EVERSUN: a phase 2 trial of alternating sunitinib and everolimus as first-line therapy for advanced renal cell carcinoma.

BACKGROUND: We hypothesised that alternating inhibitors of the vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin pathways would delay the development of resistance in advanced renal cell carcinoma (aRCC). PATIENTS AND METHODS: A single-arm, two-stage, multicentre, phase 2 trial to determine the activity, feasibility, and safety of 12-week cycles of sunitinib 50 mg daily 4 weeks on / 2 weeks off, alternating with everolimus 10 mg daily for 5 weeks on / 1 week off, until disease progression or prohibitive toxicity in favourable or intermediate-risk aRCC. The primary end point was proportion alive and progression-free at 6 months (PFS6m). The secondary end points were feasibility, tumour response, overall survival (OS), and adverse events (AEs). The correlative objective was to assess biomarkers and correlate with clinical outcome. RESULTS: We recruited 55 eligible participants from September 2010 to August 2012. DEMOGRAPHICS: mean age 61, 71% male, favourable risk 16%, intermediate risk 84%. Cycle 2 commenced within 14 weeks for 80% of participants; 64% received ≥22 weeks of alternating therapy; 78% received ≥22 weeks of any treatment. PFS6m was 29/55 (53%; 95% confidence interval [CI] 40% to 66%). Tumour response rate was 7/55 (13%; 95% CI 4% to 22%, all partial responses). After median follow-up of 20 months, 47 of 55 (86%) had progressed with a median progression-free survival of 8 months (95% CI 5-10), and 30 of 55 (55%) had died with a median OS of 17 months (95% CI 12-undefined). AEs were consistent with those expected for each single agent. No convincing prognostic biomarkers were identified. CONCLUSIONS: The EVERSUN regimen was feasible and safe, but its activity did not meet pre-specified values to warrant further research. This supports the current approach of continuing anti-VEGF therapy until progression or prohibitive toxicity before changing treatment. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12609000643279.

Chemotherapy-related cardiomyopathy: a neglected aspect of cancer survivorship.

Improvements in survival from cancer have led to a large population who are at risk of late complications of chemotherapy. One of the most serious cardiovascular complications is chemotherapy-related cardiomyopathy (CRC), which may become clinically overt years or even decades after treatment and has over threefold higher mortality rate compared with idiopathic dilated cardiomyopathy. The early stages of this condition appear to respond well to cardioprotective medications (i.e. angiotensin-converting enzyme inhibitors, ß-blockers). Periodic cardiac monitoring is necessary in this population to identify patients who would benefit from treatment. Cardio-oncology clinics have been established in recognition of this hazard in survivorship. This review summarises the epidemiology and pathophysiology of CRC, the evidence base for different non-invasive imaging modalities for screening and diagnosis and the rationale for treatment.

Use of 'rainy day' autologous haemopoietic stem cells: a single-institution experience over 10 years.

BACKGROUND: High-dose chemotherapy and autologous haematopoietic stem cell transplantation is an important therapeutic modality in the treatment of many haematological malignancies. Generally, stem cells are collected close to the time of the transplant, but an alternative is to collect and cryopreserve cells at an early stage of the illness so they are available for later use ('rainy day harvesting'). Although this practice has been commonplace in Australia, there is little evidence to document eventual use of cells collected in this manner. METHODS: We conducted an audit of indications for and eventual transplantation of 'rainy day' harvests performed at our institution over a 10-year period. RESULTS: Although there was some variation across different disease groups, we found that only 14% of cells were transplanted. The median delay to transplantation was 19 months. CONCLUSION: Together with recent advances in stem cell mobilisation techniques, results from this audit suggest that the practice may not be an effective use of limited health resources.

Lymphoma studies by the Australasian Leukaemia and Lymphoma Group.

The Australasian Leukaemia and Lymphoma Group (ALLG) can trace its origins to 1973. It now encompasses virtually all the major hospitals in Australia and New Zealand that treat leukaemias and lymphomas. Over the years the Group as a whole, and members individually, have participated in many clinical treatment trials for aggressive lymphomas. Initially trials were conceived and carried out locally, but in recent years, in addition to continuing its own studies, the Group has been a major contributor to international trials including two that have been particularly influential, known as MInT and CORAL. The MInT study confirmed the value of adding rituximab to standard chemotherapy for aggressive lymphomas; CORAL helped define optimum methods of autografting for relapse. The ALLG has contributed and continues to contribute to the improving outcome for patients with aggressive lymphomas.

Hypothesis. The importance of a histological diagnosis when diagnosing and treating advanced cancer. Famous patient recovery may not have been from metastatic disease.

Over the past 33 years, mystery has surrounded the diagnosis and treatment of a very influential Australian patient. In the long gap between amputation of his leg for osteogenic sarcoma and successful treatment for widespread tuberculosis, he was told he had advanced and incurable metastatic sarcoma. Details of his recovery and the treatments used have been extensively described. An alternative hypothesis is advanced to explain his recovery. This hypothesis is advanced for two reasons. The first is to underline the modern recognition of the need to consider diagnostic investigations, including biopsy, before assigning the diagnosis of advanced cancer to any patient. This principle is especially vital in cases where two diseases can present in the same way. The second is that there a risk that if diseases are incorrectly labelled, incorrect treatments may be given. This can lead to misleading interpretations being made about non-traditional treatments providing 'cures', which can influence the decision-making of patients seeking answers and even lead them away from potentially curative traditional treatments.

Risk of arterial thromboembolic events in patients with advanced colorectal cancer receiving bevacizumab.

BACKGROUND: Bevacizumab is an antiangiogenic mAb with efficacy against several cancers, but it is associated with risk of arterial thromboembolism (ATE). Further data are needed to determine the safety of bevacizumab. PATIENTS AND METHODS: We recorded grade 3, 4, or 5 ATE events and other data (including age, baseline cardiovascular risk factors, history of ATE, and aspirin use) from 471 patients with metastatic colorectal cancer in the MAX (Mitomycin, Avastin, Xeloda) trial of capecitabine monotherapy versus capecitabine with bevacizumab with or without mitomycin C. RESULTS: Bevacizumab-treated patients had 12 grade 3, 4, or 5 ATEs (3.8% incidence). ATEs occurred in 2.1% of patients >65 years, 5% of those with a history of ATE, and 5% of those with cardiac risk factors. Age, history of ATE, or vascular risk factors did not increase risk. Aspirin users had a higher incidence than nonusers (8.9% versus 2.7%) but had higher rates of vascular risk factors. CONCLUSIONS: Bevacizumab was associated with a modestly higher risk of ATE, but safety was not significantly worse in older patients or patients with a history of ATE or vascular risk factors. The effect of aspirin in preventing ATE in patients receiving bevacizumab could not be determined from this study.

Pooled analysis of recent studies on magnetic fields and childhood leukaemia.

BACKGROUND: Previous pooled analyses have reported an association between magnetic fields and childhood leukaemia. We present a pooled analysis based on primary data from studies on residential magnetic fields and childhood leukaemia published after 2000. METHODS: Seven studies with a total of 10,865 cases and 12,853 controls were included. The main analysis focused on 24-h magnetic field measurements or calculated fields in residences. RESULTS: In the combined results, risk increased with increase in exposure, but the estimates were imprecise. The odds ratios for exposure categories of 0.1-0.2 µT, 0.2-0.3 µT and ≥0.3 µT, compared with <0.1 µT, were 1.07 (95% CI 0.81-1.41), 1.16 (0.69-1.93) and 1.44 (0.88-2.36), respectively. Without the most influential study from Brazil, the odds ratios increased somewhat. An increasing trend was also suggested by a nonparametric analysis conducted using a generalised additive model. CONCLUSIONS: Our results are in line with previous pooled analyses showing an association between magnetic fields and childhood leukaemia. Overall, the association is weaker in the most recently conducted studies, but these studies are small and lack methodological improvements needed to resolve the apparent association. We conclude that recent studies on magnetic fields and childhood leukaemia do not alter the previous assessment that magnetic fields are possibly carcinogenic.

Residential exposure to electric power transmission lines and risk of lymphoproliferative and myeloproliferative disorders: a case-control study.

BACKGROUND: Studies have shown an association between electromagnetic fields and childhood leukaemia. The aim of this study was to determine whether there is an increased risk of lymphoproliferative disorders (LPD) or myeloproliferative disorders (MPD) associated with residence < or =300 m from high-voltage power lines. METHODS: Case-control study of 854 patients diagnosed with LPD or MPD (including leukaemia, lymphoma and related conditions) aged 0-94 years comprising all cases diagnosed in Tasmania between 1972 and 1980. Controls were individually matched for sex and approximate age at the time of diagnosis. RESULTS: Compared with those who had always lived >300 m from a power line, those who had ever lived within 50 m had an odds ratio (OR) of 2.06 (95% confidence interval 0.87-4.91) for developing LPD or MPD (based on 768 adult case-control pairs); those who had lived between 50 and 300 m had an OR of 1.30 (0.88-1.91). Adults who had lived within 300 m of a power line during the first 15 years of life had a threefold increase in risk (OR 3.23; 1.26-8.29); those who had lived within the same distance aged 0-5 years had a fivefold increase in risk (OR 4.74; 0.98-22.9). These associations were strengthened when analyses were repeated for 201 pairs with entirely Tasmanian residential histories. CONCLUSION: Although recognizing that this study has limitations, the results raise the possibility that prolonged residence close to high-voltage power lines, especially early in life, may increase the risk of the development of MPD and LPD later.

Extracranial metastases of a glioblastoma multiforme to the pleura, small bowel and pancreas.

Extracranial metastases of glioblastoma multiforme (GBM) are rare and usually occur in the context of recurrent intracranial GBM. We present a 39-year-old man with histologically confirmed GBM. The patient remained well for nearly 2 years, with no signs of recurrent tumour. He then presented with distant recurrence within the brain at the same time as developing pneumonia and epigastric pain. A computed tomography scan of the patient's abdomen and chest showed several intra-abdominal masses, including one in the head of the pancreas as well as a separate mass at the base of the left lung. A computed tomography-guided biopsy of the pancreatic mass demonstrated histological appearances identical to those of the original GBM. This unusual case raises the possibility of a link between prolonged survival with GBM and the occurrence of extracranial disease.

Severe persistent sciatic pain and weakness due to a gluteal artery pseudoaneurysm as a complication of bone marrow biopsy.

Complications of bone marrow trephine are thought to be uncommon. Herein, we present a case of severe debilitating sciatic nerve palsy secondary to a gluteal artery pseudoaneurysm following bone marrow biopsy. The pseudoaneurysm was treated successfully by percutaneous embolization; however, the patient remains significantly impaired with persistent painless foot drop.

Myeloproliferative and lymphoproliferative disorders in Tasmania, 1972-80: occupational and familial aspects.

All cases in a population-based series of myeloproliferative and lymphoproliferative (LP) disorders diagnosed in usual residents of Tasmania between 1972 and 1980 were asked for occupational histories and the occurrence of similar diseases in their close relatives. Occupational risks were observed for males who had farmed, mined, or worked in foundries and for women who had farmed or had been hairdressers. For individual diagnoses, the risk to farmers was seen to vary with age at diagnosis, sex, and region. With regard to familial risks, the LP and MP groups seemed to breed true, relatives being affected with a disorder from the other group not more often than would be expected by chance. The risks were of two kinds: Those to siblings and that between parent and child, particularly between mother and son. Occupational risks for the familial cases were limited to farming particularly in males diagnosed at 65 years of age or older. Females possessed elevated risks for the LP group only, and their highest relative risk was for those diagnosed before age 65. This evidence suggests that familial clustering of these disorders partly may be due to common environmental exposures in males from rural kindreds.

Myeloproliferative and lymphoproliferative disorders in Tasmania, 1972-80: patterns in space and time.

During the period 1972-80, 866 patients with myeloproliferative (MP) and lymphoproliferative (LP) disorders were diagnosed in Tasmania. The residential histories of these cases were compared with those of population-based controls. No space-time clustering was demonstrated by individuals of any single diagnosis or group of diagnoses, nor were any regional differences in incidence detected. However, urban-rural differences were observed. Rural exposures were important especially in early childhood and at specific intervals before onset for certain diagnoses. Farm residence in early life yielded heightened relative risks, especially for sufferers from chronic lymphocytic leukemia and acute nonlymphoblastic leukemia. Regional analysis demonstrated elevated risks of residence in orcharding and dairying regions and in an urban-industrial municipality. High risks were associated with latent periods before diagnosis. The findings suggest environmental agents, acting prenatally or in early life, as well as in adult life, as important risk factors in the later development of MP and LP disorders.

A quantitative method to detect fucoidan in human plasma using a novel antibody.

We have developed an antibody-based method to assess plasma uptake of a proprietary Undaria-derived fucoidan galactofucan sulfate (GFS(TM)) after oral ingestion by human volunteers. Fucoidans have high-molecular-weights but exert biological effects in experimental animals after oral intake. By using a novel antibody raised against sulfated polysaccharides, we carried out a competitive ELISA to quantitate GFS in plasma samples from healthy volunteers who ingested 3 g/day of whole Undaria containing 10% GFS fucoidan, purified 75% GFS fucoidan, or 3 g of a nonsulfated placebo polysaccharide over 12 days. Increased reactivity to the novel antibody, as measured against preingestion levels, was detected at all time points. Assuming the measured material to be intact GFS, the concentration detected (median) was 4.002 and 12.989 mg/l when 3 g of 10% or 75% pure fucoidan was ingested orally over a period of 12 days, respectively. High-molecular-weight fucoidan can be detected in plasma using an ELISA competitive assay based on a novel antibody to sulfated polysaccharides.

Cellular interactions and IL2 requirements of PHA-induced human T-lymphocyte colonies.

A number of conflicting proposals have been put forward as to the roles and identities of cooperating cells involved with human T-lymphocyte colony formation. To resolve this conflict, the principal cellular interactions of human T-lymphocyte colonies were analyzed using a two-step culture technique. Through mathematical analysis of cell dose-response curves the requirement for at least two populations of cooperating cells in addition to the colony-forming cell was demonstrated. By removing adherent cells prior to the first but not the second step, colony formation was inhibited, which suggests a restricted role for these cells during the early stages of colony formation. The dependence of the second step on interleukin 2 (IL2) availability implied that IL2-producing cells composed the other population of cooperating cells. We therefore propose that colony formation can be described by the two interdependent reactions of activation (T----T') and proliferation (T'----nT'). The first reaction requires an adherent cell (monocyte) population that together with PHA provides the necessary signals for cellular activation. Cell contact is needed to allow the expression of this adherent cell or interleukin 1 ( IL1 ) activity. As a result of these signals at least two subpopulations of lymphocytes are activated, the T-lymphocyte colony-forming cells themselves ( TLCFC ) and a population of cooperating T cells. These activated T cells interact during the second or proliferative reaction. In response to PHA the cooperating T cells release IL2, thereby enabling the activated TLCFs to proliferate into colonies. Thus for PHA-induced T-colony formation, TLCFCs required the cooperation of adherent cells for the activation reaction and IL2-producing T cells for proliferative reaction.

Prognostic value of quality of life scores in a trial of chemotherapy with or without interferon in patients with metastatic malignant melanoma.

In a multi-centre randomised clinical trial comparing dacarbazine (DTIC) plus recombinant interferon-alfa2a (IFN) versus DTIC alone for patients with metastatic malignant melanoma, aspects of quality of life (QL) were measured prospectively by patients using linear analogue self assessment (LASA) scales including the GLQ-8 and by doctors using Spitzer's QL Index. QL scores and performance status at the time of randomisation were available for 152 of 170 eligible patients. These scores carried significant prognostic information. In univariate analyses, Spitzer QL Index assessed by the doctor and LASA scores for physical wellbeing (PWB), mood, pain, appetite, nausea and vomiting, GLQ-8 total and overall QL were significant (P < 0.01) predictors of subsequent survival. QL Index and LASA scales for mood, appetite, and overall QL remained independently significant (all P < 0.05) in multivariate models allowing for significant prognostic factors other than QL (liver metastases and performance status). These findings closely parallel those in patients with metastatic breast cancer. They add further validity to the QL Index and LASA scores, provide the first evidence of the prognostic significance of the GLQ-8, and argue strongly for the routine assessment of QL in future therapy trials.

A rapid, simple method for leukemia immunophenotyping using air-dried blood and bone marrow smears.

This paper describes a modification of the peroxidase technique by which immunophenotyping may be carried out on routinely air-dried blood and bone marrow (BM) smears. The method is simple and quick, requires no special equipment, can be performed on fresh or stored specimens and gives a standard of morphological detail equal to that of routine blood films. With a monoclonal anti-HLA-DR antibody as a prototype, it was possible to demonstrate reliably, the presence of positively and negatively stained cells of appropriate morphological types in the peripheral blood of leukemia patients. Although only about one-third of antibodies tested were effective with the technique, we identified monoclonal antibodies capable of demonstrating myelomonocyte, granulocyte, monocyte, pan-leukocyte, transferrin, platelet, pan-T, 'cALLA plus B cell' and other antigens. However, we have not yet found antibodies able to identify T cell subsets, nor to distinguish 'common' acute lymphoblastic leukemia from its rare B-cell counterpart. With these limitations the method is suitable for routine use alongside cytochemistry in the differential diagnosis of leukemias and lymphomas.

Functional and phenotypic analysis of a T cell prolymphocytic leukemia.

Peripheral blood mononuclear cells obtained from a patient with prolymphocytic leukemia expressed the surface membrane markers characteristic of resting mature T helper lymphocytes. These cells responded to the T cell mitogens PHA and Con A in a blast transformation assay but not the anti-T cell monoclonal antibody Leu 4 and the B cell mitogen, PWM. The concentration of PHA or Con A eliciting maximum blast transformation was less than that required by normal mononuclear cells. The leukemic cells recognised and responded to allogeneic pooled mononuclear cells in a mixed lymphocyte culture. In addition, although they did not express Ia antigens, they served as effective stimulators in the mixed lymphocyte reaction. Consistent with the helper phenotype, the leukemic cells did not produce suppressor factors, but provided help for normal B-enriched lymphocytes to respond to PWM as assessed by both blast transformation and IgG production. T lymphocyte colonies developed when the leukemic cells were treated with PHA during a 20 h liquid culture prior to being seeded into semisolid agar medium containing either PHA or an IL2-containing lymphokine. There was no growth when untreated cells were seeded directly into IL2-containing agar. Analysis of colony formation indicated that, as with normal resting T lymphocytes, proliferation occurred in two distinct steps; activation in response to PHA and replication in response to IL2-like growth factors. These findings demonstrate that in this case the helper T prolymphocytes have the functional capabilities of normal mature T lymphocytes as predicted from their helper phenotype.

Invasive Trichosporon cutaneum infection: an increasing problem in immunosuppressed patients.

Trichosporon cutaneum (syn. T. beigelii), a saprophytic fungal organism normally found in the soil, is increasingly being recognized as a cause of life-threatening systemic illness in immunosuppressed patients. Of 42 cases reported in the literature, 27 (64%) have died, including all four occurring after bone marrow transplantation. We report here a 44-year-old man who developed an invasive pulmonary infection and fungemia with T. cutaneum following bone marrow transplantation. The infection was manifest by severe respiratory distress and hypoxemia despite a clear chest X-ray, and was diagnosed by the identification of fungal hyphae on a percutaneous lung aspirate and by culture of the organism from the blood. Despite the previous reports indicating that there is a high mortality rate in this situation, the patient recovered following treatment with amphotericin B, miconazole and ketoconazole. T. cutaneum needs to be recognized as a potentially serious but treatable pathogen in severely immunosuppressed patients, including bone marrow transplant recipients.

Association between high interleukin-6 levels and adverse outcome after autologous haemopoietic stem cell transplantation.

We studied interleukin-6 (IL-6) levels on the day of transplantation in 31 patients undergoing autologous haemopoietic stem cell transplantation (SCT) (either peripheral blood stem cell transplantation (PBSCT) or bone marrow transplantation (BMT)) for neoplastic diseases to determine if there was a relationship between IL-6 level and rate of haemopoietic recovery, length of stay in hospital, and survival. There was no apparent delay in post-transplant recovery associated with elevated IL-6 levels. However, increased values of IL-6 tended to be associated with an increased length of stay in hospital (P = 0.083). There was a highly significant adverse association between higher IL-6 levels and survival following transplantation (P = 0.0001). This association remained significant (P = 0.013) in the uniform subgroup of patients with malignant lymphoma with chemosensitive disease who had undergone BMT (that is, excluding patients who had undergone PBSCT) (n = 13). Knowledge of IL-6 levels on the day of transplant has the potential to provide valuable prognostic information in patients undergoing autologous haemopoietic SCT.

Factors influencing haemopoietic recovery following chemotherapy-mobilised autologous peripheral blood progenitor cell transplantation for haematological malignancies: a retrospective analysis of a 10-year single institution experience.

We retrospectively analysed the factors that influenced rate of haemopoietic recovery (HR) in 243 patients after transplantation with chemotherapy-mobilised autologous peripheral blood progenitor cells (PBPC). Approximately half the patients also received haemopoietic growth factors (HGF) for mobilisation. Conditioning for transplantation was with either chemotherapy alone or chemotherapy plus total body irradiation (TBI). Median time to recovery of granulocytes > or = 0.5 x 10(9)/l was 13 days (range 7-93 days) and of platelets > or = 50 x 10(9)/l 14 days (7-440). Speed of HR was greater, both for neutrophils and platelets for patients who received more rather than less CFU-GM than our median value of 18.9 x 10(4)/kg (P < 0.0001 in both instances) and more rather than less CD34-positive cells than our median value of 8.8 x 10(6)/kg (P < 0.0001 and P < 0.0005, respectively). For granulocyte recovery, in the multivariate analysis the dose of infused CFU-GM (P = 0.05) and the use of HGF for both mobilisation and post-transplantation (P < 0.0014) were significant positive factors. For platelet recovery in the multivariate analysis the dose of infused CFU-GM (P < 0.0016) was a positive factor. The use of busulphan and of TBI were significant adverse factors for rate of platelet recovery (P = 0.005 and 0.0004, respectively). When compared with non-HGF-mobilised PBPC, HGF-mobilised PBPC reduced the number of days of hospitalisation (28 vs 24, P = 0.0001) and of treatment with intravenous antibiotics (15 vs 11, P = 0.0004). These findings emphasise the importance of cell dose in accelerating haemopoietic recovery after autologous blood stem cell transplantation.