Prognostic nomogram for diffuse large B-cell lymphoma incorporating the International Prognostic Index with interim-positron emission tomography findings.

BACKGROUND/AIMS: Results from interim-positron emission tomography (PET) studies in diffuse large B-cell lymphoma (DLBCL) patients are varied. We evaluated the prognostic value of interim-PET in our centre. To improve concordance, interim-PET was combined with the International Prognostic Index (IPI). METHODS: We retrospectively reviewed 100 new consecutive DLBCL patients treated with immunochemotherapy from 2005 to 2010. Twenty-four patients did not receive interim-PET and were excluded. Interim-PET images were re-examined using a qualitative assessment technique. Progression-free survival (PFS) and overall survival (OS) were analysed by the Cox proportional hazards model and prognostic accuracy was assessed using Harrell's C statistics (C). RESULTS: Eleven patients were positive, and 65 were negative at interim-PET. The 2-year OS and PFS were 70.8% and 60.0%, respectively, in the PET-negative group, 36.4% and 36.4% for the PET-positive group (log-rank P-value 0.0008 for PFS, 0.0001 for OS). The IPI and interim-PET were minimally correlated. On Cox regression analysis, both were significant indicators of PFS (P < 0.001 and P = 0.002 respectively). The prognostic accuracy for PFS of a negative PET result was limited (C = 0.63), as it was for IPI (C = 0.75), but with the two indicators combined, the predictive accuracy was improved (C = 0.81). A nomogram, predictive for relapse-free survival at 2 years, was constructed. CONCLUSION: In DLBCL patients treated with immunochemotherapy, the IPI and interim-PET provide independent prognostic information. In combination, a more powerful predictive model may be created as a nomogram. This can be refined in prospective trials and may help clinical decision making.

Acute myeloid leukaemia in Western Australia 1991-2005: a retrospective population-based study of 898 patients regarding epidemiology, cytogenetics, treatment and outcome.

BACKGROUND: Patient characteristics and cytogenetics of acute myeloid leukaemia (AML) in clinical trials do not reflect that of the general population. There has not been a large population-based study that has examined cytogenetic features and outcomes of AML in Australia. AIM: Investigation of epidemiological, prognostic, treatment and outcome data in adults diagnosed with AML in Western Australia between 1991 and 2005. METHODS: Patients were identified utilising the Western Australia Cancer Registry, cytogenetic databases and hospital inpatient discharge diagnoses. Data were retrospectively collected from patients presenting to tertiary hospitals on patient characteristics, karyotype, induction therapy, remission, transplantation and survival. RESULTS: A total of 987 patients with AML was identified, of which 91% (898) attended a tertiary hospital. Median age was 67 years and 45% of cases represented secondary AML. Cytogenetic analysis was available in 81% of patients. Frequent karyotypes were normal (38.8%), complex (13.8%) and -7/add(7q)/del(7q) (12.1%). Aggressive therapy was initiated in 62.6%. Less than 15% were enrolled in clinical trials. Overall 16.5% received a stem cell transplant. Median overall survival for all patients was 5.6 months. In patients treated aggressively, complete remission was achieved in 56.9% and median overall survival was 12.2 months. Age, secondary disease and karyotype were significantly predictive of remission and overall survival. CONCLUSION: Age distribution, remission and survival rates were comparable with published population-based studies. High median age was reflected in the rate of secondary AML and trial eligibility. These findings highlight the need for prospective data collection.

Second cancer incidence and cancer mortality among chronic lymphocytic leukaemia patients: a population-based study.

BACKGROUND: Patients with chronic lymphocytic leukaemia (CLL) are known to have increased risks of second cancer. The incidence of second cancers after CLL has not been reported in detail for Australia, a country with particularly high levels of ultraviolet radiation (UVR). METHODS: The study cohort comprised of all people diagnosed with a primary CLL between 1983 and 2005 in Australia. Standardised incidence ratios (SIRs) and standardised mortality ratios (SMRs) were calculated using Australian population rates. RESULTS: Overall, the risk of any second incident cancer was more than double that of the general population (SIR=2.17, 95% confidence interval (CI)=2.07, 2.27) and remained elevated for at least 9 years after CLL. Risks were increased for many cancers, particularly melanoma (SIR=7.74, 95% CI=6.85, 8.72). The risk of melanoma increased at younger ages, but was constant across >9 years of follow-up. Chronic lymphocytic leukaemia patients also had an increased risk of death because of melanoma (SMR=4.79, 95% CI=3.83, 5.90) and non-melanoma skin cancer (NMSC; SMR=17.0, 95% CI=14.4, 19.8), suggesting that these skin cancers may be more aggressive in CLL patients. CONCLUSION: We speculate that a shared risk factor, such as general immune suppression, modulated by UVR exposure may explain the increased risk of melanoma and NMSC in CLL patients.

The effect of self-selected complementary therapies on cancer patients' quality of life and symptom distress: A prospective cohort study in an integrative oncology setting.

OBJECTIVE: To examine the effectiveness of a multifaceted complementary therapies intervention, delivered in a systematic manner within an Australian public hospital setting, on quality of life and symptom distress outcomes for cancer patients. METHODS: Adults receiving treatment for any form of cancer were eligible to participate in this study. Self-referred participants were offered a course of six complementary therapy sessions. Measures were administered at baseline, and at the third and sixth visit. The primary outcomes were quality of life and symptom distress. Linear mixed models were used to assess change in the primary outcomes. RESULTS: In total, 1376 cancer patients participated in this study. The linear mixed models demonstrated that there were significant improvements in quality of life and significant reductions in symptom distress over six sessions. Body-based therapies demonstrated significantly superior improvement in quality of life over counselling, but no other differences between therapies were identified. Reduced symptom distress was not significantly associated with any particular type of therapy. CONCLUSION: A self-selected complementary therapies intervention, provided in an Australian public hospital by accredited therapists, for cancer patients significantly mproved quality of life and reduced symptom distress. The effect of this intervention on quality of life has particular salience, since cancer impacts on many areas of people's lives and impairs quality of life.

Patient Evaluation of Emotional Comfort Experienced (PEECE): developing and testing a measurement instrument.

OBJECTIVES: The Patient Evaluation of Emotional Comfort Experienced (PEECE) is a 12-item questionnaire which measures the mental well-being state of emotional comfort in patients. The instrument was developed using previous qualitative work and published literature. DESIGN: Instrument development. SETTING: Acute Care Public Hospital, Western Australia. PARTICIPANTS: Sample of 374 patients. INTERVENTIONS: A multidisciplinary expert panel assessed the face and content validity of the instrument and following a pilot study, the psychometric properties of the instrument were explored. MAIN OUTCOME MEASURES: Exploratory and confirmatory factor analysis assessed the underlying dimensions of the PEECE instrument; Cronbach's α was used to determine the reliability; κ was used for test-retest reliability of the ordinal items. RESULTS: 2 factors were identified in the instrument and named 'positive emotions' and 'perceived meaning'. A greater proportion of male patients were found to report positive emotions compared with female patients. The instrument was found to be feasible, reliable and valid for use with inpatients and outpatients. CONCLUSIONS: PEECE was found to be a feasible instrument for use with inpatient and outpatients, being easily understood and completed. Further psychometric testing is recommended.

Critical review of complementary therapies in haemato-oncology.

There is evidence of the increasing use of complementary and alternative medicine by Australians diagnosed with cancer. Given the increasing desire of cancer patients to use complementary and alternative medicine, it is important that clinicians have a good understanding of the evidence available in this field. This critical review aims to provide an overview of the current evidence pertaining to a range of complementary therapies that are used in a supportive role in the treatment of cancer patients. Treatment methods considered are acupuncture, music therapy, massage and touch therapies and psychological interventions. The efficacy of these complementary therapies in terms of improvement in symptoms and quality of life is examined. Evidence that relates to an effect on immune function and survival is also investigated.

Prospective randomised trial of amifostine cytoprotection in myeloma patients undergoing high-dose melphalan conditioned autologous stem cell transplantation.

In this prospective multicentre trial, 90 patients undergoing autologous stem cell transplantation (ASCT) were randomised to receive (n=43) or not receive (n=47) amifostine 910 mg/m(2) prior to melphalan 200 mg/m(2). Patients were monitored for regimen-related toxicity, engraftment, supportive care, response and survival. Both groups underwent ASCT at a median of 8 months from diagnosis and were matched for disease characteristics, prior therapy and pre-ASCT disease responsiveness. Amifostine infusional side-effects were frequent, occurring in 65% of patients, but of mild severity. Amifostine use was associated with a reduction in the median grade of oral mucositis (1 vs 2, P=0.01) and the frequency of severe (WHO grades 3 or 4) mucositis (12 vs 33%, P=0.02), but no reduction in the requirement for parenteral nutrition or analgesic use. Conversion to complete remission post-ASCT occurred in 30 and 14% of the amifostine and control groups, respectively (P=0.09). With a median follow-up of 35 months, there was no statistically significant difference between the median progression-free or overall survival times for the two groups. We conclude that amifostine can be safely administered prior to high-dose melphalan and significantly reduces the frequency and severity of therapy-induced oral mucositis.

Molecular analysis of the LMP (latent membrane protein) oncogene in Hodgkin's disease.

Molecular analysis of the LMP (latent membrane protein) oncogene was performed in 21 Epstein-Barr virus (EBV) positive cases of Hodgkin's disease (HD) with proven LMP gene expression. In each case, viral DNA of the LMP gene was assessed for polymorphism (deletions, insertions, mutations) by polymerase chain reaction (PCR) amplification with selected primers. Specificity of the amplified targets was proven by internal oligonucleotide hybridisation and nested primer PCR. Homogeneity of the 5' LMP gene region coding for the amino terminal, transmembrane, and short extracytoplasmic domains of the protein was identified in all cases. However, deletions or insertions of small DNA sequences within the coding region for the intracytoplasmic LMP domain were observed in about 20% of cases. In one of them, a 30-base-pair deletion was precisely localized by DNA sequencing. A particularly high frequency of DNA polymorphism (30% of cases) was found in the 3' untranslated LMP region. However, when analysing the LMP gene in seven benign conditions, no DNA polymorphism was found. These data suggest conservation of oncogenic LMP regions coding for the protein domains known to be associated with transforming capacities and immunogenic functions. They also show a considerable genomic heterogeneity of the coding region for the intracytoplasmic domain and the 3' untranslated mRNA region. This LMP DNA polymorphism identified within a localized (Swiss) population suffering from HD is unexpected. Its eventual clinical significance remains to be determined.

Imatinib produces significantly superior molecular responses compared to interferon alfa plus cytarabine in patients with newly diagnosed chronic myeloid leukemia in chronic phase.

We analyzed molecular responses in 55 newly diagnosed chronic-phase chronic myeloid leukemia (CML) patients enrolled in a phase 3 study (the IRIS trial) comparing imatinib to interferon-alfa plus cytarabine (IFN+AraC). BCR-ABL/BCR% levels were measured by real-time quantitative RT-PCR and were significantly lower for the imatinib-treated patients at all time points up to 18 months, P<0.0001. The median levels for imatinib-treated patients continued to decrease and had not reached a plateau by 24 months. A total of 24 IFN+AraC-treated patients crossed over to imatinib. Once imatinib commenced, the median BCR-ABL/BCR% levels in these patients were not significantly different to those on first-line imatinib for the equivalent number of months. The incidence of progression in imatinib-treated patients, defined by hematologic, cytogenetic or quantitative PCR criteria, was significantly higher in the patients who failed to achieve a 1 log reduction by 3 months or a 2 log reduction by 6 months, P=0.002. A total of 49 patients were screened for BCR-ABL kinase domain mutations. Mutations were detected in two imatinib-treated patients who crossed over from IFN+AraC and both lost their imatinib response. In conclusion, first-line imatinib-treated patients had profound reductions in BCR-ABL/BCR%, which significantly exceeded those of IFN+AraC-treated patients and early measurements were predictive of subsequent response.

Reconstitution with Philadelphia chromosome-negative recipient haematopoiesis early after allogeneic BMT for CML.

We report a 33-year-old man with Ph chromosome-positive CML who underwent an allogeneic BMT from an unrelated donor. DNA microsatellite studies showed complete donor chimaerism immediately after BMT followed by mixed chimaerism; by day + 45 haematopoiesis was exclusively of recipient origin. Throughout the first year post-transplant all marrow metaphases were Ph negative but with non-clonal rearrangements consistent with autologous recovery. Cytogenetic relapse of leukaemia was first detected 15 months post-transplant. This case is unusual in that non-malignant stem cells of recipient origin survived the transplant and reconstituted haematopoiesis very early after BMT. Later the leukaemic cells reasserted their 'proliferative' advantage.

Autologous haematopoietic stem cell transplants for autoimmune disease--feasibility and transplant-related mortality. Autoimmune Disease and Lymphoma Working Parties of the European Group for Blood and Marrow Transplantation, the European League Against Rheumatism and the International Stem Cell Project for Autoimmune Disease.

This ongoing multicentre prospective phase I/II trial enrolled 74 consecutive patients from 22 centres worldwide with severe autoimmune disease, 35 with rheumatological disorders, 31 with neurological, five with haematological and three with vasculitides. They were treated with autologous peripheral blood or bone marrow transplants according to predetermined criteria. Two patients died after mobilisation before transplant. Seventy-two patients were given 73 transplants, seven bone marrow, and 66 mobilised peripheral blood stem cell transplants. The graft was manipulated to remove T and/or B cells in 43 cases. All 73 transplants engrafted. Five patients died of transplant-related complications: two from bleeding, three from infections. Two patients died of progressive disease. The transplant-related mortality at 1 year of 9% (1-17%; 95% CI) is comparable to the transplant-related mortality of 6% (3-9%; 95% CI) in patients transplanted during the same period in Europe for non-Hodgkin's lymphoma in sensitive relapse (P = 0.39). Sixty patients are evaluable for response, 40 patients (65%) showed some improvement in their disease. Haematopoietic stem cell transplants are feasible for patients with severe refractory autoimmune disease. Transplant-related mortality is comparable to results in patients with non-Hodgkin's lymphoma in responsive relapse. Two-thirds of the patients show at least some response. These preliminary data are promising. Although associated with considerable risk, randomised trials comparing autologous stem cell transplants to conventional therapy are warranted.

Significance of the detection of Epstein-Barr virus DNA in lymph nodes in patients with Hodgkin's disease.

Epstein-Barr virus (EBV) DNA is frequently identified in benign and malignant lymphoproliferative conditions. As shown by in situ hybridization studies viral DNA is localized within malignant cells as well as benign lymphocytes. Clonal and nonclonal EBV genomes are present in Hodgkin's disease (HD), lymphomas of the immunocompromised host and reactive lymph node hyperplasia. Lytic infection with formation of linear genomes is observed in the same conditions but appears to be infrequent in HD as shown by quantitation of mRNA coding for viral capsid antigen. Expression of the oncogene LMP (latent membrane protein) is seen in Sternberg-Reed (SR) cells and immunoblasts of AIDS-related lymphoma and infectious mononucleosis (IM). In HD, the region of the BNLF1 oncogene coding for the amino terminal and transmembrane domains (associated with oncogenic function) of LMP appears to be homogeneous whereas the region coding for the intracytoplasmic (carboxy terminal) domain of LMP is heterogeneous. Cytological similarities between SR cells and immunoblasts of IM and AIDS-related lymphomas are consistent with the hypothesis that the BNLF1 oncogene is one possible inducer of morphological features of SR cells. Whether chromosomal integration of EBV DNA is an important factor in activation of such a transforming activity remains to be elucidated. EBV DNA positive and negative HD cases with numerous SR cells lack significant mRNA expression of the two recombinase activating genes (RAG-1 and RAG-2). Therefore the SR cells appear to be derived from lymphocytes beyond the pre-B-cell or common thymocyte stage which may or may not subsequently become infected by EBV.

Polymorphisms in the interleukin 10 gene promoter are associated with susceptibility to aggressive non-Hodgkin's lymphoma.

Interleukin-10 (IL-10) is mainly an anti-inflammatory cytokine produced by a number of cells including normal and neoplastic B cells. It has been implicated in autoimmunity, transplantation tolerance and tumourigenesis. Polymorphisms in the IL-10 gene promoter genetically determine inter-individual differences in IL-10 production. The aim of this study was to determine whether polymorphisms in the IL-10 gene promoter play a role in predisposing an individual to lymphoma. We analysed the frequencies of three single base substitutions in the IL-10 promoter in patients with aggressive lymphoma (B-cell DLCL n = 46, other aggressive histologies n = 17), Hodgkin's disease (n = 44) or low/intermediate grade lymphoma (n = 46), compared to healthy controls. The frequency of the low-IL-10 producing AA allele (at position -1082) was significantly higher in patients with aggressive lymphoma compared to controls (p = 0.0344, Odds ratio 1.974, 95% C.I 1.066-3.655). Similarly, the frequency of the low IL-10 producing ATA or the intermediate-IL-10- producing ACC haplotype was significantly higher in patients with aggressive disease compared to controls (p = 0.0255, Odds ratio 1.647, 95% C.I 1.077-2.518). No association was found between IL-10 genotypes and Hodgkin's disease or less aggressive forms of lymphoma. Thus, polymorphisms in the IL-10 gene promoter which are associated with a low IL-10 producing phenotype may influence susceptibility to aggressive forms of lymphoma or may contribute to the pathogenesis of this disease.

When the safety net of treatment has been removed: patients' unmet needs at the completion of treatment for haematological malignancies.

OBJECTIVE: To determine patients' information, emotional and support needs at the completion of treatment for a haematological malignancy. METHODS: A self-report questionnaire was mailed to 113 adult patients. RESULTS: Sixty-six questionnaires were returned. The most frequently endorsed patient needs related to care co-ordination and help to manage the fear of recurrence. The most frequently endorsed unmet needs included managing the fear of recurrence, the need for a case-manager and the need for communication between treating doctors. Predictors of unmet needs included younger patients (p=0.01), marital status (p=0.03) and employment (p=0.03). Almost two-thirds of patients (59%) reported they would have found it helpful to talk with a health care professional about their experience of diagnosis and treatment at the completion of treatment and endorsed significantly more need in the arenas of Quality of Life (p=0.03) and Emotional and Relationships (p=0.04). CONCLUSION: This study provides valuable data on haematological cancer patients' needs in the first 12 months of finishing treatment. It appears that many needs emerge or remain unresolved at this time. PRACTICE IMPLICATIONS: An opportunity for patients to talk with a health professional about making the transition from active treatment to extended survivorship may be helpful.

Monitoring 6 weeks of progressive endurance training with plasma glutamine.

The distinction between positive and negative training adaptation is an important prerequisite in the identification of any marker for monitoring training in athletes. To investigate the glutamine responses to progressive endurance training, twenty healthy males were randomly assigned to a training group or a non-exercising control group. The training group performed a progressive (3 to 6 x 90 minute sessions per week at 70 % V.O (2max)) six-week endurance training programme on a cycle ergometer, while the control group did not participate in any exercise during this period. Performance assessments (V.O (2max) and time to exhaustion) and resting blood samples (for haemoglobin concentration, haematocrit, cortisol, ferritin, creatine kinase, glutamine, uric acid and urea analysis) were obtained prior to the commencement of training (Pre) and at the end of week 2, week 4 and week 6. The training group showed significant improvements in time to exhaustion (p < 0.01), and V.O (2max) (p < 0.05) at all time points (except week 2 for V.O (2max)), while the control group performance measures did not change. In the training group, haemoglobin concentration and haematocrit were significantly lower (p < 0.01) than pretraining values at week 2 and 4, as percentage changes in plasma volume indicated a significant (p < 0.01) haemodilution (+ 6 - 9 %) was present at week 2, 4 and 6. No changes were seen in the control group. In the training group, plasma glutamine (week 2, 4 and 6), creatine kinase (week 2 and 4), uric acid (week 2 and 4) and urea (week 2 and 4) all increased significantly from pretraining levels. No changes in cortisol or ferritin were found in the training group and no changes in any blood variables were present in the control group. Plasma glutamine was the only blood variable to remain significantly above pretraining (966 +/- 32 micromol . 1 (-1)) levels at week 6 (1176 +/- 24 micromol . 1 (-1); p < 0.05) The elevation seen here in glutamine levels, after 6 weeks of progressive endurance training, is in contrast to previous reports of decreased glutamine concentrations in overtrained athletes. In conclusion, 6 weeks of progressive endurance training steadily increased plasma glutamine levels, which may prove useful in the monitoring of training responses.