Showing papers by "St Bartholomew's Hospital published in 2009"

Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: Results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

Abstract: Background: Ovarian cancer has a high case–fatality ratio, with most women not diagnosed until the disease is in its advanced stages. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is a randomised controlled trial designed to assess the effect of screening on mortality. This report summarises the outcome of the prevalence (initial) screen in UKCTOCS. Methods: Between 2001 and 2005, a total of 202 638 post-menopausal women aged 50–74 years were randomly assigned to no treatment (control; n=101 359); annual CA125 screening (interpreted using a risk of ovarian cancer algorithm) with transvaginal ultrasound scan as a second-line test (multimodal screening [MMS]; n=50 640); or annual screening with transvaginal ultrasound (USS; n=50 639) alone in a 2:1:1 ratio using a computer-generated random number algorithm. All women provided a blood sample at recruitment. Women randomised to the MMS group had their blood tested for CA125 and those randomised to the USS group were sent an appointment to attend for a transvaginal scan. Women with abnormal screens had repeat tests. Women with persistent abnormality on repeat screens underwent clinical evaluation and, where appropriate, surgery. This trial is registered as ISRCTN22488978 and with ClinicalTrials.gov, number NCT00058032. Findings: In the prevalence screen, 50 078 (98·9%) women underwent MMS, and 48 230 (95·2%) underwent USS. The main reasons for withdrawal were death (two MMS, 28 USS), non-ovarian cancer or other disease (none MMS, 66 USS), removal of ovaries (five MMS, 29 USS), relocation (none MMS, 39 USS), failure to attend three appointments for the screen (72 MMS, 757 USS), and participant changing their mind (483 MMS, 1490 USS). Overall, 4355 of 50 078 (8.7%) women in the MMS group and 5779 of 48 230 (12·0%) women in the USS group required a repeat test, and 167 (0·3%) women in the MMS group and 1894 (3·9%) women in the USS group required clinical evaluation. 97 of 50 078 (0·2%) women from the MMS group and 845 of 48 230 (1·8%) from the USS group underwent surgery. 42 (MMS) and 45 (USS) primary ovarian and tubal cancers were detected, including 28 borderline tumours (eight MMS, 20 USS). 28 (16 MMS, 12 USS) of 58 (48·3%; 95% CI 35·0–61·8) of the invasive cancers were stage I/II, with no difference (p=0·396) in stage distribution between the groups. A further 13 (five MMS, eight USS) women developed primary ovarian cancer during the year after the screen. The sensitivity, specificity, and positive-predictive values for all primary ovarian and tubal cancers were 89·4%, 99·8%, and 43·3% for MMS, and 84·9%, 98·2%, and 5·3% for USS, respectively. For primary invasive epithelial ovarian and tubal cancers, the sensitivity, specificity, and positive-predictive values were 89·5%, 99·8%, and 35·1% for MMS, and 75·0%, 98·2%, and 2·8% for USS, respectively. There was a significant difference in specificity (p<0·0001) but not sensitivity between the two screening groups for both primary ovarian and tubal cancers as well as primary epithelial invasive ovarian and tubal cancers. Interpretation: The sensitivity of the MMS and USS screening strategies is encouraging. Specificity was higher in the MMS than in the USS group, resulting in lower rates of repeat testing and surgery. This in part reflects the high prevalence of benign adnexal abnormalities and the more frequent detection of borderline tumours in the USS group. The prevalence screen has established that the screening strategies are feasible. The results of ongoing screening are awaited so that the effect of screening on mortality can be determined. Funding: Medical Research Council, Cancer Research UK and the Department of Health, UK; with additional support from the Eve Appeal, Special Trustees of Bart's and the London, and Special Trustees of University College London Hospital.

Guidelines for Acromegaly Management: An Update

Abstract: Objective: The Acromegaly Consensus Group reconvened in November 2007 to update guidelines for acromegaly management. Participants: The meeting participants comprised 68 pituitary specialists, including neurosurgeons and endocrinologists with extensive experience treating patients with acromegaly. Evidence/Consensus Process: Goals of treatment and the appropriate imaging and biochemical and clinical monitoring of patients with acromegaly were enunciated, based on the available published evidence. Conclusions: The group developed a consensus on the approach to managing acromegaly including appropriate roles for neurosurgery, medical therapy, and radiation therapy in the management of these patients.

Highly Active Antiretroviral Therapy and the Incidence of Non–AIDS-Defining Cancers in People With HIV Infection

Abstract: Purpose The effect of highly active antiretroviral therapy (HAART) on the incidence of non–AIDS-defining cancers (NADCs) is unclear. Methods We have investigated the occurrence of NADCs in a prospective cohort of 11,112 HIV-positive individuals, with 71,687 patient-years of follow-up. Standardized incidence ratios (SIRs) were calculated using general population incidence data. We investigated the effect of calendar period, HIV parameters, and immunologic and treatment-related factors on the incidence of these cancers using univariate and multivariate analyses. Results The SIR for all NADCs was 1.96 (95% CI, 1.66 to 2.29). There was no significant excess in incidence in the pre-HAART era (1983 to 1995; SIR, 0.95; 95% CI, 0.58 to 1.47). However, the incidence increased in the early HAART period (1996 to 2001) and remains elevated in the most recent established HAART period (2002 to 2007; SIR, 2.05; 95% CI, 1.51 to 2.72, and SIR 2.49; 95% CI, 2.00 to 3.07, respectively). Multivariate analysis showed that use...

Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: impact of a dose‐modification guideline

Abstract: The frequency, characteristics and reversibility of bortezomib-associated peripheral neuropathy were evaluated in the phase III APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial in patients with relapsed myeloma, and the impact of a dose-modification guideline on peripheral neuropathy severity and reversibility was assessed. Patients received bortezomib 1.3 mg/m(2) (days 1, 4, 8, 11, eight 21-d cycles, then days 1, 8, 15, 22, three 35-d cycles); bortezomib was held, dose-reduced or discontinued depending on peripheral neuropathy severity, according to a protocol-specified dose-modification guideline. Overall, 124/331 patients (37%) had treatment-emergent peripheral neuropathy, including 30 (9%) with grade >or=3; incidence and severity were not affected by age, number/type of prior therapies, baseline glycosylated haemoglobin level, or diabetes history. Grade >or=3 incidence appeared lower versus phase II trials (13%) that did not specifically provide dose-modification guidelines. Of patients with grade >or=2 peripheral neuropathy, 58/91 (64%) experienced improvement or resolution to baseline at a median of 110 d, including 49/72 (68%) who had dose modification versus 9/19 (47%) who did not. Efficacy did not appear adversely affected by dose modification for grade >or=2 peripheral neuropathy. Bortezomib-associated peripheral neuropathy is manageable and reversible in most patients with relapsed myeloma. Dose modification using a specific guideline improves peripheral neuropathy management without adversely affecting outcome.

Treatment of Pituitary-Dependent Cushing’s Disease with the Multireceptor Ligand Somatostatin Analog Pasireotide (SOM230): A Multicenter, Phase II Trial

Abstract: Context: There is currently no medical therapy for Cushing’s disease that targets the pituitary adenoma. Availability of such a medical therapy would be a valuable therapeutic option for the management of this disorder. Objective: Our objective was to evaluate the short-term efficacy of the novel multireceptor ligand somatostatin analog pasireotide in patients with de novo, persistent, or recurrent Cushing’s disease. Design: We conducted a phase II, proof-of-concept, open-label, single-arm, 15-d multicenter study. Patients: Thirty-nine patients with either de novo Cushing’s disease who were candidates for pituitary surgery or with persistent or recurrent Cushing’s disease after surgery without having received prior pituitary irradiation. Intervention: Patients self-administered sc pasireotide 600 μg twice daily for 15 d. Main Outcome Measure: Normalization of urinary free cortisol (UFC) levels after 15 d treatment was the main outcome measure. Results: Of the 29 patients in the primary efficacy analysis, ...

Rat osteoclasts adhere to a wide range of rgd (arg‐gly‐asp) peptide‐containing proteins, including the bone sialoproteins and fibronectin, via a β3 integrin

Abstract: The ligand binding ability of rat osteoclast adhesion receptors was investigated in an attachment assay using osteoclasts disaggregated from bone. Osteoclasts adhered well to the Arg-Gly-Asp (RGD)-containing proteins osteopontin (bone sialoprotein I) and BSP (bone sialoprotein II), vitronectin, fibrinogen, von Willebrand factor, and fibronectin. Osteoclasts also adhered, but less strongly, to type I collagen. No attachment of osteoclasts was observed to thrombospondin, tenascin, laminin, or a range of non-RGD-containing bone proteins and proteins from other sources. The attachment of osteoclasts to all ligands was abolished in the presence of GRGDSP peptide, indicating the involvement of the RGD cell binding sequence in ligand binding. Attachment of osteoclasts to all substrates, with the exception of type I collagen, was also strongly inhibited by the addition of monoclonal antibody F11 to the beta 3 integrin subunit, indicating that a beta 3 integrin, probably the vitronectin receptor, was involved. Attachment to type I collagen was blocked by EDTA chelation of divalent cations and was not significantly affected by anti-beta 3 or anti-beta 1 antibodies; when taken with the inhibition by RGD peptide, this suggests the involvement of various receptors, possibly including nonintegrin collagen receptors, in the binding of osteoclasts to this protein. These results define the wide range of ligands for extracellular matrix receptors in osteoclasts in vitro. It remains to be established which of these proteins are important in osteoclast adhesion and osteoclastic bone resorption in vivo.

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly.

Abstract: The worldwide shortage of donor livers to transplant end stage liver disease patients has prompted the search for alternative cell therapies for intractable liver diseases, such as acute liver failure, cirrhosis and hepatocellular carcinoma (HCC). Under normal circumstances the liver undergoes a low rate of hepatocyte 'wear and tear' renewal, but can mount a brisk regenerative response to the acute loss of two-thirds or more of the parenchymal mass. A body of evidence favours placement of a stem cell niche in the periportal regions, although the identity of such stem cells in rodents and man is far from clear. In animal models of liver disease, adopting strategies to provide a selective advantage for transplanted hepatocytes has proved highly effective in repopulating recipient livers, but the poor success of today's hepatocyte transplants can be attributed to the lack of a clinically applicable procedure to force a similar repopulation of the human liver. The activation of bipotential hepatic progenitor cells (HPCs) is clearly vital for survival in many cases of acute liver failure, and the signals that promote such reactions are being elucidated. Bone marrow cells (BMCs) make, at best, a trivial contribution to hepatocyte replacement after damage, but other BMCs contribute to the hepatic collagen-producing cell population, resulting in fibrotic disease; paradoxically, BMC transplantation may help alleviate established fibrotic disease. HCC may have its origins in either hepatocytes or HPCs, and HCCs, like other solid tumours appear to be sustained by a minority population of cancer stem cells.

Long-term follow-up of 233 patients with hairy cell leukaemia, treated initially with pentostatin or cladribine, at a median of 16 years from diagnosis

Abstract: Hairy cell leukaemia (HCL) was first described 50 years ago. Median survival was then 4 years. The purine analogues, introduced in the 1980s, transformed this prognosis. We reviewed data retrospectively from 233 patients, treated with pentostatin (n = 188) or cladribine (n = 45), to investigate the current long-term outlook. Median follow-up was 16 years. There were no significant differences in outcome between the two agents. Overall, the complete response (CR) rate was 80% and median relapse-free survival was 16 years. After relapse (n = 79) or non-response (n = 5), 26 patients received pentostatin and 58 cladribine; 69% achieved CR and median relapse-free survival was 11 years. After third-line therapy (n = 23), 50% achieved CR and median relapse-free survival was 6.5 years. However, CRs were equally durable, whether after first, second or third-line therapy. Complete responders and those with both haemoglobin >100 g/l and platelet count >100 x 10(9)/l before treatment had the longest relapse-free survival (P < 0.0001). Patients still in CR at 5 years had only a 25% risk of relapse by 15 years. Outcomes for patients with recurrent disease improved with the monoclonal antibody rituximab, combined with either purine analogue. Overall only eight patients died of HCL-related causes. Patients achieving a CR can expect a normal lifespan.

Family factors in the intergenerational transmission of offending.

Abstract: Background Convicted parents tend to have convicted children, but there have been few previous studies of transmission between three generations, especially including both records and interviews for hundreds of people. Method In the Cambridge Study in Delinquent Development (CSDD), 411 south London males have been followed up from age 8 to age 48. These males (generation 2, G2) are compared with their fathers and mothers (generation 1, G1), and with their biological sons and daughters (generation 3, G3). Results There was significant intergenerational transmission of convictions from G1 males to G2 males, and from G2 males to G3 males. Convictions of fathers still predicted convictions of sons after controlling for risk factors, but the predictive efficiency was reduced. Transmission was less from G1 females to G2 males, and from G2 males to G3 females. There was little evidence of intergenerational transmission from G1 to G3, except from grandmothers to granddaughters. Conclusions The intergenerational transmission of offending may be mediated by family, socio-economic and individual risk factors. Intervention to reduce intergenerational transmission could target these risk factors. Copyright © 2009 John Wiley & Sons, Ltd.

Development of adolescence‐limited, late‐onset, and persistent offenders from age 8 to age 48

Abstract: This article investigates the life success at ages 32 and 48 of four categories of males: nonoffenders, adolescence-limited offenders (convicted only at ages 10-20), late-onset offenders (convicted only at ages 21-50), and persistent offenders (convicted at both ages 10-20 and 21-50). In the Cambridge Study in Delinquent Development, 411 South London males have been followed up from age 8 to 48 in repeated personal interviews. There was considerable continuity in offending over time. Persistent offenders had the longest criminal careers (averaging 18.4 years), and most of them had convictions for violence. Persistent offenders were leading the most unsuccessful lives at ages 32 and 48, although all categories of males became more successful with age. By age 48, the life success of adolescence-limited offenders was similar to that of nonoffenders. The most important risk factors at ages 8-18 that predicted which offenders would persist after age 21 were heavy drinking at age 18, hyperactivity at ages 12-14, and low popularity and harsh discipline at ages 8-10. The most important risk factors that predicted which nonoffenders would onset after age 21 were poor housing and low nonverbal IQ at ages 8-10, high neuroticism at age 16, and anti-establishment attitudes and motoring convictions at age 18. It was suggested that nervousness and neuroticism may have protected children at risk from offending in adolescence and the teenage years.

IDEC-C2B8 anti-CD20 (rituximab) immunotherapy in patients with low-grade non-Hodgkin's lymphoma and lymphoproliferative disorders: evaluation of response on 48 patients.

Abstract: This study focused on the efficacy of IDEC-C2B8 (chimeric anti-CD20) immunotherapy relative to specific subtypes of low-grade lymphoproliferative disorders/non-Hodgkin's lymphomas (LPD/NHL). Forty-eight patients with resistant or relapsed disease completed the IDEC-C2B8 infusion schedule of 375 mg/m2/wk × 4 wk. The LPD/NHL subtypes included: (a) follicular centre cell lymphoma (FCC) in 22 patients; (b) mantle cell lymphoma (MCL) in 10; (c) 1 diffuse large cell lymphoma (DLCL); and (d) the category of small lymphocytic lymphoma/chronic lymphocytic leukaemia (SLL/CLL) and related disorders in 15 patients. No patient obtained a complete remission. Ten patients (21%) achieved partial remission: 6 FCC, 2 MCL, 1 DLCL and 1 patient from the SLL/CLL group. Twenty-eight patients had stable disease and 10 progressed during immunotherapy. In patients with CLL and MCL in leukaemic phase, there was no correlation between the marked decrease in circulating neoplastic cells following antibody infusions and amelioration of the tumour burden. The results suggest that the subtype of LPD/NHL and the intensity of CD20 on the tumour cells influence the effectiveness of IDEC-C2B8. The antibody was most efficacious against FCC lymphoma. The efficacy (at the dose schedule of 375 mg/m2/wk × 4) against MCL and SLL/CLL appeared to be limited, however.

ENETS consensus guidelines for the standards of care in neuroendocrine tumors: Somatostatin receptor imaging with IIIIn-pentetreotide

Abstract: ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors : Somatostatin Receptor Imaging with In-111-Pentetreotide

Effects of luteinizing hormone, insulin, insulin-like growth factor-I and insulin-like growth factor small binding protein 1 in the polycystic ovary syndrome.

Abstract: This study explores the clinical and endocrine implications of hyperinsulinaemia in the polycystic ovary syndrome (PCOS). Oral glucose tolerance tests were performed on 34 lean and 19 obese women with PCOS and on 13 lean women with normal ovaries. Insulin measurements were compared with basal gonadotrophins, androgens, insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein 1 (IGFBP-1). Unselected lean women with PCOS were found to have fasting hyperinsulinaemia and the raised serum insulin concentrations were associated with menstrual disturbance and hyperandrogenaemia. In addition, serum insulin concentrations in lean women with PCOS correlated positively with serum IGF-I and negatively with serum IGFBP-1 concentrations. Ovarian stimulation by insulin appears to be independent of luteinizing hormone (LH) and is an important feature in 30% of lean women with PCOS.

Perspectives: adhesion receptors in bone.

Abstract: Revue de la litterature. Prescription de l'etat des connaissances sur les recepteurs (integrines et non integrines) des cellules osseuses, en particulier des osteoclastes. Role de ces recepteurs et de leurs ligands dans la regulation de la croissance et de l'activite de cellules osseuses. Discussion des centres d'interet devant faire preferentiellement l'objet des recherches futures.

Full-field digital versus screen-film mammography: comparison within the UK breast screening program and systematic review of published data.

Abstract: Purpose: To (a) compare the performance of full-field digital mammography (FFDM), using hard-copy image reading, with that of screen-film mammography (SFM) within a UK screening program (screening once every 3 years) for women aged 50 years or older and (b) conduct a meta-analysis of published findings along with the UK data. Materials and Methods: The study complied with the UK National Health Service Central Office for Research Ethics Committee guidelines; informed patient consent was not required, since analysis was carried out retrospectively after data anonymization. Between January 2006 and June 2007, a London population-based screening center performed 8478 FFDM and 31 720 SFM screening examinations, with modality determined by the type of machine available at the screening site. Logistic regression was used to assess whether breast cancer detection rates and recall rates differed between screening modalities. For the meta-analysis, random-effects models were used to combine study-specific estimate...

ENETS consensus guidelines for the standards of care in neuroendocrine tumors: Follow-up and documentation

Abstract: Summary of follow-up recommendations in patients with benign and malignant neuroendocrine tumorsFollow-upyes/no endoscopy US/CT/MRI Octreoscan CgABenign insulinoma noType 1 gastric carcinoid yes yearlyRectal carcinoid no (if completely resected)Appendiceal carcinoid T1 noAppendiceal carcinoid T2 ? (see text)Resectable tumor (uncertain behavior)G1 every 6–12 months yes(gastric carc.)yes every 2 years 2 yes 1 Resectable malignant tumor with/without nodal involvementG1 every 6–12 months yes every 2 years 2 yes 1 G2 every 6 months yes yearly 2 yes 1 G3 every 3 months yes yearly 2 yes 3 Non-resectable malignant tumor with/without nodal involvement and/or liver and other metastasesG1 every 6–12 months yes every 2 years 2 yesG2 every 6 months yes yearly 2 yesG3 every 3 months yes yearly 2 yes 31 Only in the presence of a visible tumor. 2 Recommendations regarding the time frames of Octreoscan should be adjusted to the individual situation. 3 In poorly differentiated tumors and negative CgA NSE may act as a suitable marker.

Epigenetic silencing of argininosuccinate synthetase confers resistance to platinum-induced cell death but collateral sensitivity to arginine auxotrophy in ovarian cancer.

Abstract: Evidence indicates that acquired resistance of cancers to chemotherapeutic agents can occur via epigenetic mechanisms Down-regulation of expression of argininosuccinate synthetase (ASS1), the rate-limiting enzyme in the biosynthesis of arginine, has been associated with the development of platinum resistance in ovarian cancer treated with platinum-based chemotherapy The aim of the present study was to analyse epigenetic regulation of ASS1 in ovarian cancer tissue taken at diagnosis and relapse and determine its significance as a predictor of clinical outcome in patients treated with platinum-based chemotherapy In addition, expression and epigenetic regulation of ASS1 were analysed in human ovarian cancer cell lines, and ASS1 expression correlated with the ability of the lines to grow in media containing cisplatin, carboplatin or taxol or in arginine-depleted media Our results show that aberrant methylation in the ASS1 promoter correlated with transcriptional silencing in ovarian cancer cell lines ASS1 silencing conferred selective resistance to platinum-based drugs and conferred arginine auxotrophy and sensitivity to arginine deprivation In ovarian cancer, ASS1 methylation at diagnosis was associated with significantly reduced overall survival (p = 001) and relapse-free survival (p = 001) In patients who relapse, ASS1 methylation was significantly more frequent at relapse (p = 0008) These data establish epigenetic inactivation of ASS1 as a determinant of response to platinum chemotherapy and imply that transcriptional silencing of ASS1 contributes to treatment failure and clinical relapse in ovarian cancer The collateral sensitivity of cells lacking endogenous ASS1 to arginine depletion suggests novel therapeutic strategies for the management of relapsed ovarian cancer

Mutation analysis of coding sequences for type I procollagen in individuals with low bone density

Abstract: Mutations in one of the two genes encoding type I procollagen (COL1A1 and COL1A2) are frequently the cause of osteogenesis imperfecta (OI), a disorder characterized by brittle bones. Here we tested whether patients with low bone density also have mutations in these genes. The 26 patients studied had no apparent metabolic bone disease, but most had a positive family history of osteopenia or osteoporosis. Although a diagnosis of OI was considered by the clinician in some cases, the clinical criteria for OI were not satisfied. Our strategy for mutation analysis consisted of PCR amplification of cDNA made to fibroblast mRNA using primers specific for the coding regions of COL1A1 and COL1A2. The PCR products were then sequenced directly with primers located within each PCR product. We found that 3 of 26 patients had mutations that altered the encoded amino acid. One mutation, at position alpha 2(I)-661 has been reported (Spotila et al. 1991 Proc Natl Acad Sci USA PNAS 88:5423). The other 2 patients, who were not related to each other, had a mutation that altered the proline codon at alpha 1(I)-27 to alanine. This mutation was not found in 81 normal individuals or in 37 additional osteopenic individuals. However, its effect on the biologic function of type I collagen, as well as its role in osteopenia, is uncertain. In addition to the two mutations, we found a polymorphism in codon alpha 2(I)-459. Although this polymorphism involved an amino acid substitution, it was present with equal frequency in the patient and the normal population. By analyzing this and previously reported neutral sequence variants in the COL1A2 gene, we determined that all patients expressed both alleles of the COL1A2 gene. The 12 patients who were heterozygous for a COL1A1 neutral sequence variant also expressed both alleles. Here we present all PCR primer and sequencing primer information. The results suggest that surveying a larger group of similarly selected individuals may reveal additional mutations in the COL1A1 or COL1A2 genes.

Fistulas in malignant gynecologic disease: etiology, imaging, and management.

Abstract: A fistula that occurs in association with a malignancy of the female reproductive tract may be caused by a primary or recurrent tumor or may be a complication of surgery or radiation therapy. Identification of the cause, complexity, and location of a fistula is essential for optimal management planning. Radiologic imaging, particularly with computed tomography and magnetic resonance techniques, is invaluable for the assessment of gynecologic fistulas and may help direct the clinician toward the most appropriate management pathway. The modality and technique selected for the initial imaging evaluation depend largely on the clinical history and manifestations. However, imaging with a combination of techniques often is required for accurate diagnosis and effective treatment planning. Radiologists should be familiar with suggestive clinical signs and symptoms as well as with the characteristic appearances of rectovaginal, vesicovaginal, ureterovaginal, enterovesical, enterocutaneous, and other pelvic fistulas at multimodality imaging.

Modulation of vitronectin receptor-mediated osteoclast adhesion by Arg-Gly-Asp peptide analogs: a structure-function analysis.

Abstract: This study details the investigation of induction of retractile shape change in the osteoclast through inhibition of adhesion between osteoclasts and matrix with (1) peptide analogs bearing an Arg-Gly-Asp (RGD) sequence, (2) antibodies to the integrin alpha V beta 3 vitronectin receptor, and (3) the RGD-containing snake venom peptide echistatin. Osteoclast retraction on dentin has been demonstrated for GRGDSP peptide, in contrast to the inactivity of the analog containing the conservative RGE sequence modification. An osteoclast adhesion assay employing rat or chick bone cells and serum-coated glass coverslips as substrate was developed for routine evaluation of inhibition of adhesion. Antibodies F4 and F11 to the beta 3 chain of rat vitronectin receptor were effective at submicromolar concentrations in rat osteoclasts (IC50 0.29 and 0.05 microM, respectively), whereas MAb 23C6 to human/chick vitronectin receptor was somewhat less effective against chick osteoclasts (IC50 1.6 microM). A rank order of RGD analog activity (mean IC50, microM) in the serum-coated glass adhesion assay was derived for the linear peptides GRGDSP (201 microM), GRGDTP (180 microM), Ac-RGDS-NH2 (84 microM), Ac-RGDV-NH2 (68 microM), RGDV (43 microM), GRGDS (38 microM), and RGDS (26 microM). The two most potent short peptides were the cyclic analog SK&F 106760 Ac-S,S-cyclo-(Cys-(N alpha Me)Arg-Gly-Asp-Pen)-NH2 (IC50 7.0 microM), and the Telios peptide H-Gly-S,S-cyclo-(Pen-Gly-Arg-Gly-Asp-Ser-Pro-Cys)-Ala-OH (IC50 6.6 microM). The snake venom peptide echistatin was the most potent substance evaluated in the serum-coated glass assay (IC50 0.78 nM) employing either rat or chick osteoclasts.(ABSTRACT TRUNCATED AT 250 WORDS)

Integrins on rat osteoclasts: Characterization of two monoclonal antibodies (F4 and F11) to rat β3

Abstract: Two monoclonal antibodies, F4 and F11, were raised to newborn rat bone cell suspensions. These antibodies are shown by immunocytochemistry on tissue sections to recognize an antigen shared between osteoclasts, megakaryocytes, and platelets. Immunoprecipitation analysis of the antigen from C6 rat glial cells followed by SDS-PAGE showed a heterodimeric molecule with a characteristic integrin-like shift in apparent molecular mass upon reduction (137/78 kD nonreduced; 118/100 kD reduced); the low-molecular-mass band comigrates with the β3 subunit precipitated with polyclonal antihuman vitronectin receptor antiserum, and the high-molecular-mass band comigrates with the αv subunit precipitated with a polyclonal antiserum to a C-terminal amino acid sequence of human αv. Antibody F4 strongly cross-reacts with human cells and is shown in cross-blocking experiments and immunoprecipitation analysis with a human melanoma cell line DX3 to recognize a seemingly identical molecule as identified by anti-αvβ3 monoclonal antibody 23C6. Expression of F4 and F11 is reduced in platelets from a patient heterozygous for Glanzmann's thrombasthenia. Taken together, these results indicate that F4 and F11 recognize rat CD61, the integrin β3 chain, which, as was confirmed with polyclonal anti CD61 antisera, is highly expressed in rat osteoclasts. These antibodies may be useful tools in investigating the biochemical nature and biologic function of β3 integrins in rat osteoclasts. Additionally, because high expression of β3 in vivo is restricted to osteoclasts, megakaryocytes, and platelets, these antibodies may be used to help identify osteoclasts in tissue sections and bone cell suspensions. Apart from β3, rat osteoclasts were found to express high levels of αv and β1 integrins.

The prevalence and characteristic features of cyclicity and variability in Cushing's disease

Abstract: Objective: Cyclical Cushing’s syndrome may render the diagnosis and management of Cushing’s disease difficult. The aim of the present study was to investigate the prevalence of cyclicity and variability in patients with Cushing’s disease, and to identify putative distinctive features. Design: Retrospective case-note study. Methods: We analysed the case records of 201 patients with Cushing’s disease in a retrospective casenote study. Cyclicity was considered as the presence of at least one cycle, defined as a clinical and/or biochemical hypercortisolaemic peak followed by clinical and biochemical remission, followed by a new clinical and/or biochemical hypercortisolaemic peak. The fluctuations of mean serum cortisol levels, as assessed by a 5-point cortisol day curve, defined the variability. Results: Thirty (14.9%; 26 females) patients had evidence of cyclicity/variability. ‘Cycling’ patients were older but no difference in sex or paediatric distribution was revealed between ‘cycling’ and ‘noncycling’ patients. The median number of cycles was two for each patient, and 4 years was the median intercyclic period. A trend to lower cure rate post-neurosurgery and lower adenoma identification was observed in ‘cycling’ compared with ‘non-cycling’ patients. In multivariate analysis, older patients, longer follow-up, female sex and no histological identification of the adenoma were associated with an increased risk of cyclic disease. Conclusions: This large population study reveals that cyclicity/variability is not an infrequent phenomenon in patients with Cushing’s disease, with a minimum prevalence of 15%. Physicians should be alert since it can lead to frequent problems in diagnosis and management, and no specific features can be used as markers.

Treatment of Nelson's syndrome with temozolomide

Abstract: A 64-year-old woman was previously treated for Cushing's disease with trans-sphenoidal surgery, external beam radiotherapy and bilateral adrenalectomy. Progression of an aggressive corticotroph adenoma was evident 3 years post-adrenalectomy; involvement of the clivus was treated with surgery and gamma knife radiosurgery. Tumour spread through the skull base, occiput and left ear with persistent facial pain and left ear discharge; progression continued despite second gamma knife treatment. ACTH levels peaked at 2472 and 2265 pmol/l pre- and post-hydrocortisone respectively. Treatment with temozolomide resulted in a significant improvement in symptoms, a reduction of plasma ACTH to 389 pmol/l and regression of tumour on magnetic resonance imaging scan after four cycles of treatment. We propose that temozolomide is an effective and well-tolerated therapeutic tool for the treatment of Nelson's syndrome and a useful addition to the range of therapies available to treat this condition.

Patterns and predictors of early recurrence in postmenopausal women with estrogen receptor-positive early breast cancer

Abstract: Previous studies suggest that disease recurrence peaks at around 2 years in patients with early stage breast cancer (EBC), but provide no data regarding recurrence type. This retrospective analysis aimed to identify early recurrence types and risk factors in estrogen receptor-positive (ER+) EBC patients treated with adjuvant tamoxifen following breast cancer surgery. Postmenopausal women diagnosed with ER+ EBC from 1995 to 2004 were evaluated. Annual hazard ratios (HR) for recurrence at different sites were calculated. Time-dependent Cox regression analysis was used to identify predictors of recurrence within 2.5 years of diagnosis, including factors that were more strongly predictive of early than later recurrence. Of 3,614 patients evaluated, 476 developed recurrence during the 5-year median follow-up. Cumulative recurrence rates at 2.5 years (95% confidence interval) were: overall 6.3% (5.5–7.1), locoregional 1.1% (0.7–1.5), contralateral 0.5% (0.3–0.7), and distant 4.8% (4.0–5.6). The annual HR of overall recurrence peaked at 2 years (4.3% per annum). The majority of this peak represented distant recurrence (3.4% per annum). In Cox regression analysis, tumor size and grade, lymph node involvement, lymphovascular invasion, and symptomatic presentation were significant independent predictors of early recurrence. Age at diagnosis was independently predictive of recurrence within 2.5 years of diagnosis but not later recurrence. This study identified an early recurrence peak at 2 years, most of which were distant recurrences. Implementing an aromatase inhibitor after an initial 2–3 years of tamoxifen fails to address this early peak of distant recurrence and the potential breast cancer-associated mortality.

ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Biotherapy

Abstract: aDepartment of Internal Medicine, Endocrine Unit, Uppsala University Hospital, Uppsala, Sweden; bDepartments of Internal Medicine and Endocrinological and Metabolic Sciences, University of Genoa, Genoa, Italy; cG. Genimatas Hospital, Athens, Greece; dDepartment of Surgery, Rigshospitalet, Copenhagen, Denmark; eNetherlands Cancer Centre, Amsterdam, The Netherlands; fDepartment of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charite-Universitatsmedizin Berlin, Berlin, Germany

AZD1152 Rapidly and Negatively Affects the Growth and Survival of Human Acute Myeloid Leukemia Cells In vitro and In vivo

Abstract: Aurora kinases play a critical role in regulating mitosis and cell division, and their overexpression has been implicated in the survival and proliferation of human cancer. In this study, we report the in vitro and in vivo activities of AZD1152, a compound that has selectivity for aurora B kinase, in acute myeloid leukemia (AML) cell lines, primary AML samples, and cord blood cells. AZD1152 exerted antiproliferative or cytotoxic effects in all cell lines studied, inhibited the phosphorylation of histone H3 (pHis H3) on Ser10 in a dose-dependent manner, and resulted in cells with >4N DNA content. THP-1 cells treated with AZD1152 accumulated in a state of polyploidy and showed a senescent response to the drug, in contrast to the apoptotic response seen in other cell lines. Accordingly, AZD1152 profoundly affected the growth of AML cell lines and primary AML in an in vivo xenotransplantation model. However, concentration-dependent effects on cell growth, apoptosis, and cell cycle progression were also observed when human cord blood and primary lineage-negative stem and progenitor cells were analyzed in vitro and in vivo. These data suggest that the inhibition of aurora B kinase may be a useful therapeutic strategy in the treatment of AML and that further exploration of dosing and treatment schedules is warranted in clinical trials.

Long‐term experience of pegvisomant therapy as a treatment for acromegaly

Abstract: Summary Aims To evaluate the long-term efficacy and safety of pegvisomant as a treatment for acromegaly Design Retrospective analysis of clinical and trial data from all patients treated with pegvisomant since 1997 at two centres with common protocols Results Fifty-seven patients (age range 27–78 years) have been treated with pegvisomant since 1997 for up to 91 months (median 18 months) Before commencing pegvisomant, patients had an IGF-I above the upper limit of normal (ULN) of the age-related reference range (median 1·8 × ULN, range 1·2–4·1) Ninety-five per cent normalized IGF-I using a median dose of 15 mg daily (range 10 mg alternate day to 60 mg daily) with no influence of gender on dose requirement Five patients had combination therapy with either somatostatin analogues (SSA) or cabergoline Two patients initially controlled on 10 mg and 20 mg required dose increases (to 20 mg + 40 mg) over 24 months to reduce IGF-I Twenty-seven patients stopped pegvisomant Reasons included side-effects [abnormal liver function tests (LFTs)] and patient choice Two patients developed elevated liver transaminases, which normalized on stopping pegvisomant Patients had 6–12-monthly pituitary magnetic resonance imaging (MRI) scans One patient had significant tumour size increase Conclusion This long-term experience in 57 patients indicates pegvisomant to be effective, safe and well-tolerated Raised transaminases occurred within the first month of therapy in two patients, and tumour growth was seen in one patient (tumour was growing prior to pegvisomant) In two patients increasing doses of pegvisomant were required to keep IGF-I within the target range