Chronic myeloid leukemia (CML) management changed dramatically with the development of imatinib mesylate (IM), the first tyrosine kinase inhibitor targeting the BCR-ABL1 oncoprotein. In Sweden, the ...drug was approved in November 2001. We report relative survival (RS) of patients with CML diagnosed during a 36-year period.
Using data from the population-based Swedish Cancer Registry and population life tables, we estimated RS for all patients diagnosed with CML from 1973 to 2008 (n = 3173; 1796 males and 1377 females; median age, 62 years). Patients were categorized into five age groups and five calendar periods, the last being 2001 to 2008. Information on use of upfront IM was collected from the Swedish CML registry.
Relative survival improved with each calendar period, with the greatest improvement between 1994-2000 and 2001-2008. Five-year cumulative relative survival ratios (95% CIs) were 0.21 (0.17 to 0.24) for patients diagnosed 1973-1979, 0.54 (0.50 to 0.58) for 1994-2000, and 0.80 (0.75 to 0.83) for 2001-2008. This improvement was confined to patients younger than 79 years of age. Five-year RSRs for patients diagnosed from 2001 to 2008 were 0.91 (95% CI, 0.85 to 0.94) and 0.25 (95% CI, 0.10 to 0.47) for patients younger than 50 and older than 79 years, respectively. Men had inferior outcome. Upfront overall use of IM increased from 40% (2002) to 84% (2006). Only 18% of patients older than 80 years of age received IM as first-line therapy.
This large population-based study shows a major improvement in outcome of patients with CML up to 79 years of age diagnosed from 2001 to 2008, mainly caused by an increasing use of IM. The elderly still have poorer outcome, partly because of a limited use of IM.
Inadequate molecular and clinical stratification of the patients with high-risk diffuse large B-cell lymphoma (DLBCL) is a clinical challenge hampering the establishment of personalized therapeutic ...options. We studied the translational significance of liquid biopsy in a uniformly treated trial cohort. Pretreatment circulating tumor DNA (ctDNA) revealed hidden clinical and biological heterogeneity, and high ctDNA burden determined increased risk of relapse and death independently of conventional risk factors. Genomic dissection of pretreatment ctDNA revealed translationally relevant phenotypic, molecular, and prognostic information that extended beyond diagnostic tissue biopsies. During therapy, chemorefractory lymphomas exhibited diverging ctDNA kinetics, whereas end-of-therapy negativity for minimal residual disease (MRD) characterized cured patients and resolved clinical enigmas, including false residual PET positivity. Furthermore, we discovered fragmentation disparities in the cell-free DNA that characterize lymphoma-derived ctDNA and, as a proof-of-concept for their clinical application, used machine learning to show that end-of-therapy fragmentation patterns predict outcome. Altogether, we have discovered novel molecular determinants in the liquid biopsy that can noninvasively guide treatment decisions.
Anti-silencing function 1a (ASF1a) is a histone H3-H4 chaperone isoform involved in chromatin assembling and transcription regulation. Recently, ASF1a has been shown to be up-regulated in certain ...human malignancies and required for the expression of telomerase reverse transcriptase (TERT), a factor essential for the immortal phenotype of cancer cells; however, its role in oncogenesis remains poorly defined. In the present study, we determine whether ASF1a is required for the unlimited proliferation of cancer cells, a key cancer hallmark. Elevated ASF1a mRNA expression was observed in hepatocellular carcinoma (HCC) tumors. The overexpression of ASF1a was similarly found in 20 cancer types contained in TCGA and GTEx datasets. ASF1a knockdown led to growth arrest and senescence of wild-type (wt) p53-carrying HCC and prostate cancer cells. Cellular senescence mediated by ASF1a inhibition resulted from the robust up-regulation of p53 and p21
expression, but without detectable changes in TERT expression. p53 inhibition attenuated p21
induction caused by ASF1a depletion. Mechanistically, ASF1a-knocked down cells displayed widespread DNA damage. The TCGA dataset analysis revealed a negative correlation between ASF1a and p21
expression in multiple types of primary tumors, including HCC, prostate, gastric, and breast cancer. Higher ASF1a and lower p21
expression predicted a poor outcome in patients with HCC. Our results reveal that ASF1a overexpression is widespread in human malignancies and is required for the infinite proliferation of cancer cells, whereas its inhibition induces DNA damage and subsequent up-regulation of p53-p21
expression, thereby triggering cellular senescence. Thus, ASF1a may serve as a potential target in cancer therapy.
Background & Aims The aberrant expression of histone-modifying enzymes such as histone deacetylases contributes to oncogenesis. It is unclear whether RBP2, a newly identified histone demethylase, is ...involved in cancer development/progression. We determined RBP2 expression in gastric cancer and its biologic function in cancer cells. Methods Cancerous and matched normal gastric specimens from 42 patients with gastric cancer were analyzed for RBP2 expression using quantitative real-time polymerase chain reaction and immunohistochemistry. Gene expression was assessed using quantitative real-time polymerase chain reaction and immunoblotting and depleted with small interference RNA. Clonogenesis and cellular senescence were examined by foci formation and β-Galactosidase staining. Promoter activity was determined by luciferase reporter assay. Chromatin immunoprecipitation was used to detect RBP2 and methylated histone H3-K4 on promoters. Results RBP2 messenger RNA and protein expression were increased in 71.5% (30/42) and 100% (20/20) of gastric cancer specimens, respectively. Significantly diminished foci numbers coupled with massive senescence/growth arrest and elevated expression of cyclin-dependent kinase inhibitors (CDKIs) p21CIP1 , p27kip1 , and/or p16ink4a occurred in RBP2-depleted gastric and cervical cancer cells. RBP2 depletion-mediated senescence and clonogenic defect were attenuated by inhibiting p21CIP1 or p27kip1 expression. The promoter activity of all 3 CDKIs genes was enhanced by RBP2 inhibition. RBP2 occupied these promoters in control cells, and the loss of RBP2 occupancy was accompanied by enhanced H3-K4 trimethylation following RBP2 depletion. Conclusions RBP2 is overexpressed in gastric cancer, and its inhibition triggers senescence of malignant cells at least partially by derepressing its target genes CDKIs. Histone demethylase inhibition by targeting RBP2 may be an anticancer strategy.
Goals of work
The selection process of type of central venous access device (CVAD) in patients with acute leukaemia (AL) is generally based on appropriate catheter capacity/function and risk of ...complications in relation to the planned length of therapy. Advantages and disadvantages of the CVAD from the patient’s perspective should also be important parts in the selection of type of device. Perceptions on having a CVAD were thus analysed in a series of adult patients with AL included in a prospective randomised study evaluating the use of a double lumen totally implantable subcutaneous port system (PORT) or a double lumen central venous catheter (CVC) regarding survival time and complication rate.
Materials and methods
Perceptions were registered in 32 patients (median age 68 years, range 24–83 years) on three occasions (T1; the day after placement, T2; 3 weeks after placement and T3 after 12 weeks and/or when the CVAD was removed) with the use of two study specific questionnaires.
Main results
Overall, many patients reported minor catheter related discomfort, feelings of anxiety and restrictions. Half of the patients (6/11) who experienced a local bleeding after CVAD insertion described the placement procedure as unpleasant. More patients in the CVC group compared with the PORT group stated that they thought of having a CVAD (T3;
p
= 0.02) and that the CVAD interfered when dressing themselves (T2;
p
= 0.02 and T3; 0.04) or taking a shower (T3;
p
= 0.009).
Conclusion
Our findings support the view that the PORT is less restrictive in daily life than the CVC.
Abstract 4868
Bacteremia is a major cause of morbidity and mortality in patients with hematological disorders during chemotherapy-induced neutropenia. Initial antimicrobial treatment is chosen ...empirically. Increasing antimicrobial resistance is a global obstacle for improving outcome for hematological patients. The aim of this study was to compare temporal trends in species distribution and antimicrobial susceptibility in bacteremic patients hospitalized in a hematology ward at Karolinska University Hospital, Stockholm, Sweden, over a 21-year period.
A total of 794 clinically significant isolates, 667 clinical episodes of bacteremia in 463 patients were identified during the last 7 years and the results were compared with those published from the same ward during the preceding 14 years. Isolates and episodes were identified from the laboratory information system, which has been in use during the entire 21-year period. For coagulase-negative staphylococci (CoNS), Corynebacterium spp., Propionibacterium spp. and Bacillus spp. bacteremia was considered significant only if the isolates were detected in two or more blood specimens. No major changes in patient selection were introduced during these 21 years and quinolone prophylaxis was used only to a very limited extent.
Any shift between Gram-negative and Gram-positive bacteria has not been noted at any time and the proportion of Gram-positive isolates has remained at a level of 53–55%. In the last 7-year period the male patient predominance increased from 58% to 62%, and the median age increased from 58 to 62 years. The 7- and 30-day crude mortality rates were 5.3% and 14.8%, respectively, compared with 6.3% and 16% in the preceding 7-year period (p>0.05). Polymicrobial bacteremia, defined as growth of more than one organism during the same bacteremic episode within 24 hours or 72 hours, was seen in 13.7% and 14.8% of patients respectively, compared to 11% (24 hours) in the preceding 7-year period (p>0.05). Polymicrobial bacteremia was seen in 25% and 28% respectively of patients who died within 7 days. Crude mortality at day 7 in patients with polymicrobial bacteremia was significantly higher than for patients with monomicrobial bacteremia (p=<0.0001).
As in the previous periods the dominating pathogens were Escherichia coli (18%), CoNS (15%), viridans streptococci (14%) and Klebsiella spp. (10%). A significant increase of Enterobacter spp. (from 3.1 to 5.4%) and decrease of Staphylococcus aureus (from 10 to 6.9%) was seen compared with the middle 7-year period. Enterococcus faecium increased during the middle 7-year period and has remained frequent and stable at 8%.
In E. coli resistance to piperacillin-tazobactam (TZP) was 9.2%, ciprofloxacin (CIP) 8.5% and ceftazidime (CAZ) 2.1%, whereas no resistance was observed to imipenem-cilastatin (IPM). In Klebsiella spp. resistance to TZP was 9.0%, CIP 1.3% and CAZ 1.3%, whereas no resistance was observed to IPM. Among Enterobacter spp. resistance to TZP was 26%, CAZ 26%, IPM 2.3% and CIP 4.7%. In P. aeruginosa resistance to IPM was 12%, TZP 4.8% and CIP 7.1%, whereas no CAZ-resistant strains were found. Among CoNS resistance to isoxazolyl-penicillin was 71% in the last period, compared to 58% in the middle period. Only one isolate of E. faecium (cultured in the last 7-year period) was resistant to vancomycin. Two methicillin-resistant S. aureus were detected in the last 7-year period. Resistance to benzyl-penicillin among viridans streptococci was 20% in the last 7-year period and 12% in the middle 7-year period. Only the increase in CIP resistance in E. coli during the last 7-year period was statistically significant (p= 0.02).
We observed a stable distribution of species and a low rate of antimicrobial resistance during a period of 21 years. In the last 7-year period a significant increase in CIP-resistance was observed in E. coli. This finding can possibly be related to a very limited use of antibacterial prophylaxis in our centre, but also reflects the general low level of antimicrobial resistance in Sweden. Crude mortality was unchanged during the study period. Mortality was higher in patients with poly- th.
No relevant conflicts of interest to declare.
To define patterns of survival among all multiple myeloma (MM) patients diagnosed in Sweden during a 30-year period.
A total of 14,381 MM patients (7,643 males; 6,738 females) were diagnosed in ...Sweden from 1973 to 2003 (median age, 69.9 years; range 19 to 101 years). Patients were categorized into six age categories and four calendar periods (1973 to 1979, 1980 to 1986, 1987 to 1993, and 1994 to 2003). We computed relative survival ratios (RSRs) as measures of patient survival.
One-year survival improved (P < .001) over time in all age groups and RSRs were 0.73, 0.78, 0.80, and 0.82 for the four calendar periods; however, improvement in 5-year (P < .001) and 10-year (P < .001) RSR was restricted to patients younger than 70 years and younger than 60 years, respectively. For the first time, in analyses restricted to MM patients diagnosed at age younger than 60 years, we found a 29% (P < .001) reduced 10-year mortality in the last calendar period (1994 to 2003) compared with the preceding calendar period (1987 to 1993). Females with MM had a 3% (P = .024) lower excess mortality than males.
One-year MM survival has increased for all age groups during the last decades; 5-year and 10-year MM survival has increased in younger patients (younger than 60 to 70 years). High-dose melphalan with subsequent autologous stem-cell transplantation, thalidomide, and a continuous improvement in supportive care measures are probably the most important factors contributing to this finding. New effective agents with a more favorable toxicity profile are needed to improve survival further, particularly in the elderly.
Tyrosine kinase inhibitors (TKIs) have increased survival dramatically for patients with chronic myeloid leukemia (CML), but continuous administration of these drugs may elicit long-term toxicity.
To ...investigate the incidence of vascular events in patients with CML treated with first- and second-generation TKIs.
Retrospective cohort study using nationwide population-based registries.
Sweden.
All patients diagnosed with chronic-phase CML in Sweden from 2002 to 2012 and treated with a TKI, and 5 age- and sex-matched control individuals per patient.
Relative risks, expressed as incidence rate ratios comparing patients with control individuals, were calculated. Events per 1000 person-years were assessed in interdrug comparisons.
896 patients, 94.4% with documented TKI treatment, were followed for a median of 4.2 years. There were 54 arterial and 20 venous events in the CML cohort, corresponding to relative risks of 1.5 (95% CI, 1.1 to 2.1) and 2.0 (CI, 1.2 to 3.3), respectively. The event rate for myocardial infarction was higher in patients treated with nilotinib or dasatinib (29 and 19 per 1000 person-years, respectively) than in those receiving imatinib (8 per 1000 person-years), although data are limited and the CIs were wide and overlapped. Among 31 patients treated with a TKI who had myocardial infarction, 26 (84%) had at least 1 major cardiac risk factor diagnosed before the event occurred.
Patients may have been exposed to multiple TKIs. Data on second- and third-generation TKIs were limited.
An increased risk for arterial and venous vascular events was seen in patients with CML treated with a TKI. Further study is needed to determine whether the risk for myocardial infarction increases with second-generation drugs.
No external funding.
The causes of myeloproliferative neoplasm (MPN) are unknown. We conducted a large population-based study including 11,039 myeloproliferative neoplasm patients and 43,550 matched controls with the aim ...of assessing the associations between a personal history of a broad span of autoimmune diseases and subsequent risk of myeloproliferative neoplasm. We found a prior history of any autoimmune disease to be associated with a significantly increased risk of myeloproliferative neoplasms (odds ratio (OR)=1.2; 95% confidence interval (CI) 1.0-1.3; P=0.021). Specifically, we found an increased risk of MPNs associated with a prior immune thrombocytopenic purpura (2.9; 1.7-7.2), Crohn's disease (1.8; 1.1-3.0), polymyalgia rheumatica (1.7; 1.2-2.5), giant cell arteritis (5.9; 2.4-14.4), Reiter's syndrome (15.9; 1.8-142) and aplastic anemia (7.8; 3.7-16.7). The risk of myeloproliferative neoplasms associated with prior autoimmune diseases is modest but statistically significant. Future studies are needed to unravel the effects of these autoimmune diseases themselves, their treatment, or common genetic susceptibility.
Tackling Two Diseases with HDL Hansson, Göran K.; Björkholm, Magnus
Science (American Association for the Advancement of Science),
06/2010, Letnik:
328, Številka:
5986
Journal Article
Recenzirano
A lipoprotein that transports cholesterol to the liver also controls the proliferation of myeloid stem cells.
High-density lipoproteins (HDLs) transport cholesterol from peripheral tissues to the ...liver, helping to protect against diseases such as atherosclerosis. On page 1689 in this issue, Yvan-Charvet
et al.
present an entirely new role for HDL in regulating stem cell proliferation in the bone marrow (
1
). A relationship between cellular cholesterol content, HDL, and cells of the myelomonocytic lineage opens up the possibility that disorders characterized by the proliferation of immature white blood cells could be treated by targeting cholesterol transport in these cells.
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