Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements.

To assess the clinical heterogeneity among patients with acute lymphoblastic leukemia (ALL) and various 11q23 abnormalities, we analyzed data on 497 infants, children and young adults treated between 1983 and 1995 by 11 cooperative groups and single institutions. The substantial sample size allowed separate analyses according to age younger or older than 12 months for the various cytogenetic subsets. Infants with t(4;11) ALL had an especially dismal prognosis when their disease was characterized by a poor early response to prednisone (P=0.0005 for overall comparison; 5-year event-free survival (EFS), 0 vs 23+/-+/-12% s.e. for those with good response), or age less than 3 months (P=0.0003, 5-year EFS, 5+/-+/-5% vs 23.4+/-+/-4% for those over 3 months). A poor prednisone response also appeared to confer a worse outcome for older children with t(4;11) ALL. Hematopoietic stem cell transplantation failed to improve outcome in either age group. Among patients with t(11;19) ALL, those with a T-lineage immunophenotype, who were all over 1 year of age, had a better outcome than patients over 1 year of age with B-lineage ALL (overall comparison, P=0.065; 5-year EFS, 88+/-+/-13 vs 46+/-14%). In the heterogeneous subgroup with del(11)(q23), National Cancer Institute-Rome risk criteria based on age and leukocyte count had prognostic significance (P=0.04 for overall comparison; 5-year EFS, 64+/-+/-8% (high risk) vs 83+/-+/-6% (standard risk)). This study illustrates the marked clinical heterogeneity among and within subgroups of infants or older children with ALL and specific 11q23 abnormalities, and identifies patients at particularly high risk of failure who may benefit from innovative therapy.     

General practice – a fertile lagoon in the ocean of medical knowledge

General practitioners (GPs) often find that linear, deductive knowledge does not provide a sufficient map for clinical management. But experience, accompanied by enduring familiarity with individual patients, may offer unique complementary skills to interpret a patient’s symptoms and navigate skilfully through diagnosis, treatment, follow-up and prevention.In this article, we draw attention to the nature of this tacit knowing that is executed by many GPs every day. We argue that the nonlinear, unpredictable complexity of this domain nurtures a particular logic of clinical knowing. This kind of knowledge is not intuition and can to some extent be intersubjectively accessible. We substantiate and discuss how and why general practice research can contribute to knowledge development by transforming reflection-in-action to reflection-on-action.We briefly present some concepts for reflection-on-action of clinical knowing in general practice. The VUCA model (volatility, uncertainty, complexity, ambiguity) embraces dynamic and confusing situations in which agile work (adaptive, flexible and responsive behaviour and cognitive creativity) is assumed to be an appropriate response. Using such perspectives, we may sharpen our gaze and apply reflexivity and analytic elaboration to interpret unique incidents and experiences and appreciate the complexity of general practice. In this way, exploratory research can fertilize general practice and offer innovation to the entire domain of clinical knowledge.     

Bcl-2 family members in childhood acute lymphoblastic leukemia: relationships with features at presentation, in vitro and in vivo drug response and long-term clinical outcome.

We have found that, in addition to Bcl-2 and Bax, the expression levels of apoptosis inducers (Bad, Bak) and inhibitors (Bcl-xL, Mcl-1) were highly variable in blasts from 78 children with newly diagnosed acute lymphoblastic leukemia (ALL). The patients were enrolled in the national study ALL-7 of the Dutch Childhood Leukemia Study Group. In contrast to Bcl-2 that inversely correlated with %S-phase cells and WBC, and was lower in T than in B-lineage ALL, the Bcl-2 family members were not found to be associated with features at presentation. These expression levels were also compared with drug resistance in in vitro MTT (methyl-thiazol-tetrazolium) assays for prednisolone, vincristine and asparaginase in 46 children. Protein expression levels of the Bcl-2 family were not found to correlate with in vitroresistance to the individual drugs or the combined drug resistance profile. In addition, neither peripheral blast reduction after 1 week of prednisone monotherapy nor long-term disease-free interval or survival showed a correlation with protein expression. Our results indicate that the anti-proliferative function of Bcl-2 dominates its anti-apoptotic function in ALL, but neither Bcl-2 nor the Bcl-2 family members gained prognostic information in the risk-adapted protocol ALL-7.     

Outcomes of Using a Modified Seldinger Technique for Long Term Intravenous Therapy in Hospitalized Patients with Difficult Venous Access

Background and SignificanceMany hospitalized patients require an intravenous (IV) catheter to maintain vascular access or for administration of fluids and medications. The best approach to attaining peripheral intravenous (PIV) access for long term therapy is unknown, particularly in patients with a history of difficult IV placement.PurposeTo measure clinical outcomes using a Modified Seldinger Technique (MST) with ultrasound (US) guidance to achieve and maintain PIV for long term IV therapy.MethodsSubjects were patients with a history of difficult peripheral intravenous catheter placement and need for IV therapy longer than 72 hours. Modified Seldinger Technique was used with US guidance to place all PIVs in the deep veins of the upper extremities.ResultsA convenience sample of 157 subjects was enrolled in the study. Mean dwell time for catheter duration was seven days. First attempt placement success was 95%, 88.5% of patients had completion of IV therapy, and a low overall complication rate (9.57/1000 catheter days).ConclusionUsing MST for access for long term PIV therapy was associated with low complications and effective in our study population. Using MST requires specialized knowledge and skills, including the use of US and specialized insertion techniques. In patients who require extended PIV therapy with a history of difficult IV placement, this type of insertion technique may have benefit.     

Recombinant adeno-associated virus-mediated gene transfer into hematopoietic progenitor cells [published erratum appears in Blood 1995 Feb 1;85(3):862]

Recombinant adeno-associated viruses (rAAV) containing only the inverted terminal repeats (ITR) from the wild-type virus are capable of stable integration into the host cell genome, and expression of inserted genes in cultured cells. We have now defined the ability of rAAV to introduce genes into primary hematopoietic progenitors. A vector was constructed containing the coding sequences for beta- galactosidase (beta-gal), including a nuclear localization signal, under the control of a strong viral promotor. Infectious vector particles were prepared by cotransfection of the vector plasmid with a second plasmid that contained the coding sequences for AAV proteins into adenovirus-infected human embryonic kidney cells. These vector preparations transferred and expressed the beta-gal gene in human K562 erythroleukemia and Detroit 6 cells. Positive immunoselection yielded a population of enriched CD34+ cells that were transduced with the rAAV beta-gal vector. Nuclear localized enzyme expression was documented in 60% to 70% of infected cells. Progenitor-derived colonies that developed after 2 weeks in clonogenic cultures were shown to have viral- associated DNA at an estimated copy number of 1 to 2 per cell using a semiquantitative polymerase chain reaction (PCR) method. Integration of AAV into hematopoietic progenitors was documented using wild-type virus, as its genome may integrate at a preferred site on chromosome 19. Our data suggest that rAAV will transfer and express genes in primitive hematopoietic progenitors with high frequency, and support the development of this vector system for therapeutic gene transfer.