Showing papers by "St Bartholomew's Hospital published in 2011"

Biological properties of carrageenan

Abstract: During the past decade carrageenan has become much used experimentally mainly for its ability to induce an acute inflammation. Despite the lack of knowledge on the pathogenesis of this reaction, the fate of hundreds of new compounds as anti-inflammatory drugs still depends on their ability to suppress carrageenan foot oedema in the rat. Nevertheless the range of the biological properties displayed by carrageenan extends much further. Thus the peculiar features of granuloma induced by carrageenan, its actions on blood coagulation and the kinin system, the contrasting observations reported on its effects on peptic ulcer, its recently discovered immunological properties as well as its interference in immune phenomena, all indicate an increasing interest in carrageenan. Since the comprehensive review of Anderson (1967), many stimulating results in subsequent years have prompted this review with the aim of clarifying its biological properties and examining its future use as a tool to investigate physiological and pathological processes.

Screens for anti-inflammatory drugs.

Abstract: British Pharmacopoeia (1963). Addendum (1966). London : Pharmaceutical Press. BROOKS, S. A., DAVIES, J. W. L., GRABER, I. G. & RICKETTS, C. R. (1960) Nature, Lond., 188,675676. Handbook of Circulation (1959). Editors: Dittmer, D. S. &Grebe, R. M. Philadelphiaand London: W. B. Saunders Co. HARDWICKE, J., HULME, B., JONES, J. H. & RICKETTS, C. R. (1968). RICKETTS, C. R. (1966). Clin. Sci., 34, 505-514. Nature, Lond., 210, 1113-1115.

UK guidelines for the management of pituitary apoplexy

Abstract: Classical pituitary apoplexy is a medical emergency and rapid replacement with hydrocortisone maybe life saving. It is a clinical syndrome characterized by the sudden onset of headache, vomiting, visual impairment and decreased consciousness caused by haemorrhage and/or infarction of the pituitary gland. It is associated with the sudden onset of headache accompanied or not by neurological symptoms involving the second, third, fourth and sixth cranial nerves. If diagnosed patients should be referred to a multidisciplinary team comprising, amongst others, a neurosurgeon and an endocrinologist. Apart from patients with worsening neurological symptoms in whom surgery is indicated, it is unclear currently for the majority of patients whether conservative or surgical management carries the best outcome. Post apoplexy, there needs to be careful monitoring for recurrence of tumour growth. It is suggested that further trials be carried out into the management of pituitary apoplexy to optimize treatment.

Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss

Abstract: We used an exome-sequencing strategy and identified an allelic series of NOTCH2 mutations in Hajdu-Cheney syndrome, an autosomal dominant multisystem disorder characterized by severe and progressive bone loss. The Hajdu-Cheney syndrome mutations are predicted to lead to the premature truncation of NOTCH2 with either disruption or loss of the C-terminal proline-glutamate-serine-threonine-rich proteolytic recognition sequence, the absence of which has previously been shown to increase Notch signaling.

Length-Dependent Retention of Carbon Nanotubes in the Pleural Space of Mice Initiates Sustained Inflammation and Progressive Fibrosis on the Parietal Pleura

Abstract: The fibrous shape of carbon nanotubes (CNTs) raises concern that they may pose an asbestos-like inhalation hazard, leading to the development of diseases, especially mesothelioma. Direct instillation of long and short CNTs into the pleural cavity, the site of mesothelioma development, produced asbestos-like length-dependent responses. The response to long CNTs and long asbestos was characterized by acute inflammation, leading to progressive fibrosis on the parietal pleura, where stomata of strictly defined size limit the egress of long, but not short, fibers. This was confirmed by demonstrating clearance of short, but not long, CNT and nickel nanowires and by visualizing the migration of short CNTs from the pleural space by single-photon emission computed tomographic imaging. Our data confirm the hypothesis that, although a proportion of all deposited particles passes through the pleura, the pathogenicity of long CNTs and other fibers arises as a result of length-dependent retention at the stomata on the parietal pleura.

Guidelines for the diagnosis and management of multiple myeloma 2011.

Abstract: 653. Spencer, A., Prince, H.M., Roberts, A.W., Prosser, I.W., Bradstock, K.F., Coyle, L., Gill, D.S., Horvath, N., Reynolds, J. & Kennedy, N. (2009) Consolidation therapy with low-dose thalido- mide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. Journal of Clinical Oncology, 27, 1788–1793. Srkalovic, G., Cameron, M.G., Rybicki, L., Deitcher, S.R., Kattke-Marchant, K. & Hussein, M.A. (2004) Monoclonal gammopathy of undeter- mined significance and multiple myeloma are associated with an increased incidence of venothromboembolic disease. Cancer, 101, 558– 666. Stadtmauer, E.A., Weber, D.M., Niesvizky, R., Belch, A., Prince, M.H., San Miguel, J.F., Facon, T., Olesnyckyj, M., Yu, Z., Zeldis, J.B., Knight, R.D. Guideline 74 a 2011 Blackwell Publishing Ltd, British Journal of Haematology, 154, 32–75 & Dimopoulos, M.A. (2009) Lenalidomide in combination with dexamethasone at first relapse in comparison with its use as later salvage therapy in relapsed or refractory multiple myeloma. European Journal of Haematology, 82, 426–432. Stewart, A.K., Vescio, R., Schiller, G., Ballester, O., Noga, S., Rugo, H., Freytes, C., Stadtmauer, E., Tarantolo, S., Sahebi, F., Stiff, P., Meharchard, J., Schlossman, R., Brown, R., Tully, H., Benyunes, M., Jacobs, C., Berenson, R., White, M., DiPersio, J., Anderson, K.C. & Berenson, J. (2001) Purging of autologous peripheral-blood stem cells using CD34 selection does not improve overall or progression-free survival after high-dose chemo- therapy for multiple myeloma: results of a multicenter randomized controlled trial. Journal of Clinical Oncology, 19, 3771–3779. Stewart, A.K., Chen, C.I., Howson-Jan, K., White, D., Roy, J., Kovacs, M.J., Shustik, C., Sadura, A., Shepherd, L., Ding, K., Meyer, R.M. & Belch, A.R. (2004) Results of a multicenter randomized phase II trial of thalidomide and prednisone mainte- nance therapy for multiple myeloma after autol- ogous stem cell transplant. Clinical Cancer Research, 10, 8170–8176. Stewart, A.K., Bergsagel, P.L., Greipp, P.R., Dis- penzieri, A., Gertz, M.A., Hayman, S.R., Kumar, S., Lacy, M.Q., Lust, J.A., Russell, S.J., Witzig, T.E., Zeldenrust, S.R., Dingli, D., Reeder, C.B., Roy, V., Kyle, R.A., Rajkumar, S.V. & Fonseca, R. (2007) A practical guide to defining high-risk myeloma for clinical trials, patient counseling and choice of therapy. Leukemia, 21, 529–534. Terpos, E. & Dimopoulos, M.A. (2005) Myeloma bone disease: pathophysiology and management. Annals of Oncology, 16, 1223–1231. Terpos, E. & Rahemtulla, A. (2004) Bisphosphonate treatment for multiple myeloma. Drugs of today (Barcelona, Spain: 1998), 40, 29–40. Terpos, E., Sezer, O., Croucher, P.I., Garcia-Sanz, R., Boccadoro, M., San Miguel, J., Ashcroft, J., Blade, J., Cavo, M., Delforge, M., Dimopoulos, M.A., Facon, T., Macro, M., Waage, A. & Son- neveld, P. (2009) The use of bisphosphonates in multiple myeloma: recommendations of an ex- pert panel on behalf of the European Myeloma Network. Annals of Oncology, 20, 1303–1317. Tosi, P., Zamagni, E., Cellini, C., Cangini, D., Tac- chetti, P., Tura, S., Baccarani, M. & Cavo, M. (2004) Thalidomide alone or in combination with dexamethasone in patients with advanced, relapsed or refractory multiple myeloma and renal failure. European Journal of Haematology, 73, 98–103. Tosi, P., Zamagni, E., Cellini, C., Plasmati, R., Cangini, D., Tacchetti, P., Perrone, G., Pastorelli, F., Tura, S., Baccarani, M. & Cavo, M. (2005) Neurological toxicity of long-term (>1 yr) thalidomide therapy in patients with multiple myeloma. European Journal of Haematology, 74, 212–216. Vela-Ojeda, J., Garcia-Ruiz-Esparza, M.A., Padilla- Gonzalez, Y., Gomez-Almaguer, D., Gutierrez- Aguirre, C.H., Gomez-Rangel, D., Morales- Toquero, A., Ruiz-Delgado, G.J., Delgado-Lamas, J.L. & Ruiz-Arguelles, G.J. (2007) Autologous peripheral blood stem cell transplantation in multiple myeloma using oral versus I.V. melphalan. Annals of Hematology, 86, 277–282. van de Velde, H.J., Liu, X., Chen, G., Cakana, A., Deraedt, W. & Bayssas, M. (2007) Complete response correlates with long-term survival and progression-free survival in high-dose therapy in multiple myeloma. Haematologica, 92, 1399–1406. Vigneau, C., Ardiet, C., Bret, M., Laville, M., Fiere, D., Tranchand, B. & Fouque, D. (2002) Inter- mediate-dose (25 mg/m) IV melphalan for multiple myeloma with renal failure. Journal of Nephrology, 15, 684–689. Vogel, C.L., Yanagihara, R.H., Wood, A.J., Schnell, F.M., Henderson, C., Kaplan, B.H., Purdy, M.H., Orlowski, R., Decker, J.L., Lacerna, L. & Hohneker, J.A. (2004) Safety and pain palliation of zoledronic acid in patients with breast cancer, prostate cancer, or multiple myeloma who previously received bisphosphonate therapy. Oncologist, 9, 687–695. Waage, A., Gimsing, P., Juliusson, G., Turesson, I., Gulbrandsen, N., Eriksson, T., Hjorth, M., Niel- sen, J.L., Lenhoff, S., Westin, J. & Wisloff, F. (2004) Early response predicts thalidomide efficiency in patients with advanced multiple myeloma. British Journal of Haematology, 125, 149–155. Wang, M., Knight, R., Dimopoulos, M., Siegel, D., Rajkumar, S.V., Facon, T., Alexanian, R., Yu, Z., Zeldis, J., Olesnyckyj, M. & Weber, D. (2006) Lenalidomide in combination with dexametha- sone was more effective than dexamethasone in patients who have received prior thalidomide for relapsed or refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts), 108, Abstract 3553. Weber, D.M., Gavino, M., Delasalle, K., Rankin, K., Giralt, S. & Alexanian, R. (1999) Thalidomide alone or with dexamethasone for multiple mye- loma. Blood, 94(Suppl. I), 604a. Weber, D., Wang, M., Chen, C., Belch, A., Stadt- mauer, E.A., Niesvisky, R., Yu, Z., Olesnyckyj, M., Zeldis, J., Knight, R.D. & Dimopoulos, M. (2006) Lenalidomide Plus High-Dose Dexamethasone Provides Improved Overall Survival Compared to High-Dose Dexamethasone Alone for Relapsed or Refractory Multiple Myeloma (MM): Results of 2 Phase III Studies (MM-009, MM-010) and Subgroup Analysis of Patients with Impaired Renal Function. Blood (ASH Annual Meeting Abstracts), 108, 3547. Weber, D.M., Chen, C., Niesvizky, R., Wang, M., Belch, A., Stadtmauer, E.A., Siegel, D., Borrello, I., Rajkumar, S.V., Chanan-Khan, A.A., Lonial, S., Yu, Z., Patin, J., Olesnyckyj, M., Zeldis, J.B. & Knight, R.D. (2007) Lenalidomide plus dexa- methasone for relapsed multiple myeloma in North America. New England Journal of Medicine, 357, 2133–2142. Wechalekar, A., Amato, D., Chen, C., Stewart K., A. & Reece, D. (2005) IgD multiple myeloma–a clinical profile and outcome with chemotherapy and autologous stem cell transplantation. Annals of Hematology, 84, 115–117. Wijermans, P., Schaafsma, M., Norden, Y.v., Ammerlaan, R., Wittebol, S., Sinnige, H., Zweegman, S., Kooi, M.v.M., Griend, R.V.d., Lokhorst, H. & Sonneveld, P. (2008) Melphalan/ prednisone versus melphalan/prednisone/thalid- omide in induction therapy for multiple myelo- ma in elderly patients: final analysis of the dutch cooperative group HOVON 49 study. Blood (ASH Annual Meeting Abstracts), 112, Abstract 649. Zervas, K., Mihou, D., Katodritou, E., Pouli, A., Mitsouli, C.H., Anagnostopoulos, A., Delibasi, S., Kyrtsonis, M.C., Anagnostopoulos, N., Terpos, E., Zikos, P., Maniatis, A. & Dimopoulos, M.A. (2007) VAD-doxil versus VAD-doxil plus tha- lidomide as initial treatment for multiple mye- loma: results of a multicenter randomized trial of the Greek Myeloma Study Group. Annals of Oncology, 18, 1369–1375. Zucchelli, P., Pasquali, S., Cagnoli, L. & Ferrari, G. (1988) Controlled plasma exchange trial in acute renal failure due to multiple myeloma. Kidney International, 33, 1175–1180. Guideline a 2011 Blackwell Publishing Ltd, British Journal of Haematology, 154, 32–75 75

Diverse patterns of myocardial fibrosis in lifelong, veteran endurance athletes

Abstract: This study examined the cardiac structure and function of a unique cohort of documented lifelong, competitive endurance veteran athletes (>50 yr). Twelve lifelong veteran male endurance athletes [m...

Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial

Abstract: Background: When cure is impossible, cancer treatment should focus on both length and quality of life. Maximisation of time without toxic effects could be one effective strategy to achieve both of these goals. The COIN trial assessed preplanned treatment holidays in advanced colorectal cancer to achieve this aim. Methods: COIN was a randomised controlled trial in patients with previously untreated advanced colorectal cancer. Patients received either continuous oxaliplatin and fluoropyrimidine combination (arm A), continuous chemotherapy plus cetuximab (arm B), or intermittent (arm C) chemotherapy. In arms A and B, treatment continued until development of progressive disease, cumulative toxic effects, or the patient chose to stop. In arm C, patients who had not progressed at their 12-week scan started a chemotherapy-free interval until evidence of disease progression, when the same treatment was restarted. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and B is described in a companion paper. Here, we compare arms A and C, with the primary objective of establishing whether overall survival on intermittent therapy was non-inferior to that on continuous therapy, with a predefined non-inferiority boundary of 1·162. Intention-to-treat (ITT) and per-protocol analyses were done. This trial is registered, ISRCTN27286448. Findings: 1630 patients were randomly assigned to treatment groups (815 to continuous and 815 to intermittent therapy). Median survival in the ITT population (n=815 in both groups) was 15·8 months (IQR 9·4–26·1) in arm A and 14·4 months (8·0–24·7) in arm C (hazard ratio [HR] 1·084, 80% CI 1·008–1·165). In the per-protocol population (arm A, n=467; arm C, n=511), median survival was 19·6 months (13·0–28·1) in arm A and 18·0 months (12·1–29·3) in arm C (HR 1·087, 0·986–1·198). The upper limits of CIs for HRs in both analyses were greater than the predefined non-inferiority boundary. Preplanned subgroup analyses in the per-protocol population showed that a raised baseline platelet count, defined as 400 000 per μL or higher (271 [28%] of 978 patients), was associated with poor survival with intermittent chemotherapy: the HR for comparison of arm C and arm A in patients with a normal platelet count was 0·96 (95% CI 0·80–1·15, p=0·66), versus 1·54 (1·17–2·03, p=0·0018) in patients with a raised platelet count (p=0·0027 for interaction). In the per-protocol population, more patients on continuous than on intermittent treatment had grade 3 or worse haematological toxic effects (72 [15%] vs 60 [12%]), whereas nausea and vomiting were more common on intermittent treatment (11 [2%] vs 43 [8%]). Grade 3 or worse peripheral neuropathy (126 [27%] vs 25 [5%]) and hand–foot syndrome (21 [4%] vs 15 [3%]) were more frequent on continuous than on intermittent treatment. Interpretation: Although this trial did not show non-inferiority of intermittent compared with continuous chemotherapy for advanced colorectal cancer in terms of overall survival, chemotherapy-free intervals remain a treatment option for some patients with advanced colorectal cancer, offering reduced time on chemotherapy, reduced cumulative toxic effects, and improved quality of life. Subgroup analyses suggest that patients with normal baseline platelet counts could gain the benefits of intermittent chemotherapy without detriment in survival, whereas those with raised baseline platelet counts have impaired survival and quality of life with intermittent chemotherapy and should not receive a treatment break. Funding: Cancer Research UK.

Sensitivity of transvaginal ultrasound screening for endometrial cancer in postmenopausal women: a case-control study within the UKCTOCS cohort

Abstract: Summary Background The increase in the worldwide incidence of endometrial cancer relates to rising obesity, falling fertility, and the ageing of the population. Transvaginal ultrasound (TVS) is a possible screening test, but there have been no large-scale studies. We report the performance of TVS screening in a large cohort. Methods We did a nested case-control study of postmenopausal women who underwent TVS in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) following recruitment between April 17, 2001, and Sept 29, 2005. Endometrial thickness and endometrial abnormalities were recorded, and follow-up, through national registries and a postal questionnaire, documented the diagnosis of endometrial cancer. Our primary outcome measure was endometrial cancer and atypical endometrial hyperplasia (AEH). Performance characteristics of endometrial thickness and abnormalities for detection of endometrial cancer within 1 year of TVS were calculated. Epidemiological variables were used to develop a logistic regression model and assess a screening strategy for women at higher risk. Our study is registered with ClinicalTrials.gov, number NCT00058032, and with the International Standard Randomised Controlled Trial register, number ISRCTN22488978. Findings 48 230 women underwent TVS in the UKCTOCS prevalence screen. 9078 women were ineligible because they had undergone a hysterectomy and 2271 because their endometrial thickness had not been recorded; however, 157 of these women had an endometrial abnormality on TVS and were included in the analysis. Median follow-up was 5·11 years (IQR 4·05–5·95). 136 women with endometrial cancer or AEH within 1 year of TVS were included in our primary analysis. The optimum endometrial thickness cutoff for endometrial cancer or AEH was 5·15 mm, with sensitivity of 80·5% (95% CI 72·7–86·8) and specificity of 86·2% (85·8–86·6). Sensitivity and specificity at a 5 mm or greater cutoff were 80·5% (72·7–86·8) and 85·7% (85·4–86·2); for women with a 5 mm or greater cutoff plus endometrial abnormalities, the sensitivity and specificity were 85·3% (78·2–90·8) and 80·4% (80·0–80·8), respectively. For a cutoff of 10 mm or greater, sensitivity and specificity were 54·1% (45·3–62·8) and 97·2% (97·0–97·4). When our analysis was restricted to the 96 women with endometrial cancer or AEH who reported no symptoms of postmenopausal bleeding at the UKCTOCS scan before diagnosis and had an endometrial thickness measurement available, a cutoff of 5 mm achieved a sensitivity of 77·1% (67·8–84·3) and specificity of 85·8% (85·7–85·9). The logistic regression model identified 25% of the population as at high risk and 39·5% of endometrial cancer or AEH cases were identified within this high risk group. In this high-risk population, a cutoff at 6·75 mm achieved sensitivity of 84·3% (71·4–93·0) and specificity of 89·9% (89·3–90·5). Interpretation Our findings show that TVS screening for endometrial cancer has good sensitivity in postmenopausal women. The burden of diagnostic procedures and false-positive results can be reduced by limiting screening to a higher-risk group. The role of population screening for endometrial cancer remains uncertain, but our findings are of immediate value in the management of increased endometrial thickness in postmenopausal women undergoing pelvic scans for reasons other than vaginal bleeding. Funding Cancer Research UK, Medical Research Council, NHS Research and Development, and The Eve Appeal.

Ethnic differences in prostate cancer.

Abstract: It is recognised that the risk of prostate cancer is higher in black men than in white men worldwide. Recent studies suggest that a number of genetic mutations in black men predispose them to this disease; hence, race as well as environmental factors such as diet and migration are thought to be the determining factors. This review compares data from the United States (US), which suggest that African-American men have a 60% higher risk for developing prostate cancer with poorer prognosis in comparison with their white counterparts, with similar studies carried out in the United Kingdom (UK) and also in African and Caribbean countries. Studies from the United States and the United Kingdom came to significantly different conclusions, and this has implications for policy development, awareness raising among black men in each country and clinical practice.

Adrenocortical carcinoma: the range of appearances on CT and MRI.

Abstract: OBJECTIVE. Adrenocortical carcinoma (ACC) is a rare, aggressive tumor arising from the adrenal cortex that typically presents late with a large mass. The increased use of cross-sectional imaging for unrelated reasons has led to a greater number of ACCs being detected incidentally at an earlier stage. Recognition of the typical clinical, biochemical, and imaging findings is imperative for rapid diagnosis, prompt intervention, and early use of the appropriate therapy. CONCLUSION. Cross-sectional imaging with CT and MRI is essential for determining the extent of local and distant tumor spread. Complete surgical resection is currently the only potentially curative treatment of ACC, and the information attained from CT and MRI is important to guide surgery and further patient management.

Molecular subtyping of DCIS: heterogeneity of breast cancer reflected in pre-invasive disease

Abstract: Molecular subtyping of DCIS: heterogeneity of breast cancer reflected in pre-invasive disease

Prolonged expression of the γ-H2AX DNA repair biomarker correlates with excess acute and chronic toxicity from radiotherapy treatment

Abstract: The normal tissue tolerance levels to fractionated radiotherapy have been appreciated by a century of careful clinical observations and radiobiological studies in animals. During clinical fractionated radiotherapy, these normal tissue tolerance levels are respected, and severe sequelae of radiotherapy are avoided in the majority of patients. Notwithstanding, a minority of patients experience unexpectedly severe normal tissue reactions. The ability to predict which patients might form this minority would be important. We have conducted a study to develop a rapid and reliable diagnostic test to predict excessive normal tissue toxicity (NTT) in radiotherapy patients. A flow cytometric immunocytochemical assay was used to measure DNA damage in peripheral blood lymphocytes (PBL) from cancer patients exposed to 2-Gy gamma radiation. DNA damage and repair was measured by induction of cellular γ-H2AX in unirradiated and exposed cells at specific time points following exposure. In 12 cancer patients that experienced severe atypical NTT following radiotherapy, there was a failure to repair DNA double-strand breaks (DSB) as measured by γ-H2AX induction and persistence. In ten cancer patients that experienced little or no NTT and in seven normal (noncancer controls), efficient repair of DNA DSB was observed in the γ-H2AX assay. We conclude that a flow cytometric assay based on γ-H2AX induction in PBL of radiotherapy patients may represent a robust, rapid and reliable biomarker to predict NTT during radiotherapy. Further research is required with a larger patient cohort to validate this important study.

13q deletion anatomy and disease progression in patients with chronic lymphocytic leukemia.

Abstract: Historically, genes targeted by recurrent chromosomal deletions have been identified within the smallest genomic region shared in all patients, the minimally deleted region (MDR). However, deletions this small do not occur in all patients and are a simplification of the impact larger heterogeneous deletions have during carcinogenesis. We use the example of 13q14 deletions in chronic lymphocytic leukemia to show that genes outside MDRs are associated with disease progression. Genomic profiling of 224 patients identified 205 copy number alterations on chromosome 13 in 132 cases. Deletions including DLEU2 were heterogeneous (845 Kb–96.2 Mb) and identified two breakpoint cluster regions within short interspersed nuclear elements proximal to DLEU2 and within long interspersed nuclear elements/L1 repeats distal to GUCY1B2. After defining a deletion class on the basis of size and location, we show that (a) at diagnosis, larger deletions (class II) were associated with a significantly increased risk of disease progression (odds ratio=12.3; P=0.005), (b) in progressive patients, class II deletions were enriched (P=0.02) and (c) this association was independent of IgVH mutational status, ZAP70 expression and ATM/TP53 deletion. Deletion of a 1 Mb gene cluster (48.2–49.2 Mb), including SETDB2, PHF11 and RCBTB1, was significantly associated (P<0.01) with disease progression. Here, we show that the deletion of genes outside MDRs can influence clinical outcome.

A membrane model of the human oral mucosa as derived from buccal absorption performance and physicochemical properties of the β-blocking drugs atenolol and propranolol

Abstract: The buccal absorption characteristics and physicochemical properties of the beta-adrenoceptor blocking agents propranolol and atenolol have been investigated to evaluate their permeation properties across biological lipid membranes. The dissociation constants, solubilities of free base, and n-heptane partition coefficients show that propranolol in its unionized form is much more lipophilic than atenolol, both drugs being bases with a similar pKa. Buccal absorption was studied under conditions of varying drug concentration, contact time, and pH, and controlled through the use of a non-absorbable marker. The absorption findings are in general agreement with the pH-partition theory. A new compartmental diffusional model that includes membrane storage and a hypothetical "aqueous pH-buffering surfaces system" allowed a more exhaustive interpretation to be made. A method for the estimation of the intrinsic pH and buffer capacity of the postulated surface system from drug pH-absorption data and partition coefficients alone is described. With human oral mucosa the intrinsic pH was near 6.7, and the buffering capacity of the system (expressed as the ratio deltapH/deltapH eff) about 2.86. The method was validated using published absorption data from the rat small intestine. Absorption of unionized drug through pores is shown to be negligible in the buccal absorption situation. The time course of absorption suggests membrane storage of lipophilic compounds; the in vivo partition coefficient of unionized propranolol relative to the mucous membrane could be calculated for the peusdo-steady state of absorption, i.e. the partition equilibrium between mouth content and membrane, to be approximately 776; this value is of the same order as the in vitro partition coefficient for the erythrocyte/plasma system. The lipid biophase of the buccal membrane is estimated semiquantitatively to be of intermediate polarity (epsilon = 3-4).

CT, MRI and PET imaging in peritoneal malignancy

Abstract: Imaging plays a vital role in the evaluation of patients with suspected or proven peritoneal malignancy. Nevertheless, despite significant advances in imaging technology and protocols, assessment of peritoneal pathology remains challenging. The combination of complex peritoneal anatomy, an extensive surface area that may host tumour deposits and the considerable overlap of imaging appearances of various peritoneal diseases often makes interpretation difficult. Contrast-enhanced multidetector computed tomography (MDCT) remains the most versatile tool in the imaging of peritoneal malignancy. However, conventional and emerging magnetic resonance imaging (MRI) and positron emission tomography (PET)/CT techniques offer significant advantages over MDCT in detection and surveillance. This article reviews established and new techniques in CT, MRI and PET imaging in both primary and secondary peritoneal malignancies and provides an overview of peritoneal anatomy, function and modes of disease dissemination with illustration of common sites and imaging features of peritoneal malignancy.

What can molecular pathology contribute to the management of renal cell carcinoma

Abstract: Although renal cell carcinoma (RCC) is increasing in incidence and is associated with a poor outcome, there is no molecular test to identify which patients will relapse and who will respond to targeted therapies. In this Review, the authors discuss the biochemical, histological and genetic characteristics of RCC, and why these characteristics have not been translated into a useful prognostic and predictive test for patients with kidney cancer.

Characterization of fractionated atrial electrograms critical for maintenance of atrial fibrillation: a randomized, controlled trial of ablation strategies (the CFAE AF trial).

Abstract: Background— Whether ablation of complex fractionated atrial electrograms (CFAE) modifies atrial fibrillation (AF) by eliminating drivers or atrial debulking remains unknown. This randomized study aimed to determine the effect of ablating different CFAE morphologies compared with normal electrograms (ie, debulking normal tissue) on the cycle length of persistent AF (AFCL). Methods and Results— After pulmonary vein isolation left and right atrial CFAE were targeted, until termination of AF or abolition of CFAE before DC cardioversion. Ten-second electrograms were classified according to a validated scale, with grade 1 being most fractionated and grade 5 normal. Patients were randomly assigned to have CFAE grades eliminated sequentially, from grade 1 to 5 (group 1) or grade 5 to 1 (group 2). An increase in AFCL (mean of left and right atrial appendage) ≥5 ms after a lesion was regarded as significant. CFAE (n=968) were targeted in 20 patients. AFCL increased after targeting 51±35% of grade 1 CFAE, 30±15% grade 2, 12±5% grade 3, 33±12% grade 4, and 8±15% grade 5 CFAE ( P <0.01 for grades 1, 2, and 4 versus 5; 3 versus 5, not significant). The proportion of lesions causing AFCL prolongation was unaffected by the order in which CFAE were targeted. Conclusions— Targeting CFAE is not simply atrial debulking. Ablating certain grades of CFAE increases AFCL, suggesting they are more important in maintaining AF. Clinical Trial Registration— URL: . Unique identifier: [NCT00894400][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00894400&atom=%2Fcircae%2F4%2F5%2F622.atom

Advances in magnetic resonance imaging of endometrial cancer

Abstract: Endometrial cancer is the most commonly diagnosed gynaecological malignancy in affluent societies [1]. It occurs most frequently in white women, with peak incidence between ages 55 and 65. Risk factors include unopposed oestrogen intake, use of tamoxifen, nulliparity, obesity, and diabetes. The incidence of endometrial cancer in the United Kingdom has increased by more than 40% between 1993 and 2007. This significant rise is predominantly due to a large increase in incidence in women aged 60–79 [1]. These trends are very similar for most European countries [2]. The increase in prevalence of obesity and decreases in fertility may partly account for the observed rapid increase in incidence and imply that endometrial cancer in postmenopausal women will become a more substantial public health problem in the future. Prognosis depends on a number of factors, including stage, depth of myometrial invasion, lymphovascular invasion, nodal status and histological grade. Depth of myometrial invasion is the single most important morphologic prognostic factor, correlating with tumour grade, lymph node metastases and overall patient survival. Incidence of lymph node metastases increases from 3% with superficial myometrial invasion (stage IA) to 46% with deep myometrial invasion (stage IB) [3]. Preoperative knowledge of these factors is crucial in tailoring the surgical approach. The histological grade can be determined at endometrial sampling, whereas depth of myometrial invasion can only be assessed preoperatively by MRI. Therefore, MRI can assist in preoperative assessment and treatment planning by accurately predicting depth of myometrial invasion, cervical stromal invasion and lymph node involvement. This information allows selection of patients for pelvic or para-aortic lymph node sampling whilst obviating the need for surgery in patients with low risk disease. MRI can also provide additional useful information such as uterine size, tumour volume, ascites and adnexal pathology which in turn may determine whether the surgical approach is transabdominal, transvaginal or laparoscopic. Lymphadenectomy in early (stage I) endometrial cancer remains a controversial issue. Two large prospective multicentre studies investigated whether pelvic lymphadenectomy could improve survival of women with endometrial cancer [4, 5]. Both studies reported no benefit in overall or recurrence free survival in the patients randomized to lymphadenectomy. Conversely, the SEPAL study [6] showed that in patients with intermediate or high risk of endometrial cancer recurrence, combined pelvic and paraaortic lymphadenectomy reduced the risk of death compared with pelvic lymphadenectomy alone. The authors acknowledged that MRI is an important factor for predicting lymph node metastasis, and in combination with tumour grade and histology could be helpful to discriminate patients with very low risk of recurrence. Therefore, E. Sala Addenbrooke’s Hospital, University Department of Radiology, Box 218, Level 5, Hills Road, Cambridge CB2 0QQ, UK e-mail: es220@radiol.cam.ac.uk

Catheter Ablation for Atrial Fibrillation on Uninterrupted Warfarin: Can It Be Done Without Echo Guidance?

Abstract: AF Ablation on Uninterrupted Warfarin. Introduction: Catheter ablation for atrial fibrillation is an effective treatment for symptomatic patients who have failed drug therapy. Recent studies using intracardiac echocardiography have demonstrated that ablation can be performed safely on uninterrupted warfarin and may be superior to bridging low molecular weight heparin (LMWH). We sought to assess the safety of an uninterrupted warfarin protocol using a simplified ablation protocol in a prospective controlled study. Methods: Two anticoagulation regimes for patients undergoing catheter ablation for atrial fibrillation were evaluated—a bridging LMWH group and an uninterrupted warfarin group. Bleeding complications were compared between the 2 groups. Results: In total 198 patients were evaluated (109 bridging LMWH, 89 uninterrupted warfarin). The preprocedure INR in the LMWH group (mean age 60.6 years, 72% male) was 1.2 ± 0.3 compared to 2.3 ± 0.5 in the uninterrupted warfarin group (mean age 60.9 years, 69% male). The primary outcome (a composite of major and minor bleeding complications) was observed in 78% in the LMWH group compared to 56% in the warfarin group (P = 0.001), mainly due to increased pain at the venous access site (41% vs 16%, P = 0.001). Two patients undergoing ablation on warfarin required pericardiocentesis for cardiac tamponade. Drug costs were lower in the warfarin group ($64.77 ± 31.86 vs $20.76 ± 15.60, P = 0.005), but the overall cost of treatment per patient (including bed occupancy costs) was similar in the LMWH group compared to the warfarin group ($883.96 ± 278.78 vs $816.59 ± 182.72, P = 0.06). Conclusion: Catheter ablation for atrial fibrillation can be performed safely on uninterrupted warfarin without intracardiac echocardiography, with a reduced risk of bleeding complications. (J Cardiovasc Electrophysiol, Vol. 22, pp. 265-270, March 2011)

Sunitinib and other targeted therapies for renal cell carcinoma

Abstract: Targeted therapy has radically altered the way metastatic renal cancer is treated. Six drugs are now licensed in this setting, with several other agents under evaluation. Sunitinib is currently the most widely used in the first line setting with impressive efficacy and an established toxicity profile. However, as further randomised studies report and as newer drugs become available this may change. In this review, we address our current understanding of targeted therapy in renal cancer. We also discuss areas in which our knowledge is incomplete, including the identification of correlative biomarkers and mechanisms of drug resistance. Finally, we will describe the major areas of clinical research that will report over the next few years.

A multi-centre randomised phase III trial of Dexamethasone vs Dexamethasone and diethylstilbestrol in castration-resistant prostate cancer: immediate vs deferred Diethylstilbestrol

Abstract: A multi-centre randomised phase III trial of Dexamethasone vs Dexamethasone and diethylstilbestrol in castration-resistant prostate cancer: immediate vs deferred Diethylstilbestrol

Optimizing management of invasive mould diseases

Abstract: We describe an integrated care pathway (ICP) for the optimal management of invasive mould disease (IMD). The ICP is for use by health professionals involved in the care of patients with haematological malignancies and haematopoietic stem cell transplant recipients who are at increased risk of IMD. The ICP is not intended for use in other patient groups where the evidence base is more limited. The ICP involves the patient and their carers, as well as describing the roles and the complex interaction of healthcare professionals in different departments. Therefore, the management of IMD as described in the ICP must be appropriate for the overall organization, and will be dependent on the facilities [e.g. high-efficiency particulate air (HEPA) filtration] and services available. The ICP deals with risk stratification, diagnostic tests, prophylactic and treatment strategies and how to incorporate these into the ICP. Outpatient drug management after hospital discharge and cessation of therapy are outlined. Local implementation of this ICP will vary from centre to centre: the ICP is a generic template for guidance indicating the requirements for optimal IMD management and as such provides a standard against which local practice can be audited. For clinical governance, to minimize variation in practice and, ultimately, to improve patient outcomes, each centre should regularly monitor and document compliance with the local ICP, from provision of patient information, appropriate prescribing and diagnostic investigation to clinical outcomes.

The interaction between growth hormone and the thyroid axis in hypopituitary patients

Abstract: Alterations in the hypothalamo-pituitary-thyroid axis have been reported following growth hormone (GH) administration in both adults and children with and without growth hormone deficiency. Reductions in serum free thyroxine (T4), increased tri-iodothyronine (T3) with or without a reduction in serum thyroid-stimulating hormone secretion have been reported following GH replacement, but there are wide inconsistencies in the literature about these perturbations. The clinical significance of these changes in thyroid function remains uncertain. Some authors report the changes are transient and revert to normal after a few months or longer. However, in adult hypopituitary patients, GH replacement has been reported to unmask central hypothyroidism biochemically in 36-47% of apparently euthyroid patients, necessitating thyroxine replacement and resulting in an attenuation of the benefit of GH replacement on quality of life in those who became biochemically hypothyroid after GH replacement. The group at highest risk are those with organic pituitary disease or multiple pituitary hormone deficiencies. It is therefore prudent to monitor thyroid function in hypopituitary patients starting GH therapy to identify those who will develop clinical and biochemical features of central hypothyroidism, thus facilitating optimal and timely replacement.