Management and outcome of patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era - analysis of the European LeukemiaNet Blast Phase Registry.

Blast phase (BP) of chronic myeloid leukemia (CML) still represents an unmet clinical need with a dismal prognosis. Due to the rarity of the condition and the heterogeneity of the biology and clinical presentation, prospective trials and concise treatment recommendations are lacking. Here we present the analysis of the European LeukemiaNet Blast Phase Registry, an international collection of the clinical presentation, treatment and outcome of blast phases which had been diagnosed in CML patients after 2015. Data reveal the expected heterogeneity of the entity, lacking a clear treatment standard. Outcomes remain dismal, with a median overall survival of 23.8 months (median follow up 27.8 months). Allogeneic stem cell transplantation (alloSCT) increases the rate of deep molecular responses. De novo BP and BP evolving from a previous CML do show slightly different features, suggesting a different biology between the two entities. Data show that outside clinical trials and in a real-world setting treatment of blast phase is individualized according to disease- and patient-related characteristics, with the aim of blast clearance prior to allogeneic stem cell transplantation. AlloSCT should be offered to all patients eligible for this procedure.

Redefinition of life experience following total hip replacement: a qualitative study.

PURPOSE: We drew on a qualitative research design to examine patients' experiences of coping following total hip replacement (THR) by obtaining their perspectives through participants' personal language. METHOD: Post-operative patients who were able to explore their experiences and express them verbally were purposively sampled from an out-patient orthopaedic department of a UK hospital. Narrative interviews were conducted with the participants at two points in time. Interviews were transcribed verbatim and analysed using Coffey and Atkinson's model (1996). RESULTS: They employed different psychological coping mechanisms to adjust themselves to the new stressful situations that led to reinterpretation of the meaning of life. They used problem-focused, emotion-focused, comparative, spiritual and self-oriented coping strategies and shifted their focus from disease-related problems to other aspects of their lives. CONCLUSION: The participants in this study used a range of coping strategies to accommodate to the challenges of their hip condition and the consequences of the THR. They placed greater emphasis on positive gains from their experiences and alleviated the harmful effects of pain and physical limitations by reinterpreting the meaning of life. It is suggested that the findings of the study could have clinical implications when applying patient-reported outcome measures over time.

When can real-time quantitative RT-PCR effectively define molecular relapse in acute promyelocytic leukemia patients? (Results of the French Belgian Swiss APL Group).

10-20% of APL patients relapse and the challenge remains to early identify these patients to improve survival rate. We report PML-RARalpha transcript detection by RQ-PCR in 260 consecutive APL patients (n = 970 samples). 223 patients with samples of sufficient RNA quality to demonstrate they reached molecular remission were monitored for MRD. During follow-up, 38 of these patients were tested positive for PML-RARalpha mRNA. 13 out of the 38 patients (34%) effectively developed hematological relapse. In the first positive sample, specific PML-RARalpha NCN thresholds over which, or under which, patients could effectively be predicted to relapse or not, were identified and subsequently validated in a second cohort.

DNA topoisomerase II in therapy-related acute promyelocytic leukemia.

BACKGROUND: Chromosomal translocations leading to chimeric oncoproteins are important in leukemogenesis, but how they form is unclear. We studied acute promyelocytic leukemia (APL) with the t(15;17) translocation that developed after treatment of breast or laryngeal cancer with chemotherapeutic agents that poison topoisomerase II. METHODS: We used long-range polymerase chain reaction and sequence analysis to characterize t(15;17) genomic breakpoints in therapy-related APL. To determine whether topoisomerase II was directly involved in mediating breaks of double-stranded DNA at the observed translocation breakpoints, we used a functional in vitro assay to examine topoisomerase II-mediated cleavage in the normal homologues of the PML and RARA breakpoints. RESULTS: Translocation breakpoints in APL that developed after exposure to mitoxantrone, a topoisomerase II poison, were tightly clustered in an 8-bp region within PML intron 6. In functional assays, this "hot spot" and the corresponding RARA breakpoints were common sites of mitoxantrone-induced cleavage by topoisomerase II. Etoposide and doxorubicin also induced cleavage by topoisomerase II at the translocation breakpoints in APL arising after exposure to these agents. Short, homologous sequences in PML and RARA suggested the occurrence of DNA repair by means of the nonhomologous end-joining pathway. CONCLUSIONS: Drug-induced cleavage of DNA by topoisomerase II mediates the formation of chromosomal translocation breakpoints in mitoxantrone-related APL and in APL that occurs after therapy with other topoisomerase II poisons.

A theory of shoe wear pattern influence incorporating a new paradigm for the podiatric medical profession.

Qualitative analysis of shoe wear patterns collected from a questionnaire evaluating podiatric physicians' experiences in this area suggests that wear patterns could indicate causative function within a known pathologic context. Several different functions are suggested by patterns associated with each of the pathologic entities involved, and analysis of the relationship between patterns and reasons given by respondents for pattern-form variations show the strongest associations to be with functionally termed conditions. A basic model is proposed to present factors important in wear pattern production, suggesting that a new concept of primary walking intention is more influential than foot pathologies in wear pattern formation and that external factors are also influential, with the combined factors being described as the "holistic foot function." This model may provide a variety of benefits to podiatric medicine; as shoe wear patterns are records of the usual long-term activity of the functioning foot, this paradigm could form a basis for podiatric medical practice.

Phase-II study of the new aza-anthracenedione, BBR 2778, in patients with relapsed aggressive non-Hodgkin's lymphomas.

BACKGROUND AND OBJECTIVES: BBR 2778 is a new aza-anthracenedione. Its activity against hematologic neoplasias in a mouse model is greater than that of doxorubicin or mitoxantrone. A phase-I study in patients with non-Hodgkin's lymphoma (NHL) showed that the drug has promising anti-tumor activity. Therefore, a phase-II study in patients with relapsed aggressive NHL was initiated. DESIGN AND METHODS: The primary objective was to determine the efficacy of 85 mg/m2 BBR 2278 for a q1w x3 treatment schedule (repeat day 29). Secondary objectives included the evaluation of response duration and safety in this open-label, non-randomized, multicenter trial. Patients with relapsed aggressive NHL according to the REAL-classification were included. RESULTS: Eight centers enrolled a total of 33 patients. The median age of these patients was 66 years (range 24-81). The majority of patients had diffuse large B-cell lymphoma (n=24) or mantle-cell lymphoma (n=7), pretreated with a median of 2 regimens. Confirmed responses included 5 complete and 4 partial remissions, with the period between the first appearance of response and any signs or symptoms of progression being up to 17+ months. The main toxicity was neutropenia. INTERPRETATIONS AND CONCLUSIONS: These results indicate that 85 mg/m2 BBR 2778 in a q1w x 3 schedule is active in elderly and pretreated patients with relapsed aggressive NHL and was generally well tolerated. Thus, we recommend further clinical evaluation of this new compound in phase-III studies for the treatment of NHL.