor-derived fibroblasts promoted higher levels of invasion than normal fibroblasts (p = 0.041). When IPC was related to genotype, higher levels of IPC were generated by tumor fibroblasts with the high-expressing MMP-3 5A/5A genotype compared with the 5A/6A and 6A/6A genotypes (p = 0.05 and 0.07, respectively), and this was associated with enhanced MMP-3 release. The functional importance of MMP-3 was demonstrated by enhanced invasion in the presence of recombinant MMP-3, whereas reduction occurred in the presence of a specific MMP-3 inhibitor. An inverse relationship was demonstrated between fibroblast IPC and the high-expressing MMP-1 genotype (p = 0.031), but no relationship was seen with MMP-9 SNP status. In contrast, normal fibroblasts showed no variation in IPC in relation to MMP genotype, with MMP-3 5A/5A fibroblasts exhibiting significantly lower levels of IPC than their tumor-derived counterparts (p = 0.04).

Conclusion

This study has shown that tumor-derived fibroblasts exhibit higher levels of IPC than normal fibroblasts and that the MMP-3 5A/5A genotype contributes to this through enhanced MMP-3 release. Despite a high-expressing genotype, normal fibroblasts do not exhibit higher IPC or enhanced MMP release. This suggests that more complex changes occur in tumor-derived fibroblasts, enabling full expression of the MMP SNP genotype and these possibly are epigenetic in nature. The results do suggest that, in women with breast cancer, a high-expressing MMP-3 genotype may promote tumor progression more effectively.
MicroRNA expression profiling of human breast cancer identifies new markers of tumor subtype
Authors: Blenkiron Cherie , Goldstein Leonard D , Thorne Natalie P , Spiteri Inmaculada , Chin Suet-Feung , Dunning Mark J , Barbosa-Morais Nuno L , Teschendorff Andrew E , Green Andrew R , Ellis Ian O , Tavaré Simon , Caldas Carlos , Miska Eric A
Published: October 2007

Background

MicroRNAs (miRNAs), a class of short non-coding RNAs found in many plants and animals, often act post-transcriptionally to inhibit gene expression.

Results

Here we report the analysis of miRNA expression in 93 primary human breast tumors, using a bead-based flow cytometric miRNA expression profiling method. Of 309 human miRNAs assayed, we identify 133 miRNAs expressed in human breast and breast tumors. We used mRNA expression profiling to classify the breast tumors as luminal A, luminal B, basal-like, HER2+ and normal-like. A number of miRNAs are differentially expressed between these molecular tumor subtypes and individual miRNAs are associated with clinicopathological factors. Furthermore, we find that miRNAs could classify basal versus luminal tumor subtypes in an independent data set. In some cases, changes in miRNA expression correlate with genomic loss or gain; in others, changes in miRNA expression are likely due to changes in primary transcription and or miRNA biogenesis. Finally, the expression of DICER1 and AGO2 is correlated with tumor subtype and may explain some of the changes in miRNA expression observed.

Conclusion

This study represents the first integrated analysis of miRNA expression, mRNA expression and genomic changes in human breast cancer and may serve as a basis for functional studies of the role of miRNAs in the etiology of breast cancer. Furthermore, we demonstrate that bead-based flow cytometric miRNA expression profiling might be a suitable platform to classify breast cancer into prognostic molecular subtypes.
High-resolution aCGH and expression profiling identifies a novel genomic subtype of ER negative breast cancer
Authors: Chin Suet F , Teschendorff Andrew E , Marioni John C , Wang Yanzhong , Barbosa-Morais Nuno L , Thorne Natalie P , Costa Jose L , Pinder Sarah E , van de Wiel Mark A , Green Andrew R , Ellis Ian O , Porter Peggy L , Tavaré Simon , Brenton James D , Ylstra Bauke , Caldas Carlos
Published: October 2007

Background

The characterization of copy number alteration patterns in breast cancer requires high-resolution genome-wide profiling of a large panel of tumor specimens. To date, most genome-wide array comparative genomic hybridization studies have used tumor panels of relatively large tumor size and high Nottingham Prognostic Index (NPI) that are not as representative of breast cancer demographics.

Results

We performed an oligo-array-based high-resolution analysis of copy number alterations in 171 primary breast tumors of relatively small size and low NPI, which was therefore more representative of breast cancer demographics. Hierarchical clustering over the common regions of alteration identified a novel subtype of high-grade estrogen receptor (ER)-negative breast cancer, characterized by a low genomic instability index. We were able to validate the existence of this genomic subtype in one external breast cancer cohort. Using matched array expression data we also identified the genomic regions showing the strongest coordinate expression changes ('hotspots'). We show that several of these hotspots are located in the phosphatome, kinome and chromatinome, and harbor members of the 122-breast cancer CAN-list. Furthermore, we identify frequently amplified hotspots on 8q22.3 (EDD1, WDSOF1), 8q24.11-13 (THRAP6, DCC1, SQLE, SPG8) and 11q14.1 (NDUFC2, ALG8, USP35) associated with significantly worse prognosis. Amplification of any of these regions identified 37 samples with significantly worse overall survival (hazard ratio (HR) = 2.3 (1.3-1.4) p = 0.003) and time to distant metastasis (HR = 2.6 (1.4-5.1) p = 0.004) independently of NPI.

Conclusion

We present strong evidence for the existence of a novel subtype of high-grade ER-negative tumors that is characterized by a low genomic instability index. We also provide a genome-wide list of common copy number alteration regions in breast cancer that show strong coordinate aberrant expression, and further identify novel frequently amplified regions that correlate with poor prognosis. Many of the genes associated with these regions represent likely novel oncogenes or tumor suppressors.
Access to Pediatric Cancer Care by Age, Race, and Diagnosis, and Outcomes of Cancer Treatment in Pediatric and Adolescent Patients in the State of Georgia
Authors: Howell Della L. , Ward Kevin C. , Austin Harland D. , Young John L. , Woods William G.
Published: October 2007

Purpose

There have been concerns among pediatric oncologists that adolescent and minority patients are not getting adequate access to care. This study examines access to cancer care and survival outcomes based on age, race, and type of cancer in patients in Georgia.

Patients and Methods

We performed a retrospective review of 1,751 cancer patients aged 0 to 19 years, diagnosed between 1998 and 2002, in the Georgia Comprehensive Cancer Registry, which identified patients who were treated at one of five Georgia pediatric cancer centers (Children's Oncology Group [COG] members) at any point in their treatment. Data were further analyzed for age at diagnosis, race, county of residence, and 5-year survival.

Results

Eighty-seven percent of patients aged 0 to 14 years and 36% of those aged 15 to 19 years were treated at a COG institution. Twenty-five percent of all patients were of African descent, with 75.4% of black versus 70.3% of white patients (age 0 to 19 years) treated at a COG institution (P < .01); 97.1% of other minorities were treated at a COG institution (P < .05). The 5-year actuarial survival rates for more pediatric-specific cancers were significantly lower in all leukemias (75.1% v 46.4%; P = .0015), and acute lymphoblastic leukemia specifically (86.3% v 53.3%; P < .05) for patients not treated at a COG institution. Actuarial survival rates were much lower for blacks than whites in all cancers as a whole (70% v 82%; P < .001) and for many specific subtypes.

Conclusion

Adolescent-aged patients are less likely to be referred to a COG institution, potentially exposing them to worse outcomes in some cancer subtypes. Reassuringly, minority populations are receiving adequate access to pediatric cancer care; unfortunately their survival rates are lower.
Pharmacogenetic Assessment of Toxicity and Outcome After Platinum Plus Taxane Chemotherapy in Ovarian Cancer: The Scottish Randomised Trial in Ovarian Cancer
Authors: Marsh Sharon , Paul Jim , King Cristi R. , Gifford Gillian , McLeod Howard L. , Brown Robert
Published: October 2007

Purpose

Standard therapy for advanced ovarian cancer consists of a platinum agent in combination with a taxane, which has a 5-year survival rate of approximately 45%. The large individual variability for ovarian cancer patients in both outcome and toxicity risk from chemotherapy makes the identification of pharmacogenetic markers that can be used to screen patients before therapy selection an attractive prospect.

Patients and Methods

We assessed 27 selected polymorphisms based on previously described associations or putative functional effects in 16 key genes from pathways that may influence cellular sensitivity to taxanes (ABCB1, ABCC1, ABCC2, ABCG2, CDKN1A, CYP1B1, CYP2C8, CYP3A4, CYP3A5, MAPT, and TP53) and platinum (ABCC2, ABCG2, ERCC1, ERCC2, GSTP1, MPO, and XRCC1) using polymerase chain reaction and Pyrosequencing in 914 ovarian cancer patients from the Scottish Randomised Trial in Ovarian Cancer phase III trial who were treated at presentation with carboplatin and taxane regimens after cytoreductive surgery.

Results

No reproducible significant associations between genotype and outcome or toxicity were found for any of the genes analyzed. Previously reported genotype associations could not be replicated in this large study of a well-defined patient population within one specific clinical trial.

Conclusion

There are no clear candidates for taxane/platinum pharmacogenetic markers. This study highlights the need for validation of putative genetic markers in large, well-defined clinical sample sets.
Hepatic Resection After Rescue Cetuximab Treatment for Colorectal Liver Metastases Previously Refractory to Conventional Systemic Therapy
Authors: Adam René , Aloia Thomas , Lévi Francis , Wicherts Dennis A. , de Haas Robbert J. , Paule Bernard , Bralet Marie-Pierre , Bouchahda Mohamed , Machover David , Ducreux Michel , Castagne Vincent , Azoulay Daniel , Castaing Denis
Published: October 2007

Purpose

In patients with unresectable colorectal liver metastases (CLM) resistant to first-line chemotherapy, the impact of cetuximab therapy on resectability is unknown. This study was performed to determine the post-cetuximab resectability rate and to examine postoperative outcomes for these heavily pretreated patients.

Patients and Methods

From February 2004 to April 2006, we evaluated 151 patients with unresectable CLM resistant to initial chemotherapy and subsequently treated with systemic cetuximab. Resectability rates, patient outcomes, and tumoral and nontumoral liver pathology were assessed.

Results

A total of 27 patients underwent surgery after a median of six cycles of cetuximab + irinotecan (20 of 27), oxaliplatin (four of 27), or both (one of 27). Eighteen patients (67%) had experienced treatment failure after at least two lines of chemotherapy before cetuximab. Twenty-five of the 27 patients who had surgery underwent hepatectomy: nine of 133 patients who were treated completely at our institution (resectability rate, 7%) and 16 of 18 patients who were referred from other institutions after systemic cetuximab therapy. Postoperative mortality was 3.7% (one of 27), with a complication rate of 50%. Histopathologic liver abnormalities were found in nine patients (36%), without specific lesions attributable to cetuximab. After median follow-up of 16 months, 23 of 25 patients who underwent resection (92%) were alive, and 10 patients (40%) were disease free. Median overall (OS) and progression-free survival (PFS) from initiation of cetuximab therapy were 20 and 13 months, respectively.

Conclusion

For CLM refractory to conventional chemotherapy, combination therapy with cetuximab increases resectability rates without increasing operative mortality or liver injury. The median OS and PFS of 20 and 13 months, respectively, suggest that this novel oncosurgical strategy benefits patients with previously refractory disease who respond subsequently to cetuximab.
Actual 10-Year Survival After Resection of Colorectal Liver Metastases Defines Cure
Authors: Tomlinson James S. , Jarnagin William R. , DeMatteo Ronald P. , Fong Yuman , Kornprat Peter , Gonen Mithat , Kemeny Nancy , Brennan Murray F. , Blumgart Leslie H. , D'Angelica Michael
Published: October 2007

Purpose

Resection of colorectal liver metastases (CLM) in selected patients has evolved as the standard of care during the last 20 years. In the absence of prospective randomized clinical trials, a survival benefit has been deduced relative to historical controls based on actuarial data. There is now sufficient follow-up on a significant number of patients to address the curative intent of resecting CLM.

Methods

Retrospective review of a prospectively maintained database was performed on patients who underwent resection of CLM from 1985 to 1994. Postoperative deaths were excluded. Disease-specific survival (DSS) was calculated from the time of hepatectomy using the Kaplan-Meier method.

Results

There were 612 consecutive patients identified with 10-year follow-up. Median DSS was 44 months. There were 102 actual 10-year survivors. Ninety-nine (97%) of the 102 were disease free at last follow-up. Only one patient experienced a disease-specific death after 10 years of survival. In contrast, 34% of the 5-year survivors suffered a cancer-related death. Previously identified poor prognostic factors found among the 102 actual 10-year survivors included 7% synchronous disease, 36% disease-free interval less than 12 months, 25% bilobar metastases, 50% node-positive primary, 39% more than one metastasis, and 35% tumor size more than 5 cm.

Conclusion

Patients who survive 10 years appear to be cured of their disease, whereas approximately one third of actual 5-year survivors succumb to a cancer-related death. In well-selected patients, there is at least a one in six chance of cure after hepatectomy for CLM. The presence of poor prognostic factors does not preclude the possibility of long-term survival and cure.
Tumor Necrosis Factor α As a New Target for Renal Cell Carcinoma: Two Sequential Phase II Trials of Infliximab at Standard and High Dose
Authors: Harrison Michelle L. , Obermueller Eva , Maisey Nick R. , Hoare Susan , Edmonds Kim , Li Ningfeng F. , Chao David , Hall Kate , Lee Chooi , Timotheadou Eleni , Charles Kellie , Ahern Roger , King D. Mike , Eisen Tim , Corringham Robert , DeWitte Mark , Balkwill Frances , Gore Martin
Published: October 2007

Purpose

Tumor necrosis factor α (TNF-α) may play a role in renal cell carcinoma (RCC). We performed two sequential phase II studies of infliximab, an anti–TNF-α monoclonal antibody, in patients with immunotherapy-resistant or refractory RCC.

Patients and Methods

Patients progressing after cytokine therapy were treated with intravenous infliximab as follows: study 1 (19 patients), 5 mg/kg at weeks 0, 2, and 6, and then every 8 weeks; study 2 (18 patients), 10 mg/kg at weeks 0, 2, and 6, and then every 4 weeks. Treatment continued until disease progression (PD). Response was assessed according to Response Evaluation Criteria in Solid Tumors. Plasma levels of TNF-α, CCL2, and interleukin-6 (IL-6) were measured before and during treatment.

Results

TNF-α and its receptors were detected in malignant cells in RCC biopsies. In study 1, three patients (16%) achieved partial response (PR) and three patients (16%) achieved stable disease (SD). Median duration of response (PR + SD) was 7.7 months (range, 5.0 to 40.5+ months). In study 2, 11 patients (61%) achieved SD. Median duration of response was 6.2 months (range, 3.5 to 24+ months). One patient developed grade 3 hypersensitivity and another died as a result of pulmonary infection/sepsis. Enzyme-linked immunosorbent assay analysis of plasma revealed that higher levels of TNF-α at baseline and higher levels of CCL2 during treatment were associated with PD. There were also correlations between higher levels of TNF-α, IL-6, and CCL2 and poor survival (< 12 months).

Conclusion

This is the first direct clinical evidence suggesting that TNF-α may be a therapeutic target in RCC. Plasma levels of TNF-α, IL-6, and CCL2 may have predictive and prognostic significance.
Phase II Trial of Irinotecan in Children With Refractory Solid Tumors: A Children's Oncology Group Study
Authors: Bomgaars Lisa R. , Bernstein Mark , Krailo Mark , Kadota Richard , Das Soma , Chen Zhengjia , Adamson Peter C. , Blaney Susan M.
Published: October 2007

Purpose

A phase II study was performed to determine the efficacy of irinotecan (IRN) in children with refractory solid tumors. Secondary objectives were to evaluate toxicity, pharmacokinetics, pharmacodynamics, and UGT1A1 genotype.

Patients and Methods

A total of 181 patients were enrolled, of whom 171 were eligible. Patients received IRN 50 mg/m2/d for 5 days repeated every 3 weeks. Pharmacokinetic studies and UGT1A1 genotyping were performed.

Results

Of 161 patients assessable for response, one patient with hepatoblastoma had a complete response, with partial responses observed in patients with medulloblastoma (n = 4), rhabdomyosarcoma (n = 1), neuroblastoma (n = 1), and germinoma (n = 1), for an overall response rate of 5%. Grade 4 neutropenia and grade 3 to 4 diarrhea occurred in less than 7% of the courses administered. Pharmacokinetic studies were available for 79 patients. The mean ± standard deviation IRN plasma clearance was 374 ± 148 mL/min/m2, with median relative extent of conversion and relative extent of glucuronidation of 0.05 (range, 0.01 to 0.25) and 2.24 (range, 0.39 to 9.6), respectively. No association between UGT1A1 genotype (n = 61) and toxicity or pharmacokinetic parameters was observed.

Conclusion

IRN 50 mg/m2/d for 5 days every 21 days is well tolerated, but was not effective as a single agent in a spectrum of solid tumors, with the possible exception of patients with medulloblastoma (16% response rate). There was no association between UGT1A1*28 genotype and toxicity or pharmacokinetic parameters.
Phase I Study of Oxaliplatin, Full-Dose Gemcitabine, and Concurrent Radiation Therapy in Pancreatic Cancer
Authors: Desai Sameer P. , Ben-Josef Edgar , Normolle Daniel P. , Francis Isaac R. , Greenson Joel K. , Simeone Diane M. , Chang Alfred E. , Colletti Lisa M. , Lawrence Theodore S. , Zalupski Mark M.
Published: October 2007

Purpose

To determine a biweekly dose of oxaliplatin for combination with full-dose gemcitabine and concurrent radiation therapy (RT) in pancreatic cancer.

Patients and Methods

Patients with previously untreated pancreatic cancer received gemcitabine days 1, 8, and 15, and oxaliplatin days 1 and 15, repeated at 28-day intervals. RT (27 Gy in 1.8-Gy fractions) was administered during cycle 1. Dose escalation was guided using the time-to-event continuous reassessment method. Dose levels 1 to 4 included gemcitabine 1 g/m2 intravenously (IV) during 30 minutes and oxaliplatin 40, 55, 70, or 85 mg/m2 IV during 90 minutes, respectively; for dose levels 5 and 6, oxaliplatin dose remained 85 mg/m2 but infusion time for gemcitabine 1 g/m2 was increased to 65 or 100 minutes, respectively. The trial objective was to determine the dose level associated with dose-limiting toxicity (DLT) through cycle 2 in ≤ 20% of patients.

Results

Forty-four patients were enrolled (median age, 64 years; 27 men, 17 women) with resectable (n = 12), unresectable (n = 29), and metastatic (n = 3) pancreatic cancer. Ten DLTs occurred in nine patients, including grade 4 platelets (n = 4), decline in performance status (n = 2), GI bleeding (n = 2), and GI toxicity (n = 2). The estimated probability of DLT for dose level 3 was .21 (90% posterior probability interval [PI], .12 to .33); for dose level 4, the estimated probability was .24 (90% PI, .14 to .36).

Conclusion

The addition of oxaliplatin 85 mg/m2 days 1 and 15 to full-dose gemcitabine and radiation therapy was well tolerated. On the basis of these results, a multi-institutional neoadjuvant phase II study in resectable pancreatic cancer is planned.
Oligoarene Strategy for Catalyst Development. Hydroxylated Oligoarene-type Phosphines for Palladium-catalyzed Cross Coupling
Authors: Ishikawa Shunpei , Manabe Kei
Published: October 2007

Various oligoarene-type phosphines having a hydroxy group were synthesized based on a two-step repetitive method that we developed, and these phosphines were used as ligands for palladium in catalytic cross coupling with Grignard reagents. The study revealed that a hydroxylated terphenylphosphine accelerated the rate of the cross coupling of o-bromophenol and exhibited preference for the ortho-isomer over the meta- and para-isomers.
Facile Hydrothermal Preparation and Photocatalytic Activity of Bismuth Tungstate Polycrystalline Flake-ball Particles
Authors: Amano Fumiaki , Nogami Kohei , Abe Ryu , Ohtani Bunsho
Published: October 2007

Micrometer-sized spherical particles of bismuth tungstate (Bi2WO6) with hierarchical architecture were prepared by facile hydrothermal reaction without using any surfactants and polymers as structure-directing agents. The particles were assemblies of polycrystalline flakes composed of rectangular platelets. The hierarchical polycrystalline particles of “flake-ball” shape exhibited relatively high photocatalytic activity for oxidative decomposition of acetic acid in aqueous suspensions.
Synthesis and Characterization of S-Doped TiO2 Made by Anodic Oxidation of Titanium in Sulfuric Acid
Authors: Nakahira Atsushi , Yokota Koji , Kubo Takashi , Takahashi Masahide
Published: October 2007

TiO2 coating doped with S ions was made by the anodic oxidation process of the titanium sheet in sulfuric acid. TiO2 coating on titanium plate prepared by the anodic oxidation possessed many nanohole-like pores. XPS results showed that S6+ and S2− were incorporated in TiO2 coating after anodic oxidation. These S-doped TiO2 coatings showed the high photocatalytic activity.
Rumphellolide G, a New Caryophyllane-type Tetrahydropyran Norsesquiterpenoid from the Gorgonian Coral Rumphella antipathies (Gorgoniidae)
Authors: Sung Ping-Jyun , Chuang Li-Fan , Fan Tung-Yung , Chou Hong-Nong , Kuo Jimmy , Fang Lee-Shing , Wang Wei-Hsien
Published: October 2007

A new caryophyllane-type tetrahydropyran norsesquiterpenoid, rumphellolide G (1), has been isolated from the gorgonian coral Rumphella antipathies, collected off southern Taiwan coast. The structure of caryophyllane 1 was elucidated by the interpretation of spectral data.
Synthesis, Properties, and Structures of Difluoromethylene-bridged Coplanar p-Terphenyl and Its Aryl-capped Derivatives for Electron-transporting Materials
Authors: Ie Yutaka , Nitani Masashi , Aso Yoshio
Published: October 2007

A series of oligophenylene derivatives consisting of 6,6,12,12-tetrafluoroindenofluorene moieties were synthesized. Photophysical properties and X-ray analyses clearly showed that these conjugated molecules have potentials for electron-transporting materials.
A Facile Synthesis of New Chiral [1+1] Macrocyclic Schiff Bases
Authors: Suresh Paulsamy , Srimurugan Sankareswaran , Pati Hari N
Published: October 2007

A series of new chiral [1+1] macrocyclic Schiff bases have been synthesized in high yields and short reaction times from cyclocondensation of dialdehydes with long tethers and chiral diamines. The yields of the macrocycles were higher when the dialdehyde component is also chiral. The macrocyclisation was performed under microwave irradiation and aqueous reaction conditions employing salts of chiral diamines in contrast to free diamines normally employed.
Measurement of cotinine in urine by liquid chromatography tandem mass spectrometry
Authors: Chadwick Carrie Ann , Keevil Brian
Published: October 2007

Background: Cotinine is the major metabolite of nicotine. It is also a specific biomarker for nicotine exposure in cigarette smokers. The measurement of urine cotinine concentration will enable: (1) the assessment of the smoking status of lung transplant patients and (2) tobacco abstinence to be studied in patients during treatment under smoking cessation programmes.

Methods: We have developed and validated a method for the measurement of urinary cotinine using reversed phase high-performance liquid chromatography (HPLC) coupled to tandem mass spectrometry (LC-MS/MS). This technique utilizes online ion exchange coupled with an analytical column to eliminate ion suppression effects. The chromatography was performed using a WatersTM 2795 Alliance HT LC system.

Results: Cotinine and d3-cotinine had a retention time of 2.5 min and the cycle time from injection to injection was 4 min. The transition identified for cotinine was m/z 177.1>79.6 and for d3-cotinine m/z 180.2>79.6. This method was linear up to 1000 μg/L. Mean recovery of the assay was 112% with a range of 107-117% ( n=9). The limit of quantitation for this assay was 2.5 µg/L and the limit of detection was 0.156 µg/L. The intra- and inter-assay imprecision was <12% and <10% respectively over a concentration range of 22-660 μg/L.

Conclusions: We have developed a robust and rapid assay for measuring and analysing urine cotinine by LC-MS/MS, by utilizing a technique, which has reduced ion suppression effects. Ultimately, the method will facilitate the assessment of lung transplant patients' smoking status.
A rapid ultra performance liquid chromatography tandem mass spectrometric method for measuring amino acids associated with maple syrup urine disease, tyrosinaemia and phenylketonuria
Authors: Freeto Scott , Mason Donald , Chen Jie , Scott Robert H , Narayan Srinivas B , Bennett Michael J
Published: October 2007

Background: Patients with inherited disorders of amino acid metabolism including maple syrup urine disease, tyrosinaemia and phenylketonuria on dietary management require frequent monitoring of disease-relevant plasma amino acids in order to optimize therapeutic benefit. Poorly controlled maple syrup urine disease in particular may result in catastrophic metabolic decompensation. Most methods for monitoring amino acid concentrations are time-consuming and have clinically impractical turnaround times, particularly when the required time to run standards and control samples is taken into account.

Methods: We have analysed plasma amino acids using standard ion-exchange chromatography with ninhydrin detection in an amino acid analyser and compared the data with that obtained for the same samples using ultra-performance liquid chromatography (UPLCTM) separation with detection by tandem mass spectrometry.

Results: The two methodologies compared very well for the measurement of six important amino acids with correlation coefficients greater than 0.96 for all. The time for sample preparation was longer for the UPLC methodology as batched derivatization and evaporation is required but UPLC-tandem mass spectrometry generated sample results every 8 min while conventional ion-exchange chromatography took almost 1 h per sample.

Conclusion: UPLC-tandem mass spectrometry generates data that compares well with existing 'gold standard' methodologies but significantly reduces sample turnaround time. Decreasing the turnaround time for amino acid analyses is very likely to improve clinical care for patients with amino acid disorders as dietary adjustments can be made sooner.
Vasopressin and disorders of water balance: the physiology and pathophysiology of vasopressin
Authors: Ball S G
Published: October 2007

Disorders of water balance are a common feature of clinical practice. An understanding of the physiology and pathophysiology of the key endocrine regulator of water balance vasopressin (VP) is key to diagnosis and management of these disorders. Diabetes insipidus is the result of a lack of VP or (less commonly) resistance to the renal effects of the hormone. Diagnostic testing can clarify aetiology and direct appropriate management. VP production can be associated with hyponatraemia. A comprehensive assessment of cardiovascular status and pharmacological influences are needed in these circumstances to differentiate between primary (inappropriate) and secondary (appropriate) physiological VP production. As with diabetes insipidus, diagnostic testing can help define the aetiology of hyponatraemia and direct appropriate management. Patients with disorders of water balance benefit from a joint clinical and laboratory medicine approach to diagnosis and management.
Fibrin monomer complex in normal pregnant women: a potential thrombotic marker in pregnancy
Authors: Onishi Hiroaki , Kaniyu Kimiko , Iwashita Mitsutoshi , Tanaka Asashi , Watanabe Takashi
Published: October 2007

Background: Pregnancy represents a major risk factor for deep vein thrombosis (DVT). Most coagulation/fibrinolysis markers currently utilized change during pregnancy, and therefore they cannot accurately evaluate thrombotic events in pregnancy because the rate of false positive results is high. Fibrin monomer complex (FMC) has recently become widely available for diagnosing DVT. The present study examined whether FMC is suitable for evaluating thrombotic status in pregnancy.

Methods: Concentrations of FMC and other haemostatic markers were investigated in 87 pregnant women without major complications at early, mid- or late pregnancy. FMC concentrations were also measured in 127 normal non-pregnant women, and in one woman who developed DVT after delivery.

Results: In normal pregnant women, FMC concentrations were unchanged during early or mid-pregnancy and slightly elevated during late pregnancy. Concentrations were within reference range in most cases, and none exceeded the cut-off value for DVT. In contrast, thrombin-antithrombin complex (TAT) and D-dimer (DD) concentrations were significantly elevated in late pregnancy, and median values exceeded reference ranges. The DVT case displayed significantly elevated FMC concentrations.

Conclusions: Changes in FMC concentrations during normal pregnancy are minimal compared with other haemostatic markers. Because the rate of false positivity is lower, FMC could be a potential marker of thrombotic status in pregnancy rather than TAT and DD.
National audit of cerebrospinal fluid testing
Authors: Holbrook Ian , Beetham Robert , Cruickshank Anne , Egner William , Fahie-Wilson Mike , Keir Geoff , Patel Dina , Watson Ian , White Peter
Published: October 2007

Background: UK National External Quality Assessment Service (NEQAS) Specialist Advisory Group for EQA of CSF Proteins and Biochemistry was interested in current practice for the biochemical investigation of cerebrospinal fluid (CSF) in the UK.

Methods: A questionnaire was sent to laboratories via regional audit committees and the results collated.

Results: Most laboratories were analysing CSF in a satisfactory manner. There was some variation in the reference ranges used for glucose, protein and lactate. There was concern about the rejection policies of some laboratories on these unrepeatable samples and the wavelengths used to measure bilirubin. The survey revealed the lack of spectrophotometric scanning for haem pigments and bilirubin in some hospitals.

Conclusions: The current practice for the measurement of CSF samples in the UK is satisfactory in most laboratories responding to the questionnaire. National agreement on reference ranges for glucose, protein and lactate should be achievable. Those performing spectrophotometric scanning of the CSF were doing so in concordance with the national guidelines. Some hospitals in the UK may not have responded to the questionnaire because they did not offer spectrophotometric scanning.
The association of circulating ferritin with serum concentrations of fibroblast growth factor-23 measured by three commercial assays
Authors: Durham Brian H , Joseph Frank , Bailey Lisa M , Fraser William D
Published: October 2007

Background: The measurement of the serum concentration of fibroblast growth factor-23 (FGF-23) is beginning to be used as a diagnostic tool in renal phosphate wasting disorders. Having observed an increased serum FGF-23 in three subjects with low circulating ferritin concentrations we investigated the association between low ferritin and raised serum FGF-23.

Methods: We measured FGF-23 in 150 random anonymized serum samples with ferritin concentrations between <5 and 50 µg/L using three commercially available enzyme-linked immunosorbent assay (ELISA) kits. One kit, Human FGF-23[C-term] (Immutopics Inc, USA) measures total FGF-23 whereas the other two kits, Immutopics intact and FGF-23 ELISA (Kainos, Japan) are reported to measure only the biologically active intact molecule.

Results: We have detected a significant inverse correlation of -0.565 ( P<0.0001) between serum ferritin when <50 µg/L and FGF-23 using the C-terminal assay. This relationship is also shown with the Immutopics intact assay but is not demonstrated with the Kainos intact assay.

Conclusion: The measurement of FGF-23 by both Immutopics assays is altered in the presence of low circulating concentrations of serum ferritin whereas with the Kainos intact assay this effect was not demonstrated. Serum ferritin should be measured when an elevated FGF-23 is obtained using the Immutopics C-terminal or intact FGF-23 assay to prevent misdiagnosis of the cause of this abnormality.
Catheter-directed foam sclerotherapy of axial saphenous reflux: early results
Authors: Kölbel T , Hinchliffe R J , Lindblad B
Published: October 2007

Objectives: Foam sclerotherapy of the great saphenous vein is a relatively new and promising treatment option for patients with axial reflux. Its usefulness may be limited by low primary occlusion rates. We present a standard technique for catheter-directed foam sclerotherapy, which facilitates foam delivery precisely to its intended site of action and potentially improves occlusion rates.

Methods: A consecutive series of 53 patients were treated with foam sclerotherapy using a standard technique for foam delivery at Malmö University Hospital between September 2006 and April 2007. Patients were treated with 3% polidocanol foam through an introducer sheath, which was inserted percutaneously over a guidewire in the great saphenous vein (GSV). All successfully treated patients were examined by colour duplex one week after the procedure.

Results: Primary technical success with delivery of foam along the length of the GSV was achieved in 50 of 53 limbs (94%). All treated GSVs were occluded at one week duplex.

Conclusion: The use of an endovascular sheath inserted percutaneously over a guidewire under duplex ultrasound control is feasible in most patients and has resulted in high primary occlusion rates.
The effect of correlations between screening markers on screening performance
Authors: Morris J K , Wald N J
Published: October 2007

Objectives: It is widely thought that correlations between screening markers will tend to degrade screening performance. We performed a computer simulation study to investigate the quantitative effect of correlations between two markers on screening performance, using prenatal screening for Down's syndrome as an example, although the results apply generally.

Methods: Monte Carlo simulation was used to generate values of two hypothetical markers, A and B, in 1000 affected and 1000 unaffected pregnancies. The means, standard deviations and correlations of A and B were varied in five different examples.

Results: If markers A and B are, on average, higher in affected than unaffected pregnancies and each marker, individually, has the same detection rate for a given false-positive rate (i.e. the same screening performance), then the screening performance of A and B together tends to decrease as A and B become more positively correlated with each other (within affected or unaffected categories) and tends to increase as A and B become more negatively correlated. If A is, on average, higher in affected pregnancies and B is, on average, lower in affected pregnancies (but again each marker has the same screening performance), the opposite pattern is observed; screening performance increases as A and B become more positively correlated and screening performance decreases as they become more negatively correlated. If A and B have unequal screening performances, modest correlations between A and B have little effect on the screening performance of A and B together, but when the correlations are strong whether positive or negative (with r values greater than about 0.45 or less than −0.45) screening performance progressively increases.

Conclusion: Correlations between screening markers considered separately in affected and unaffected pregnancies can either decrease or increase screening performance. In practice, these effects are usually modest, because most screening markers are not highly correlated with each other and the effects become important only with strong correlations, whether positive or negative.
Cystic hygroma and mid-trimester maternal serum screening
Authors: Celentano Claudio , Prefumo Federico , Iezzi Irene , Guanciali-Franchi Paolo Emilio , Palka Chiara , Liberati Marco , Rotmensch Sigfried
Published: October 2007

Objective: To investigate the relationship between maternal serum screening markers and pregnancy outcome in fetuses with cystic hygroma at 15–18 weeks of gestation.

Study design: We retrospectively reviewed case-notes of 34 consecutive singleton fetuses with cystic hygroma referred at 15–18 weeks of gestation. All cases had maternal blood sampled for triple screening at the time of the ultrasound scan.

Results In total, 62% of fetuses with cystic hygroma had abnormal chromosome complements and 80% had a poor outcome. Six fetuses presenting normal values of human chorionic gonadotropin (0.5–2.5 MoM [multiples of the median]), serum alpha-fetoprotein (0.5–2.5 MoM) and unconjugated estriol (>0.5 MoM), normal karyotype and absence of associated structural anomalies had an uneventful outcome.

Conclusions Our data demonstrated that cystic hygroma at 15–18 weeks has a strong association with chromosomal abnormalities. In euploid fetuses, maternal serum screening results may have a role in the diagnostic work-up of the pregnancy.
Neonatal screening for sickle cell disease in Central Africa: a study of 1825 newborns with a new enzyme-linked immunosorbent assay test
Authors: Mutesa Léon , Boemer François , Ngendahayo Louis , Rulisa Stephen , Rusingiza Emmanuel K , Cwinya-Ay Neniling , Mazina Déogratias , Kariyo Pierre C , Bours Vincent , Schoos Roland
Published: October 2007

Objectives: To evaluate the feasibility of systematic neonatal screening for sickle cell disease in the region of Great Lakes in Central Africa using a new approach with limited costs.

Methods: Between July 2004 and July 2006, 1825 newborn dried blood samples were collected onto filter papers in four maternity units from Burundi, Rwanda and the East of the Democratic Republic of Congo. We tested for the presence of haemoglobin C and S in the eluted blood by an enzyme-linked immunosorbent assay (ELISA) test using a monoclonal antibody. All ELISA-positive samples (multiple of the median (MoM)≥ 1.5) were confirmed by a simple molecular test. The statistica software version 7.1 was used to create graphics and to fix the MoM cut-off, and the χ2 of Pearson was used to compare the genotype incidences between countries.

Results: Of the 1825 samples screened, 97 (5.32%) were positive. Of these, 60 (3.28%) samples were heterozygous for Hb S, and four (0.22%) for Hb C; two (0.11%) newborns were Hb SS homozygotes.

Conclusions: The lower cost and the high specificity of ELISA test are appropriate for developing countries, and such systematic screening for sickle cell anaemia is therefore feasible.
Diagnostic accuracy of faecal occult blood tests used in screening for colorectal cancer: a systematic review
Authors: Burch J A , Soares-Weiser K , St John D J B , Duffy S , Smith S , Kleijnen J , Westwood M
Published: October 2007

Objective: To determine the accuracy of guaiac and immunochemical faecal occult blood tests (FOBTs) for the detection of colorectal cancer in an average-risk screening population.

Methods: Fifteen electronic databases, the internet, key journals and reference lists of included studies were searched. We included diagnostic accuracy studies that compared guaiac or immunochemical FOBTs with any reference standard, for the detection of colorectal cancer in an average-risk adult population, with sufficient data to construct a 2 × 2 table.

Results: Fifty-nine studies were included. Thirty-three evaluated guaiac FOBTs, 35 immunochemical FOBTs and one evaluated sequential FOBTs. Sensitivities for the detection of all neoplasms ranged from 6.2% (specificity 98.0%) to 83.3% (specificity 98.4%) for guaiac FOBTs, and 5.4% (specificity 98.5%) to 62.6% (specificity 94.3%) for immunochemical FOBTs. Specificity ranged from 65.0% (sensitivity 44.1%) to 99.0% (sensitivity 19.3%) for guaiac FOBTs, and 89.4% (sensitivity 30.3%) to 98.5% (sensitivity 5.4%) for immunochemical FOBTs. Diagnostic case–control studies generally reported higher sensitivities. Sensitivities were higher for the detection of CRC, and lower for adenomas, in both the diagnostic cohort and diagnostic case–control studies for both guaiac and immunochemical FOBTs.

Conclusions Immudia HemSp appeared to be the most accurate immunochemical FOBT, however, there was no clear evidence to suggest whether guaiac or immunochemical FOBTs performed better, either from direct or indirect comparisons. Poor reporting of data limited the scope of this review, and the use the Standards for Reporting of Diagnostic Accuracy guidelines is recommended for reporting future diagnostic accuracy studies.
Effects of computerized decision support systems on nursing performance and patient outcomes: a systematic review
Authors: Randell Rebecca , Mitchell Natasha , Dowding Dawn , Cullum Nicky , Thompson Carl
Published: October 2007

Objective: To examine the effect of computerized decision support systems (CDSSs) on nursing performance and patient outcomes.

Method: Fifteen databases, including Medline and CINAHL, were searched up to May 2006 together with reference lists of included studies and relevant reviews. Randomized controlled trials, controlled clinical trials, controlled before and after studies and interrupted time series studies that assessed the effects of CDSS use by nurses in a clinical setting on measurable professional and/or patient outcomes were included.

Results: Eight studies, three comparing nurses using CDSS with nurses not using CDSS and five comparing nurses using CDSS with other health professionals not using CDSS, were included. Risk of contamination was a concern in four studies. The effect of CDSS on nursing performance and patient outcomes was inconsistent.

Conclusion: The introduction of CDSS may not necessarily lead to a positive outcome; further studies are needed in order to identify contexts in which CDSS use by nurses is most effective. CDSS are complex interventions and should be evaluated as such; future studies should explore the impact of the users and the protocol on which the CDSS is based, reporting details of both. Contamination is a significant issue when evaluating CDSS, so it is important that randomization is at the practitioner or the unit level. Future systematic reviews should focus on particular uses of CDSS.
What is the role of masculinity in white and South Asian men's decisions to seek medical help for cardiac chest pain?
Authors: Galdas Paul , Cheater Francine , Marshall Paul
Published: October 2007

Objectives: To explore how masculinity influences white, Indian and Pakistani men's interpretation of cardiac chest pain and the decision to seek or delay seeking medical help.

Method: Semi-structured interviews were conducted with 36 men of white ethnicity (UK ancestry) and 20 men of South Asian ethnicity (Indian or Pakistani ancestry) who had a confirmed diagnosis of acute myocardial infarction or angina pectoris. The study setting was two coronary care units and eight cardiology wards situated in two teaching hospitals in the North of England. All interviews were tape-recorded, transcribed verbatim and analysed using a constant comparative method.

Results: Displaying a high threshold for pain and discomfort was a masculine attribute valued by white men in the study but not by the Indian and Pakistani men. White men's fears of being seen to be weak contributed to delays in seeking medical treatment and led to reluctance to disclose symptoms to others. Indian and Pakistani men emphasized wisdom, education and responsibility for the family and their own health as more valued masculine attributes, and this contributed to a greater willingness to seek medical help.

Conclusion: Masculinity had a differing role in white and South Asian men's decisions to seek or delay seeking medical help for chest pain. The study supports the development of coronary heart disease policy and practice that acknowledges men's gender as an important determinant of their health behaviour, but illustrates that there is no probable single appropriate approach to tackling the delay in how men seek treatment for chest pain.
Do hospital mergers increase hospital efficiency? Evidence from a National Health Service country
Authors: Kjekshus Lars , Hagen Terje
Published: October 2007

Objectives: To analyse the effects on technical and cost efficiency of seven hospital mergers over the period 1992–2000 in Norway. The mergers involved 17 hospitals.

Methods: First, efficiency scores were generated using Data Envelopment Analysis for 53 merged and non-merged hospitals over the nine years. Second, the effect of mergers was estimated through panel data analysis.

Results: In general, the mergers showed no significant effect on technical efficiency and a significant negative effect of 2–2.8% on cost efficiency. However, positive effects on both cost and technical efficiency were found in one merger where more hospitals were involved, and where administration and acute services were centralized.

Conclusion: The findings indicate that large mergers involving radical restructuring of the treatment process may improve efficiency as intended, but most mergers do not.