Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia

In a phase 2 study, 62 patients with relapsed and refractory acute myeloid leukemia (AML; n = 31), myelodysplastic syndrome (MDS; n = 8), chronic myeloid leukemia in blastic phase (CMLBP; n = 11), and acute lymphocytic leukemia (ALL; n = 12) received 40 mg/m2 clofarabine intravenously over 1 hour daily for 5 days, every 3 to 6 weeks. Twenty patients (32%) achieved complete response (CR), 1 had a partial response (PR), and 9 (15%) achieved CR but without platelet recovery (CRp), for an overall response rate of 48%. In AML, responses were noted in 2 (18%) of 11 patients in first salvage with short first CR (相似文献   

Troxacitabine and imatinib mesylate combination therapy of chronic myeloid leukaemia: preclinical evaluation

The in vitro and in vivo activity of a deoxycytidine analogue, troxacitabine, alone or in combination with imatinib mesylate (IM), was evaluated against human chronic myeloid leukaemia (CML) cell lines both sensitive (KBM5 and KBM7) and resistant (KBM5-R and KBM7-R) to IM. These cell lines differ in their sensitivity to IM but all showed similar sensitivity to treatment with troxacitabine (IC50 = 0.5-1 micromol/l). Combined treatment with troxacitabine and IM revealed additive or synergistic effects. Greater apoptotic response was seen with combined treatment than with either agent alone in KBM7-R cells. In clonogenic assays, troxacitabine showed activity against mononuclear cells from CML patients (IC50 = 0.01 micromol/l) with either IM-sensitive or resistant disease. In vivo efficacy studies were carried out in severe combined immunodeficient mice bearing KBM5 or KBM5-R cells. Troxacitabine was administered i.p. daily for 5 d starting on day 20, at doses of 5, 10, 20, or 25 mg/kg. IM was administered i.p. twice a day for 10 d at a dose of 50 mg/kg starting on day 25. In this setting of late stage disease, troxacitabine led to a significant increase in life span, while IM did not. When IM was combined with troxacitabine at 10 and 25 mg/kg in the KBM5 xenograft model, a further increase in life span was observed and some mice achieved long-term survival. These data indicate that the combination of troxacitabine and IM has significant preclinical activity in advanced CML and that clinical evaluation of this combination is warranted.     

A survey-based assessment of the Canadian pediatric surgery workforce

Background

There is significant lack of information regarding the Canadian pediatric surgery workforce.

Methods

An IRB-approved survey aimed at assessing workforce issues was administered to pediatric surgeons and pediatric surgery chiefs in Canada in 2012.

Results

The survey was completed by 98% of practicing surgeons and 13 of the 18 division chiefs. Only 6% of surgeons are older than 60 years, and only a fifth anticipate retirement over the next decade. The workforce is stable, with 82% of surgeons unlikely to change current positions. Surgical volume showed essentially no growth during the 5-year period 2006–2010. The majority of surgeons felt they were performing the right number or too few cases and anticipated minimal or no future growth in their individual practices or that of their group. Based on anticipated vacancies, the best estimate is a need for 20 new pediatric surgeons over the next decade. This need is significantly surpassed by the current output from the Canadian training programs.

Conclusions

The Canadian pediatric surgery workforce is currently saturated. The mismatch between the number of graduating trainees and the available positions over the next decade has significant repercussions for current surgery and pediatric surgery residents wishing to practice in Canada.     

Clinical outcomes and risk factors for severe COVID-19 in patients with haematological disorders receiving chemo- or immunotherapy

Haematology patients receiving chemo- or immunotherapy are considered to be at greater risk of COVID-19-related morbidity and mortality. We aimed to identify risk factors for COVID-19 severity and assess outcomes in patients where COVID-19 complicated the treatment of their haematological disorder. A retrospective cohort study was conducted in 55 patients with haematological disorders and COVID-19, including 52 with malignancy, two with bone marrow failure and one immune-mediated thrombotic thrombocytopenic purpura (TTP). COVID-19 diagnosis coincided with a new diagnosis of a haematological malignancy in four patients. Among patients, 82% were on systemic anti-cancer therapy (SACT) at the time of COVID-19 diagnosis. Of hospitalised patients, 37% (19/51) died while all four outpatients recovered. Risk factors for severe disease or mortality were similar to those in other published cohorts. Raised C-reactive protein at diagnosis predicted an aggressive clinical course. The majority of patients recovered from COVID-19, despite receiving recent SACT. This suggests that SACT, where urgent, should be administered despite intercurrent COVID-19 infection, which should be managed according to standard pathways. Delay or modification of therapy should be considered on an individual basis. Long-term follow-up studies in larger patient cohorts are required to assess the efficacy of treatment strategies employed during the pandemic.     

Methodological challenges in the use of hip-specific composite outcomes: linking measurements from hip fracture trials to the International Classification of Functioning,Disability and Health Framework

Introduction

The prevalence of hip-specific outcome measures in randomized trials reflects what directs our outcome assessment following a hip fracture. The present study provides an overview on the most commonly-used hip-specific outcome instruments used for postoperative assessment of hip fracture with respect to their covered contents. This can facilitate the selection of appropriate items for specific purposes in clinical as well as research settings.

Methods

We used the International Classification of Functioning, Disability and Health (ICF) model to distinguish concepts within the instrument. All items from the questionnaires were categorized into one of three categories using the ICF linking rules for a standardized approach. The hip-specific composites measures were also compared to other types of prevalent measures: generic and patient-based instruments.

Results

All of the items in the instruments could be mapped to the ICF. We report the highest frequency of ICF activity and participation (71 %) within the Harris hip score (HHS) which is similar to the frequency of ICF content found in the generic measures (82 %). Hip-specific composites focused mostly on walking and moving long and short distances, while in patient-reported measures there was a concentration on the concept of sensation of pain and pain in body parts.

Discussion and conclusion

The prevalent use of the HHS, over the other hip-specific instruments, could be attributed to its likeness in concept to other generic measures. The dominance of the ICF category of activity and participation reflects what is important to clinicians treating a hip fracture. Composite scores remain problematic as they cut across different ICF concepts. As long as the popularity of composite scoring systems continues, an overall score may not represent the true patient preferences and concerns in clinical trials. Future studies could apply the results from this study for the creation of an ICF category-based item banking or investigators could operationalize the ICF categories within these candidate measures for specific interventions.     

Is Borg’s perceived exertion scale a useful indicator of muscular and cardiovascular load in blue-collar workers with lifting tasks? A cross-sectional workplace study

Purpose

To investigate associations between perceived exertion and objectively assessed muscular and cardiovascular load during a full working day among workers with manual lifting tasks.

Methods

A total of 159 men and 41 women from 14 workplaces with manual lifting tasks participated. Participants reported perceived exertion (BORG-CR10) at midday and after work. Surface electromyography of the thigh, lower back and neck muscles were normalized to isometric voluntary contractions (MVC) to express relative muscle load during the day. Cardiovascular load was measured with electrocardiography and calculated as the average percentage of the heart rate reserve capacity (((heart rate during work – resting heart rate) / (maximum heart rate ? resting heart rate)) * 100) during the day.

Results

Using linear regression, significant but weak associations (β < 0.23) were observed between perceived exertion and (1) high muscle activity (>60 % of MVC) of the neck muscles and (2) inactivity (<1 % of MVC) of the thigh muscles and (3) cardiovascular load, respectively. Using logistic regression, perceived exertion ≥4 (high exertion), referencing <4 (low-to-moderate exertion), was related to high activity of the trapezius muscle [OR 18 (95 % CI 2–143)], i.e., the odds for experiencing high exertion during work increased 18-fold for each percentage increase in time above 60 % MVC.

Conclusions

During a full working day among blue-collar workers with lifting tasks, high neck muscle activity increases the odds for experiencing high perceived physical exertion. Perceived exertion of at least 4 on the BORG CR10 scale appears to be a good indicator that high muscular loading occurs.     

Satisfaction levels of paediatric surgeons in Canada

BACKGROUND:

Surgeons’ satisfaction levels may affect patient care and the stability of the surgical workforce.

METHODS:

A detailed Internet-based satisfaction survey was administered to paediatric surgeons in Canada in 2005 and 2012. Satisfaction was rated 1 (most) to 5 (least), in five areas: quality of life, financial compensation, work environment, academics and patient care.

RESULTS:

Responses were received from 21 surgeons in 2005 and 61 in 2012, representing 43% and 98% of practicing paediatric surgeons in Canada, respectively. Satisfaction levels were generally moderate to high in most areas during both years. In academics, surgeons were more satisfied in 2012 with the amount of teaching they provided (1.8 versus 2.2; P=0.02), and clinical research they performed (2.5 versus 3.0; P=0.04). In patient care, there was higher satisfaction with the ability to provide elective services without impediment (2.5 versus 3.0; P=0.02). Over the seven-year period, surgeons increasingly preferred the Canadian health care system over that of the United States (1.7 versus 2.2; P=0.02). In the 2012 survey, no differences in levels of satisfaction were found between male and female surgeons.

CONCLUSIONS:

During the recent seven-year period, satisfaction levels of paediatric surgeons in Canada have been stable with regard to quality of life, compensation and work environment, and improving in areas of academics and patient care. Male and female surgeons are equally satisfied. The Canadian health care system is preferred over that of the United States.     

Experimental and Numerical Thickness Analysis of TRIP Steel under Various Degrees of Deformation in Bulge Test

To design a reliable forming process it is necessary to determine the mechanical and formability properties of the processed material, which are used as input parameters for forming simulations. High-strength steel is irreplaceable as a material for producing the deformation zones of current automobiles. This type of steel can be processed by conventional or unconventional forming methods. In the sheet forming process, the material is usually under uniaxial and biaxial stress. The bulge test is utilized for determination of biaxial stress–strain curves, which are often used as input material data for forming simulations. In this work, numerical simulations of bulge tests using TRIP RAK 40/70 steel were performed to study the impact of yield criteria and hardening laws on the accuracy of thickness prediction of the deformed steel sheet. Additionally, the impact of different solvers and integration schemes on the thickness prediction was tested. Furthermore, the impact of various degrees of deformation (various dome heights) on thickness prediction accuracy was evaluated. Numerical results showed a good correlation with experimental data. When the Hill90 yield criterion was used, the software with implicit solver was more accurate in predicting thickness compared to software with explicit integration scheme, in most cases. In addition, the thickness prediction of parts with lower deformation was more accurate compared to parts with greater deformation (higher dome height).     

Beta Blocker Therapy After Acute Myocardial Infarction in Patients with Heart Failure and Systolic Dysfunction

The benefit of beta blockade has been well established in acute myocardial infarction for several decades, and its benefit in chronic heart failure has been proven since the early 1990's. Several large retrospective analyses suggested the benefit of beta blockers in post-MI systolic dysfunction. Only recently has the benefit of beta blockers been proven in addition to ACE inhibitors, antiplatelet agents, and reperfusion therapy. In the year 2000, CAPRICORN became the first randomized trial to directly address beta blockade in patients with post-infarction systolic dysfunction. The trial showed a 23% reduction in all-cause mortality with carvedilol, in patients already receiving ACE inhibitors, antiplatelet agents, and reperfusion therapy. This is a review of the literature on the administration of beta blockade in patients after acute myocardial infarction with left ventricular systolic dysfunction, as well as a comment on other current treatment modalities for this subset of patients.