Search

As part of the UK NCRI AML17 trial, adult acute myeloid leukaemia patients in remission could be randomised to receive the mTOR inhibitor everolimus, sequentially with post-induction chemotherapy. Three hundred and thirty-nine patients were randomised (2:1) to receive everolimus or not for a maximum of 84 days between chemotherapy courses. The primary endpoint was relapse free survival (RFS). At 5 years there was no difference in Relapse Free Survival (29% vs 40%; OR 1.19 (0.9-1.59) p=0.2), cumulative incidence of relapse (60% vs 54%: OR 1.12( 0.82-1.52): p=0.5) or overall survival (45% vs 58%: OR 1.3 (0.94-1.81): p=0.11). The independent Data Monitoring Committee advised study termination after randomisation of 339 of the intended 600 patients due to an excess mortality in the everolimus arm without any evidence of beneficial disease control. Dose delivery of everolimus was variable, but there was no evidence of clinical benefit in patients with adequate dose delivery compared with no treatment. This study suggests that the addition of mTOR inhibition to chemotherapy provides no benefit. Clinical Trial: ISRCTN55675535

Background Nilotinib has been shown to be a more potent inhibitor of BCR-ABL than imatinib. We evaluated the efficacy and safety of nilotinib, as compared with imatinib, in patients with newly diagnosed Philadelphia chromosome–positive chronic myeloid leukemia (CML) in the chronic phase. Methods In this phase 3, randomized, open-label, multicenter study, we assigned 846 patients with chronic-phase Philadelphia chromosome–positive CML in a 1:1:1 ratio to receive nilotinib (at a dose of either 300 mg or 400 mg twice daily) or imatinib (at a dose of 400 mg once daily). The primary end point was the rate of major molecular response at 12 months. Results At 12 months, the rates of major molecular response for nilotinib (44% for the 300-mg dose and 43% for the 400-mg dose) were nearly twice that for imatinib (22%) (P

Background. Recent changes in health care financing have raised the specter of operation-specific, volume credentialing for cardiac surgeons. To meet this challenge, the leadership of The Society of Thoracic Surgeons formed an Ad Hoc Committee to study the question of the relationship of case volume to outcome. One product of the committee's work is this analysis of data from The Society of Thoracic Surgery National Cardiac Database. Methods. We examined data for all types of coronary artery bypass graft-only operations (n = 124,793) from more than 1,200 surgeons working in more than 600 hospitals for the years 1991 through 1993. All in-hospital and 30-day out-of-hospital mortality, both observed and expected as predicted by The Society of Thoracic Surgeons risk stratification method, was plotted against annualized group practice volume. Both patient-based and practice-based sampling techniques were used. Results. The data show that observed mortality ranged from 2.0% to 3.6% for practices of more than 100 cases through practices with more than 900 cases per year. Those practices with less than 100 cases (n = 18) had a mean mortality of 5%. Expected mortalities ranged from 2.4% to 3.9% and did not vary as a function of volume. No practice volume category had an observed/expected ratio of less than 0.8 and none had a ratio greater than 1.2, if annual volume was more than 100. Practices of less than 100 cases/year had an observed/expected ratio of 1.6% to 1.7%. There was great variation in observed and expected mortalities in the lower volume categories and less variation when volume was greater (more than 600 cases/year). Conclusions. Although the data are practice-group-specific only, there was no clinically relevant correlation of volume to outcome except at extremely low annual volume (less than 100 cases per year). Variability of outcome was significant in lower volume practices (less than 600 cases/year) and varied little at more than 600 cases per year. There were no differences in expected mortality regardless of the size of the practice.

New granule cells are born throughout life in the dentate gyrus of the hippocampal formation. Given the fundamental role of the hippocampus in processes underlying certain forms of learning and memory, it has been speculated that newborn granule cells contribute to cognition. However, previous strategies aiming to causally link newborn neurons with hippocampal function used ablation strategies that were not exclusive to the hippocampus or that were associated with substantial side effects, such as inflammation. We here used a lentiviral approach to specifically block neurogenesis in the dentate gyrus of adult male rats by inhibiting WNT signaling, which is critically involved in the generation of newborn neurons, using a dominant-negative WNT (dnWNT). We found a level-dependent effect of adult neurogenesis on the long-term retention of spatial memory in the water maze task, as rats with substantially reduced levels of newborn neurons showed less preference for the target zone in probe trials >2 wk after acquisition compared with control rats. Furthermore, animals with strongly reduced levels of neurogenesis were impaired in a hippocampus-dependent object recognition task. Social transmission of food preference, a behavioral test that also depends on hippocampal function, was not affected by knockdown of neurogenesis. Here we identified a role for newborn neurons in distinct aspects of hippocampal function that will set the ground to further elucidate, using experimental and computational strategies, the mechanism by which newborn neurons contribute to behavior.

At the request of the Councils of the Society of Thoracic Surgeons (STS) and the American Association of Thoracic Surgery (AATS) the Ad Hoc Liaison Committee for Standardizing Definitions of Prosthetic Heart Valve Morbidity reviewed the "Guidelines" published in September 1988 [3, 7, 8]. The purpose of the review was to update and clarify definitions within the guidelines and to consider recommendations made by other [2, 11]. The variety of cardiac valvular procedures has expanded since 1988; therefore, in this document the term "operated valve" indicates prosthetic and bioprosthetic heart valves of all types, operated or repaired native valves and allograft and autograft valves. The term "operated valve" includes any cardiac valve altered by a surgeon during an operation. Much morbidity and mortality is a direct consequence of the interaction between the patient and operated valve(s), although patient variables (e.g., age, degree of coronary arterial disease, follow-up care, etc.) may be more responsible for outcomes than an operated valve. However, no set of guidelines can identify all possible patient factors that may affect morbidity and mortality. General agreement regarding the following definitions of terms and suggestions for reporting data do not preclude more detailed analyses or constructive recommendations and investigators are encouraged to identify relevant patient factors in addition to factors related to operated valves. Purpose The purpose of these guidelines is to facilitate the analysis and reporting of results of operations on diseased cardiac valves. The definitions and recommendations that follow are guidelines, not standards, and are designed to facilitate comparisons between the experiences of different surgeons who treat different cohorts of patients at different times with different techniques and materials.

Studies were made of the effects of two doses of minoxidil (3 mg/kg), given 24 hours apart, on cardiovascular hemodynamics, regional myocardial blood flow, and cardiac morphology in beagle dogs. Minoxidil caused increases in mean right atrial and left ventricular end-diastolic pressure. Systemic and pulmonary vascular resistance were reduced; cardiac output was increased. Left ventricular stroke work and the systolic pressure time index were unchanged by monoxidil administration. The diastolic pressure time index and ratio of diastolic/systolic pressure time index were decreased by minoxidil. Regional myocardial blood flow, measured with radioactive microspheres, increased in all regions of the heart except to the left ventricular papillary muscles. Minoxidil increased blood flow to left ventricular subendocardial tissue; however, this increase was significantly less than that observed in corresponding areas of subepicardial tissue, thus reducing the subendocardial/subepicardial tissue blood flow ratio. These results suggest that minoxidil is an effective peripheral vasodilator but may result in inadequate subendocardial perfusion. Morphologic studies disclosed two types of minoxidil-induced cardiac lesions: left ventricular papillary muscle necroses, and hemorrhagic lesions which were most prominent in right atrium and were associated with inflammation, intramural hemorrhage, and fibrinoid necrosis of small arteries. The papillary muscle necroses were attributed to hypoxia. The atrial lesions were not of ischemic or hypoxic origin, because minoxidil did not decrease blood flow to atrial tissue. It is suggested that the atrial lesions are related to excessive vasodilatation.

New modes of circulatory support for right ventricular dysfunction have recently been described. The present study compared the effectiveness of pulmonary artery balloon counterpulsation with a right ventricular assist device for support of surgically induced right ventricular dysfunction. Right ventricular hypertrophy was created in 16 neonatal lambs by pulmonary artery banding. Right ventricular dysfunction was produced in all animals by performing a right ventriculotomy and maintaining the pulmonary artery band. Four unassisted animals developed severe acute right heart failure and died. Six sheep had pulmonary artery balloon counterpulsation with a Dacron graft anastomosed to the proximal pulmonary artery as a reservoir for a 40 ml intra-aortic balloon after the onset of heart failure. The remaining six sheep had a pneumatically activated ventricular assist device inserted between the proximal pulmonary artery and the right ventricular apex. Periods of circulatory support with the balloon pump and the assist device on and off were compared. Decreases in right atrial pressure were observed with both balloon counterpulsation and right ventricular assistance: 14 +/- 1 to 11 +/- 1 mm Hg, p less than 0.0001, versus 19 +/- 2 to 12 +/- 2 mm Hg, p less than 0.0002, respectively. Cardiac output increased with both balloon counterpulsation and ventricular assistance: 1.45 +/- 0.16 to 2.03 +/- 0.13 L/min, p less than 0.001, versus 0.72 +/- 0.15 to 2.24 +/- 0.23 L/min, p less than 0.0002, respectively. Aortic systolic pressure increased in both support groups: 78 +/- 7 to 99 +/- 6 mm Hg, p less than 0.0004, versus 53 +/- 9 to 85 +/- 9 mm Hg, p less than 0.0001, respectively. Ventricular assistance produced greater changes in the right atrial pressure (39% +/- 6% versus 17% +/- 3%, p less than 0.01), cardiac output (153% +/- 39% versus 54% +/- 11%, p less than 0.05), and aortic systolic pressure (85% +/- 13% versus 39% +/- 9%, p less than 0.01). The insertion of a right ventricular assist device caused a significant increment in right ventricular dysfunction. These data, obtained with the devices in place but not operating, showed significantly increased right atrial and right ventricular end-diastolic pressures and approximately 50% less cardiac output than with the pulmonary artery balloon counterpulsation system. The results demonstrate that both modes of circulatory support were effective in reversing surgically induced right ventricular failure.(ABSTRACT TRUNCATED AT 400 WORDS)

The clinical and roentgenographic features of 10 patients with pelvic lipomatosis are described.Vague abdominal pain, urinary frequency, and hypertension were the most frequent clinical complaints. Pelvic lucency, elongation of the bladder and rectosigmoid, and medial deviation of the ureters were the most common roentgenographic findings.Follow-up examinations failed to reveal progression of the roentgenographic findings.

Advances in chronic myeloid leukemia treatment, particularly regarding tyrosine kinase inhibitors, mandate regular updating of concepts and management. A European LeukemiaNet expert panel reviewed prior and new studies to update recommendations made in 2009. We recommend as initial treatment imatinib, nilotinib, or dasatinib. Response is assessed with standardized real quantitative polymerase chain reaction and/or cytogenetics at 3, 6, and 12 months. BCR-ABL1 transcript levels ≤10% at 3 months, 10% at 6 months and >1% from 12 months onward define failure, mandating a change in treatment. Similarly, partial cytogenetic response (PCyR) at 3 months and complete cytogenetic response (CCyR) from 6 months onward define optimal response, whereas no CyR (Philadelphia chromosome–positive [Ph+] >95%) at 3 months, less than PCyR at 6 months, and less than CCyR from 12 months onward define failure. Between optimal and failure, there is an intermediate warning zone requiring more frequent monitoring. Similar definitions are provided for response to second-line therapy. Specific recommendations are made for patients in the accelerated and blastic phases, and for allogeneic stem cell transplantation. Optimal responders should continue therapy indefinitely, with careful surveillance, or they can be enrolled in controlled studies of treatment discontinuation once a deeper molecular response is achieved.

Chronic myeloid leukaemia (CML) is a myeloproliferative disorder arising in a haematopoietic stem cell (HSC) and defined by the presence of BCR-ABL1, a deregulated tyrosine kinase that drives numerous oncogenic signalling pathways. Current CML therapies are tyrosine kinase inhibitors (TKIs) that target the constitutive action of BCR-ABL1. However, resistance to TKIs remains a concern for a substantial proportion of CML patients and thus investigating the mechanisms underlying poor clinical response is of great importance. The tumour suppressor protein phosphatase 2A (PP2A) plays a crucial role in the inhibition of several critical oncogenic signalling pathways. Consequently, reports of aberrant PP2A activity in human malignancies are abundant. Cancerous inhibitor of PP2A (CIP2A) is an endogenous inhibitor of PP2A that is overexpressed in a plethora of tumours; CIP2A inhibits the dephosphorylation of the oncogenic transcription factor c-Myc by PP2A. In CML, it was shown that high CIP2A protein expression at diagnosis was predictive of progression into blast crisis in imatinib-treated CML. This thesis aimed to determine if CIP2A retained its potential prognostic indicator status in CML treated with dasatinib or nilotinib. The molecular pathogenesis of the CIP2A/PP2A pathway within CML and the central role played by CIP2A is also investigated. Molecular interactions of proteins have been known to greatly differ between transcript variants of the same gene. No CIP2A transcript variant has ever been reported. This thesis aimed to identify two CIP2A transcript variants previously undescribed in vivo, and analyse their differing expressions within a CML population. Aberrant epigenetic regulation is an expanding area of interest; many genes have their expression altered via deregulated methylation, transcription factor binding and micro RNAs. This thesis focussed on the methylation of the CIP2A promoter in CML of varying disease phase and clinical outcome. In summary, this thesis provides novel information about CIP2A in response to CML treatment, CIP2A protein interactions, CIP2A gene variations and epigenetic regulation. With more knowledge of this oncoprotein, its oncogenic mechanisms may in the future be specifically targeted and overcome.