Effects of an outpatient exercise programme for Australians with cancer-related fatigue: an unmet need.

BACKGROUND: Cancer-related fatigue (CRF) is a common debilitating condition. International evidence supports an exercise prescription for CRF. The majority of Australians with cancer do not meet recommended exercise targets. AIMS: To analyse the effects of a guideline-based supervised exercise programme on CRF among a representative private hospital cancer patient sample (n = 268). METHODS: We collected data from 268 patients recruited from haematology and oncology over a 5-year period. Participants underwent a 3-month CRF exercise programme based on internationally recognised exercise guidelines. The programme, conducted by a multidisciplinary team, operated twice weekly sessions of 2 h duration comprising aerobic, resistance and balance exercises; hydrotherapy and condition counselling; fatigue management; and dietetic, speech pathology and swallowing education (head and neck cancers). The effect of the programme was measured in relation to the following outcomes: Functional Assessment of Chronic Illness Therapy, Fatigue (self-reported fatigue); Functional Assessment of Cancer Therapy, general quality of life (health-related quality of life in cancer); six-minute walk test; and Lawton's Instrumental Activities of Daily Living Scale. RESULTS: Multivariate outcomes showed statistically significant improvements in all four major outcome measures, plus a programme effect of greater than 0.7 for each outcome variable. The programme treatment outcomes were consistent over the 5 years of the programme. CONCLUSIONS: The outcomes of this programme contribute to exercise guidelines in Australia. Currently only position statements exist on the subject, but there are no programme guidelines. An exercise prescription is critical to cancer outcomes. This programme is likely to benefit cancer survivors experiencing CRF across private and public hospitals in Australia.

Red cell alloimmunization is associated with development of autoantibodies and increased red cell transfusion requirements in myelodysplastic syndrome.

Up to 90% of patients with a myelodysplastic syndrome require red blood cell transfusion; nevertheless, comprehensive data on red cell alloimmunization in such patients are limited. This study evaluates the incidence and clinical impact of red cell alloimmunization in a large cohort of patients with myelodysplastic syndrome registered in the statewide South Australian-MDS registry. The median age of the 817 patients studied was 73 years, and 66% were male. The cumulative incidence of alloimmunization was 11%. Disease-modifying therapy was associated with a lower risk of alloimmunization while alloimmunization was significantly higher in patients with a revised International Prognostic Scoring System classification of Very Low, Low or Intermediate risk compared to those with a High or Very High risk (P=0.03). Alloantibodies were most commonly directed against antigens in the Rh (54%) and Kell (24%) systems. Multiple alloantibodies were present in 49% of alloimmunized patients. Although 73% of alloimmunized patients developed alloantibodies during the period in which they received their first 20 red cell units, the total number of units transfused was significantly higher in alloimmunized patients than in non-alloimmunized patients (90±100 versus 30±52; P<0.0001). In individual patients, red cell transfusion intensity increased significantly following alloimmunization (2.8±1.3 versus 4.1±2.0; P<0.0001). A significantly higher proportion of alloimmunized patients than non-alloimmunized patients had detectable autoantibodies (65% versus 18%; P<0.0001) and the majority of autoantibodies were detected within a short period of alloimmunization. In conclusion, this study characterizes alloimmunization in a large cohort of patients with myelodysplastic syndrome and demonstrates a signficant increase in red cell transfusion requirements following alloimmunization, most probably due to development of additional alloantibodies and autoantibodies, resulting in subclinical/clinical hemolysis. Strategies to mitigate alloimmunization risk are critical for optimizing red cell transfusion support.

Dynamic assessment of RBC-transfusion dependency improves the prognostic value of the revised-IPSS in MDS patients.

RBC-transfusion dependency (RBC-TD) is an independent prognostic factor for poor overall survival (OS) in the WHO classification-based prognostic scoring system (WPSS) for MDS patients. However, WPSS did not include cytopenia, whereas revised International Prognostic Scoring System (IPSS-R) did not include RBC-TD. Thus, neither of these prognostic scoring systems incorporates both cytopenia and RBC-TD. We aimed to test whether RBC-TD adds prognostic value to the IPSS-R. We analyzed MDS patients not treated with disease-modifying therapy, and enrolled in SA-MDS Registry (derivation cohort; n = 295) and Dusseldorf registry (Germany; validation cohort; n = 113) using time-dependent Cox proportional regression and serial landmark analyses. In the derivation cohort, RBC-TD patients had inferior OS compared to RBC transfusion-independent (RBC-TI) patients (P < 0.0001) at 6- (18 vs. 64 months), 12- (24 vs. 71 months), and 24-months (40 vs. 87 months). In a Cox proportional regression analysis, RBC-TD was an independent adverse prognostic marker in addition to age, sex, and IPSS-R variables (P < 0.0001). A prognostic index (PI) was derived using these Cox-proportional regression model variables. In the validation cohort, this PI classified patients into four prognostic groups with significantly different OS (P < 0.001) as in the derivation cohort. In conclusion, multivariate analysis by Cox proportional hazards regression and serial landmark analyses clearly demonstrates that development of RBC-TD at any time during the course of MDS is associated with poor OS, independent of IPSS-R. This study demonstrates that dynamic assessment of RBC-TD provides additional prognostic value to IPSS-R and should be included in treatment decision algorithms for MDS patients.

Bone Marrow Recovery by Morphometry during Induction Chemotherapy for Acute Lymphoblastic Leukemia in Children.

Bone marrow architecture is grossly distorted at the diagnosis of ALL and details of the morphological changes that accompany response to Induction chemotherapy have not been reported before. While marrow aspirates are widely used to assess initial response to ALL therapy and provide some indications, we have enumerated marrow components using morphometric analysis of trephine samples with the aim of achieving a greater understanding of changes in bone marrow niches. Morphometric analyses were carried out in the bone marrow trephine samples of 44 children with ALL, using a NanoZoomer HT digital scanner. Diagnostic samples were compared to those of 32 control patients with solid tumors but without marrow involvement. Samples from patients with ALL had significantly increased fibrosis and the area occupied by bony trabeculae was lower than in controls. Cellularity was higher in ALL samples due to leukemic infiltration while the percentage of normal elements such as megakaryocytes, adipocytes, osteoblasts and osteoclasts were all significantly lower. During the course of Induction therapy, there was a decrease in the cellularity of ALL samples at day 15 of therapy with a further decrease at the end of Induction and an increase in the area occupied by adipocytes and the width of sinusoids. Reticulin fibrosis decreased throughout Induction. Megakaryocytes increased, osteoblasts and osteoclasts remained unchanged. No correlation was found between clinical presentation, early response to treatment and morphological changes. Our results provide a morphological background to further studies of bone marrow stroma in ALL.

Reticulin fibres anchor leukaemic blasts in the marrow of patients with acute lymphoblastic leukaemia.

Reticulin fibrosis has been recognized in childhood ALL at diagnosis as part of the altered stromal structure in the bone marrow (BM). Increased fibre density is correlated with a higher concentration of leukaemia cells in the BM and lower numbers of blasts in peripheral blood. We hypothesize that these fibres anchor the leukaemia cells within the BM in close proximity to BM stromal cells (BMSC). The BMSC are a rich source of growth factors and cytokines which enhance leukaemia cell growth and provide protection against chemotherapy. Mobilizing the cells by breaking the 'anchoring ropes' could lead to greater exposure to apoptotic signals.

Discrepancy in factor VIII 1-stage/2-stage activity in a child with Arg(531)--> His mutation.

Routine screening of infants born to known hemophilia carriers includes a factor VIII (FVIII) level. In routine practice, mild FVIII deficiency variants may be missed by laboratories that exclusively use a one-stage activated partial thromboplastin time-based activity assay. This case illustrates such a possibility with a discrepancy between the one-stage and two-stage assays performed on a child who carries the Arg(531) --> His mutation.

Cure of a patient with profoundly chemotherapy-refractory primary mediastinal large B-cell lymphoma: role of rituximab, high-dose therapy, and allogeneic stem cell transplantation.

Patients with primary large B-cell lymphomas of the mediastinum (PMBL) who suffer early relapse have a low likelihood of achieving a prolonged second remission with conventional salvage therapy. Here we describe the case of a 33-year-old woman with PMBL refractory to 6 lines of therapy before undergoing salvage therapy with rituximab, ifosfamide and etoposide followed by high-dose therapy, autologous transplantation, and sequential non-myeloablative allogeneic transplantation, who remains in ongoing complete remission for more than 39 months and is apparently cured. The specific roles of the components of the successful salvage therapy are discussed.

Durable remissions are rare following high dose therapy with autologous stem cell transplantation for adults with "paediatric" bone and soft tissue sarcomas.

BACKGROUND: The role of high dose therapy (HDT) with autologous stem cell transplantation (AuSCT) for the treatment of bone and soft tissue sarcomas remains investigational. There are few reports examining this strategy focusing on the adult population. METHODS: We retrospectively reviewed our experience of adult patients undergoing HDT and AuSCT for 'paediatric' sarcomas. RESULTS: A total of 17 patients (14 male, 3 female) with median age at transplant of 24 years (range 20 - 41) were identified. The diagnosis was Ewings sarcoma/PNET (10), osteosarcoma (5) and rhabdomyosarcoma (2). Status prior to HDT, following conventional-dose chemotherapy +/- surgery +/- radiotherapy, was complete remission (CR) (6), partial remission (PR) (6), stable disease (1) and progressive disease (4). There was no transplant-related mortality. Two patients remain disease free beyond four years and both received HDT as part of their primary therapy (CR1 and PR1) however, the median progression free survival and overall survival following AuSCT for the entire cohort was only 7 months (range: 2-92 months) and 13 months (range: 2 - 92 months), respectively. CONCLUSION: HDT and AuSCT infrequently achieves prolonged remissions in adult patients and should only be considered in patients who are in a PR or CR following conventional-dose therapy. Further studies are required to define the role of HDT with AuSCT for adult patients with sarcoma.