The finer points of writing and refereeing scientific articles.

Writing scientific papers is a skill required by all haematologists. Many also need to be able to referee papers submitted to journals. These skills are not often formally taught and as a result may not be done well. We have reviewed published evidence of errors in these processes. Such errors may be ethical, scientific or linguistic, or may result from a lack of understanding of the processes. The objective of the review is, by highlighting errors, to help writers and referees to avoid them.

NCRI phase II study of CHOP in combination with ofatumumab in induction and maintenance in newly diagnosed Richter syndrome.

Richter syndrome (RS) is associated with chemotherapy resistance and a poor historical median overall survival (OS) of 8-10 months. We conducted a phase II trial of standard CHOP-21 (cyclophosphamide, doxorubicin, vincristine, prednisolone every 21 d) with ofatumumab induction (Cycle 1: 300 mg day 1, 1000 mg day 8, 1000 mg day 15; Cycles 2-6: 1000 mg day 1) (CHOP-O) followed by 12 months ofatumumab maintenance (1000 mg given 8-weekly for up to six cycles). Forty-three patients were recruited of whom 37 were evaluable. Seventy-three per cent were aged >60 years. Over half of the patients received a fludarabine and cyclophosphamide-based regimen as prior CLL treatment. The overall response rate was 46% (complete response 27%, partial response 19%) at six cycles. The median progression-free survival was 6·2 months (95% confidence interval [CI] 4·9-14·0 months) and median OS was 11·4 months (95% CI 6·4-25·6 months). Treatment-naïve and TP53-intact patients had improved outcomes. Fifteen episodes of neutropenic fever and 46 non-neutropenic infections were observed. There were no treatment-related deaths. Seven patients received platinum-containing salvage at progression, with only one patient obtaining an adequate response to proceed to allogeneic transplantation. CHOP-O with ofatumumab maintenance provides minimal benefit beyond CHOP plus rutuximab. Standard immunochemotherapy for RS remains wholly inadequate for unselected RS. Multinational trials incorporating novel agents are urgently needed.

The signs, symptoms and help-seeking experiences of neutropenic sepsis patients before they reach hospital: a qualitative study.

PURPOSE: Neutropenic sepsis (NS) is a medical emergency in which urgent treatment with antibiotics is known to improve outcomes, yet there are minimal data about what happens to patients with NS before they reach hospital. We aimed to examine the pre-hospital experiences of patients with NS, identifying its early presenting features and exploring the factors potentially delaying patients' arrival at hospital. METHODS: We conducted in-depth, qualitative interviews with 22 cancer patients admitted to hospital for treatment of NS and 10 patient carers. The setting was a tertiary referral centre in Southern England. RESULTS: Thirty seven percent of patients took over 12 h to present to hospital after symptom onset. The mean delay in presentation was 11 h (range 0-68 h). Thematic analysis of the interviews, using grounded theory, revealed wide-ranging, potentially modifiable factors delaying patients' presentation to hospital. For example, information provided to patients about NS from different sources was inconsistent, with 'mixed messages' about urgency triggering delays. All patients self-monitored their temperature and understood the implication of a fever but few appreciated the potential significance of feeling unwell in the absence of fever. Attempts to obtain treatment were sometimes thwarted by nonspecialists' failure to recognise possible neutropenia in a patient with apparently mild signs, and several patients with NS were discharged without treatment. Some patients denied their symptoms to themselves and others to avoid hospital admission; palliative patients seemed particularly prone to these attitudes, while their carers were keen to seek medical attention. CONCLUSIONS: This investigation of patients' and carers' experiences of NS identifies numerous strategies for improving patient education, support and pre-hospital management, all of which may reduce pre-hospital delays and consequently decrease morbidity and mortality from NS.

Improving the immediate management of neutropenic sepsis in the UK: lessons from a national audit.

Recent disquiet at inadequacies in the immediate management of neutropenic sepsis in the UK led to a new, gold standard 'door-to-needle' time of 1 h for the administration of intravenous antibiotics. The aim of this audit was to identify whether that target is being met nationally, the potential barriers to its achievement, and concrete recommendations for how to overcome these. We also sought to establish the degree of regional heterogeneity in current local management protocols. Questionnaires were sent to haematologists across the UK to determine their unit's immediate management of patients presenting from the community with possible neutropenic sepsis. Local protocols and audits were also requested. Data covering 95 different hospitals were received, covering a combined catchment area of nearly 30 million people. There were marked regional inconsistencies in the definition of 'neutropenic sepsis' and almost every aspect of its immediate management. Only 26% of audited patients (n=627) received intravenous antibiotics within the target time of 1 h. Median door-to-needle times ranged from 30 min to 4 h. Long delays of over 5 h were not uncommon.

Management options for cancer therapy-related anaemia.

Anaemia is common in patients with haematological malignancy, occurring in the majority of patients with malignant disease who are treated with chemotherapy. Most patients will have their anaemia attributed to the cytokine-mediated anaemia of chronic disease. Many of these patients with anaemia will be symptomatic with fatigue, which is the single most important symptom reported. Data from many studies indicate that treatment of patients with anaemia with recombinant human erythropoietin (rHuEpo) will increase their haemoglobin level, decrease transfusion need and also improve their quality of life. Recent clinical and experimental work suggest that improving the haemoglobin level may improve the patients' prognosis but this finding needs to be confirmed. Treatment of anaemia with rHuEpo in patients with cancer may produce many benefits. Unfortunately, rHuEpo is effective in only around 60% of patients, is slow acting and is expensive. These drawbacks have restricted its use in many healthcare systems. However, a failure to treat anaemia may have important adverse effects for the patient both in terms of their quality of life and, just possibly, in terms of their life expectancy.

Erythropoiesis-stimulating agents for anemic patients with cancer.

Anemia in cancer patients is common and often associated with decreased survival and quality-of-life scores. The introduction of erythropoiesis-stimulating agents (ESAs) for the treatment of anemia in patients with solid tumors and nonmyeloid malignancies in the 1990s has proved an important alternative to red blood cell transfusions. ESAs have been consistently shown to increase hemoglobin levels and reduce transfusion requirements in anemic cancer patients whilst also being associated with improvements in quality of life. Several recent studies, however, have raised concerns about the safety of ESAs with regards to an increased number of thrombo-embolic events, decreased on-study survival and possible effects of ESAs on tumor progression. This has led to a reappraisal of the role of ESAs in the treatment of anemic cancer patients. It remains generally accepted that, if used within current guidelines and labeling recommendations, ESAs can still be considered safe in patients receiving chemotherapy once individual risks are balanced against possible benefits.

The role of the iron transporter ABCB7 in refractory anemia with ring sideroblasts.

Refractory Anemia with Ring Sideroblasts (RARS) is an acquired myelodysplastic syndrome (MDS) characterized by an excess iron accumulation in the mitochondria of erythroblasts. The pathogenesis of RARS and the cause of this unusual pattern of iron deposition remain unknown. We considered that the inherited X-linked sideroblastic anemia with ataxia (XLSA/A) might be informative for the acquired disorder, RARS. XLSA/A is caused by partial inactivating mutations of the ABCB7 ATP-binding cassette transporter gene, which functions to enable transport of iron from the mitochondria to the cytoplasm. Furthermore, ABCB7 gene silencing in HeLa cells causes an accumulation of iron in the mitochondria. We have studied the role of ABCB7 in RARS by DNA sequencing, methylation studies, and gene expression studies in primary CD34(+) cells and in cultured erythroblasts. The DNA sequence of the ABCB7 gene is normal in patients with RARS. We have investigated ABCB7 gene expression levels in the CD34(+) cells of 122 MDS cases, comprising 35 patients with refractory anemia (RA), 33 patients with RARS and 54 patients with RA with excess blasts (RAEB), and in the CD34(+) cells of 16 healthy controls. We found that the expression levels of ABCB7 are significantly lower in the RARS group. RARS is thus characterized by lower levels of ABCB7 gene expression in comparison to other MDS subtypes. Moreover, we find a strong relationship between increasing percentage of bone marrow ring sideroblasts and decreasing ABCB7 gene expression levels. Erythroblast cell cultures confirm the low levels of ABCB7 gene expression levels in RARS. These data provide an important link between inherited and acquired forms of sideroblastic anemia and indicate that ABCB7 is a strong candidate gene for RARS.

Low expression of the putative tumour suppressor gene gravin in chronic myeloid leukaemia, myelodysplastic syndromes and acute myeloid leukaemia.

The putative tumour suppressor gene gravin is down-regulated in several solid tumours and is implicated in tumorigenesis. We have evaluated the expression levels of the gravin gene in the CD34(+)/blast cells of a range of myeloid malignancies as compared with controls using real-time quantitative polymerase chain reaction (PCR). Gravin was markedly down-regulated in 41 of 41 patients with acute myeloid leukaemia (AML), nine of 10 patients with myelodysplastic syndromes (MDS) and 33 of 33 patients with chronic myeloid leukaemia (CML), of whom 24 were in blast crisis (BC). We have shown that gravin is consistently down-regulated in the CD34(+)/blast cells of myeloid malignancies and may play a role in the molecular pathogenesis of these disorders.