Febrile neutropenia and refeeding syndrome.

We describe the management of a 4-year-old child with acute lymphoblastic leukaemia (ALL) who presented with febrile neutropenia, Cryptosporidium and subsequently developed refeeding syndrome. Febrile neutropenia is common and can be life-threatening and we highlight the identification of well low-risk neutropenic children with resolved febrile illnesses suitable for early discharge. We also discuss the potential management strategies for Cryptosporidium Refeeding syndrome is not common, but should be considered as a cause of acute inpatient deterioration and is a significant risk, with potential morbidity, in children who have undergone a period of catabolism. This article reviews the current literature and provides useful guidance on these issues.

Lymphotoxin beta receptor signaling limits mucosal damage through driving IL-23 production by epithelial cells.

The immune mechanisms regulating epithelial cell repair after injury remain poorly defined. We demonstrate here that lymphotoxin beta receptor (LTßR) signaling in intestinal epithelial cells promotes self-repair after mucosal damage. Using a conditional gene-targeted approach, we demonstrate that LTßR signaling in intestinal epithelial cells is essential for epithelial interleukin-23 (IL-23) production and protection against epithelial injury. We further show that epithelial-derived IL-23 promotes mucosal wound healing by inducing the IL-22-mediated proliferation and survival of epithelial cells and mucus production. Additionally, we identified CD4(-)CCR6(+)T-bet(-) RAR-related orphan receptor gamma t (RORγt)(+) lymphoid tissue inducer cells as the main producers of protective IL-22 after epithelial damage. Thus, our results reveal a novel role for LTßR signaling in epithelial cells in the regulation of intestinal epithelial cell homeostasis to limit mucosal damage.

Progression of coronary artery calcification in asymptomatic individuals with pre-existing calcium score.

AIM: Coronary artery calcification (CAC) has been introduced as a reliable, non-invasive marker of atherosclerosis. In this retrospective study, we investigated the progression of CAC using electron beam computed tomography. METHODS: The study enrolled 598 individuals (521 males; mean age: 59.3±8.3 years) with initial CAC score (CACS) ≥10. The mean interscan period was 2.4±1.35 years (range: 1-7 years). The mean CACS, for the entire cohort, was 262.4±423.9 at baseline scan and 380.3±547.6 at follow-up. The mean annualized progression in CACS was 57.7±123.7; 47.4±66.5 in females and 58.3±128.1 in males (P=0.46). The mean annualized progression in CACS was 39.6±61.3 in individuals <60 years and 75.7±161.5 in individuals >60 years (P=0.0003). In multivariate analysis, only baseline CACS (P<0.0001) and smoking (P=0.002) were independently associated with the annual change in CACS.

Coping, meaning and symptom experience: a narrative approach to the overwhelming impacts of breast cancer in the first year following diagnosis.

PURPOSE: Women's experience of breast cancer treatment is a complex feature of survival which reflects and impacts upon the quality of their inter-personal relationships. We aimed to explore and present the issues and means through which these women relate their symptoms, treatments and effects. We utilised the 'cancer journey' as a heuristic device to chart women's experiences in the first year following diagnosis. METHOD: Thirty-nine interviews were conducted over one year with a convenience sample of 10 women newly diagnosed with breast cancer recruited from a specialist oncology centre in England in 2005. Transcriptions of the interviews were analysed using a thematic narrative approach. RESULTS: The findings suggested how women related coping and meaning to their experience of relationships, return to work, and self-management of breast cancer symptoms. The overwhelming impact of breast cancer was personal to each sufferer and yet reflects commonly reported treatment effects. These included unmet need for fatigue management, the impact of adaptation to hair loss and disfigurement, and the evident need for sexual health and relationship counselling. CONCLUSION: The multi-dimensional aspects of womens' relationships with family, friends, co-workers and care professionals impacts significantly on their coping strategies and how they make sense of their breast cancer experiences, which consequently bears upon symptom experience, and experience of survival. We suggest that narrative representation bears witness to the common and differing experiences of how women newly diagnosed with breast cancer cope with symptom experience and survival over time. Narrative representation of breast cancer is a useful pedagogical resource for supportive cancer care and highlights the needs of women that need to be addressed by health care professionals.

Management of obstetric anal sphincter injuries--a role for the colorectal surgeon.

AIM: To determine if surgical repair of third and fourth degree obstetric perineal tears by an experienced colorectal surgeon produces satisfactory functional results in the short and long term. METHOD: Consecutive deliveries were studied prospectively over a 32-month period. All patients with suspected third or fourth degree tears were referred to the colorectal team. Following confirmation of the injury, patients underwent surgical repair using a standard overlapped technique according to an established protocol. The patients were reviewed 2 months later. Long-term continence was determined, by postal and telephone follow up, after a minimum of 3 years. RESULTS: Fifty-nine sphincter injuries were identified and repaired by the colorectal team. Two months following repair 51 (86%) of patients had normal continence, four (7%) had urgency, and five (8%) had occasional incontinence of flatus. All patients with any degree of incontinence underwent endoanal ultrasound at which no sphincter defects were noted, and all improved symptomatically following pelvic floor physiotherapy. Long-term follow up data was obtained in 45 women. Thirty-nine (87%) had normal continence scores, 11 (24%) described urgency, but only three (7%) were often incontinent of liquid stool. Seven (15%) were occasionally incontinent of flatus. CONCLUSION: Excellent short and long-term functional results were obtained in the repair of third and fourth degree tears when performed by experienced colorectal surgeons. Since the protocol was established, obstetricians in North Cheshire have adopted the double overlapped technique, and now manage the majority of these injuries themselves.

Endoscopy waiting times and impact of the two week wait scheme on diagnosis and outcome of upper gastrointestinal cancer.

The NHS has introduced the two week wait scheme to detect upper gastrointestinal cancers at an early stage and improve survival rates The aim of this study was to assess the impact of this scheme and changes in endoscopy waiting times on tumour stage and resection rates over a four year period. Data were analysed prospectively for all patients diagnosed with oesophagogastric cancer between September 1998 and September 2002 and from those referred under the two week wait scheme since its introduction in 2000. Of those tumours diagnosed by this scheme (15%) only 5% were early disease (stage 1 or 2). Patients with early cancer, mainly diagnosed by routine gastroscopy, do not present with symptoms meeting the two week wait criteria. An increase in the resection rates for early disease will most probably be seen with a reduction in routine endoscopy waiting times.

Randomized clinical trials to determine the role of topical glyceryl trinitrate in peripheral intravenous nutrition.

BACKGROUND: The contribution of glyceryl trinitrate (GTN) to prevention of peripheral vein thrombophlebitis (PVT) during peripheral intravenous nutrition delivered by fine-bore midline intravenous catheter is unclear. The aim of this study was to establish its role. METHODS: Two consecutive randomized clinical trials were conducted. In trial 1 patients were randomized to receive standard peripheral intravenous nutrition containing heparin and hydrocortisone with or without the placement of a topical GTN patch (triple therapy or dual therapy). In trial 2 patients were randomized to receive standard peripheral intravenous nutrition with either dual therapy or topical GTN alone (monotherapy). RESULTS: Dual therapy was as effective as triple therapy in preventing PVT (incidence 10 of 37 versus 11 of 39 patients respectively). Dual therapy reduced the incidence and increased the time to onset of PVT compared with monotherapy (14 of 41 versus 22 of 35 patients respectively, P = 0.012; median 17.3 (95 per cent confidence interval (c.i.) 13.4 to 21.1) versus 8.9 (95 per cent c.i. 6.7 to 11.0) days, P = 0.007). CONCLUSION: Use of a topical GTN patch confers no benefit when peripheral intravenous nutrition is delivered via a fine-bore midline intravenous catheter.

The influence of early transplantation, age, GVHD prevention regimen, and other factors on outcome of allogeneic transplantation for CML following BuCy.

Results in 164 patients who underwent allogeneic marrow transplantation following busulfan and cyclophosphamide over a 15 year period were analyzed. Age (median 37, range 14-66 years) did not significantly affect the incidence of graft-versus-host disease (GVHD), but patients who received methotrexate with cyclosporine had a significantly lower incidence (P = 0.002) of chronic GVHD compared to those who received methylprednisolone with cyclosporine. Hepatic veno-occlusive disease (VOD) occurred less frequently in chronic phase patients (P = 0.002) and in those transplanted shortly after diagnosis (P = 0.001). Five year leukemia-free survival (LFS) for the entire group was 49% (95% CI 41-57%). For 102 patients who underwent transplantation in chronic phase, results were significantly improved by transplantation at a short interval following diagnosis, particularly within 3 months (P = 0.01), by the use of methotrexate and not corticosteroids for GVHD prevention (P = 0.03), and by use of HLA-identical sibling donors (P = 0.01). Age was not a significant adverse prognostic factor and transplantation was successfully performed in individuals up to age 66. Allogeneic transplantation in CML, including older patients and those with unrelated donors, can be most safely and effectively performed shortly after diagnosis.

Rapid onset retinopathy in a diabetic patient following bone marrow transplantation.

We report a 38-year-old man who presented in 1998 with advanced multiple myeloma and newly diagnosed diabetes mellitus (DM). Subsequent BMT has been successful after conditioning with melphalan and total body irradiation, but significant ischaemic retinopathy has developed. Chemotherapeutic agents, total body irradiation, and DM are likely to have been co-factors in precipitating the rapid onset of retinopathy. Routine ophthalmic surveillance is recommended for all patients after BMT, particularly for those with additional risk factors for the development of retinopathy such as DM.

Gemcitabine for relapsed or resistant lymphoma.

BACKGROUND: Gemcitabine therapy has not been widely assessed in the treatment of hematological malignancies. We have examined the efficacy and safety of gemcitabine in patients with relapsed or resistant lymphoma. PATIENTS AND METHODS: Gemcitabine (1 g/m2) was given weekly for 7 consecutive weeks, followed by a week off treatment. The drug was then given for 3 consecutive weeks, followed by a week off treatment; this regimen was continued until disease progression or drug intolerance. Fifteen patients have enrolled. Most have been extensively pre-treated for advanced diffuse large-cell or mantle-cell lymphoma. RESULTS: The drug was well tolerated; no patient suffered treatment-related sepsis, hemorrhage or death. Non-hematopoietic toxicity led to discontinuation of gemcitabine therapy in two patients. Dose reductions or delays were required for about two-thirds of treatments. Of 13 evaluable patients, one had a complete response, 3 a partial response, 3 stable disease, and 6 disease progression. After 6 infusions of gemcitabine, a patient with advanced Hodgkin's disease has had a complete remission lasting 21 months. CONCLUSIONS: Gemcitabine has substantial activity and acceptable toxicity in heavily pre-treated patients with advanced lymphoma. Further study is warranted.

Vacuum-assisted stereotactic breast biopsy: histologic underestimation of malignant lesions.

HYPOTHESIS: The histopathologic correlation between stereotactic core needle biopsy and subsequent surgical excision of mammographically detected nonpalpable breast abnormalities is improved with a larger-core (11-gauge) device. DESIGN: Retrospective medical record and histopathologic review. SETTING: University-based academic practice setting. PATIENTS: Two hundred one patients who underwent surgical excision of mammographic abnormalities that had undergone biopsy with an 11-gauge vacuum-assisted stereotactic core biopsy device. MAIN OUTCOME MEASURE: Correlation between stereotactic biopsy histologic results and the histologic results of subsequent surgical specimens. RESULTS: Results of stereotactic biopsy performed on 851 patients revealed atypical hyperplasia in 46 lesions, ductal carcinoma in situ (DCIS) in 89 lesions, and invasive cancer in 73 mammographic abnormalities. Subsequent surgical excision of the 46 atypical lesions revealed 2 cases of DCIS (4.3%) and 4 cases of invasive carcinoma (8.7%). Lesions diagnosed as DCIS on stereotactic biopsy proved to be invasive carcinoma in 10 (11.2%) of 89 patients on subsequent excision. Stereotactic biopsy completely removed 21 (23.6%) of 89 DCIS lesions and 20 (27.4%) of 73 invasive carcinomas. CONCLUSIONS: In summary, 11-gauge vacuum-assisted core breast biopsy accurately predicts the degree of disease in the majority of malignant lesions; however, understaging still occurs in 11% to 13% of lesions showing atypical hyperplasia or DCIS.

Autotransplantation following busulfan, etoposide and cyclophosphamide in patients with non-Hodgkin's lymphoma.

The purpose of the study was to determine the toxicities and effectiveness of a novel preparative regimen of busulfan (Bu) 14 mg/kg, etoposide 50 or 60 mg/kg, and cyclophosphamide (Cy) 120 mg/kg in non-Hodgkin's lymphoma (NHL) and to analyze results using doses based on different body weight parameters and the two different etoposide doses. Three hundred and eighty-two patients aged 16 to 72 underwent first autologous transplantation with mobilized peripheral blood progenitor cells between August 1992 and December 1998 at either of two transplant centers. Mucositis was the most common toxicity. Hepatic toxicity was the most common life-threatening toxicity; severe hepatic VOD occurred in 11 patients (2.9%). Ten patients (2.6%) died from treatment-related toxicity. The 3-year progression-free survival (PFS) for the entire group was 46.9% (95% CI, 40.5-53.3%). Elevated LDH, resistance to chemotherapy, and intermediate/aggressive histology were significant adverse prognostic factors. For patients in sensitive first relapse PFS was 47.0% (95% CI, 37-57%). Neither etoposide dose nor body weight parameter utilized significantly affected outcome. In conclusion, the novel preparative regimen of Bu, etoposide and Cy results in a low incidence of treatment-related mortality and is effective in the treatment of patients with NHL. Bone Marrow Transplantation (2000) 25, 1243-1248.

Interstitial pneumonitis following mitozantrone, chlorambucil and prednisolone (MCP) chemotherapy.

We describe two cases of interstitial lung disease in patients with non-Hodgkin's lymphoma who were treated with combination chemotherapy including mitozantrone. In both we had radiological and histological evidence of interstitial lung disease, with patterns of organizing pneumonia and hypersensitivity without a clear aetiological agent. Clinical resolution occurred on withdrawal of chemotherapy. One patient required a course of corticosteroid treatment. To date, both patients are well and in remission, and there has been no recurrence of their respiratory disease. We postulate that these observations are hitherto undescribed pulmonary abnormalities secondary to mitozantrone therapy.

Pharmacokinetic study of single doses of oral fludarabine phosphate in patients with "low-grade" non-Hodgkin's lymphoma and B-cell chronic lymphocytic leukemia.

PURPOSE: Fludarabine phosphate (F-AMP), a purine analog, requires daily intravenous administration. A pharmacokinetic study of an oral formulation (10 mg immediate-release tablet) was undertaken in patients with "low-grade" non-Hodgkin's lymphoma and B-cell chronic lymphocytic leukemia. PATIENTS AND METHODS: Oral F-AMP was incorporated into the "conventional" treatment schedule. Single oral trial doses of 50, 70, and 90 mg of F-AMP were given on the first day of three cycles of treatment; a comparative 50-mg intravenous trial dose was given on the first day of the fourth cycle. Intravenous F-AMP (25 mg/m2) was given on days 2 to 5 at 4-week intervals. Pharmacokinetic samples taken after each trial dose were analyzed for plasma 2-fluoro-arabinofuranosyladenine (2F-ara-A) concentration (its main metabolite); area under the curve 0 to 24 hours (AUC(0-24h)) and maximum concentration (Cmax) were calculated. Eighteen patients received all three oral trial doses, and bioavailability was determined in 15 patients who completed four courses of therapy. RESULTS: Oral administration of F-AMP resulted in a dose-dependent increase in Cmax and AUC(0-24h) of 2F-ara-A and achieved an AUC(0-24h) similar to intravenous administration, although at a lower Cm. The linear increase in mean AUC(0-24h) by factors of 1.36 +/- 0.22 (mean +/- SD) and 1.72 +/- 0.31 corresponded well with the increase in oral dose from 50 to 70 mg (factor of 1.4) and 90 mg (factor of 1.8), respectively. Bioavailability (approximately 55%, with low intraindividual variation) and time to Cmax were dose independent. CONCLUSION: Oral doses of F-AMP can achieve an AUC(0-24h) of 2F-ara-A similar to intravenous administration, with dose-independent bioavailability. The tablet will greatly enhance the use of F-AMP in a palliative setting.

Combination therapy with fludarabine and cyclophosphamide as salvage treatment in lymphoproliferative disorders.

Seventeen patients (aged 50-85 years) with relapsed or refractory non-Hodgkin's lymphoma (NHL, 10 patients) or chronic lymphocytic leukaemia (CLL, seven patients) were treated with a combination of fludarabine 25 mg/m2/d and cyclophosphamide 250 mg/m2/d for 3 d repeated every 4 weeks. 12 patients had previously received purine analogue therapy of which four had progressive disease during treatment. The overall response rate of patients with CLL was 71% (28% CR, 43% PR) and for NHL was 50% (0% CR, 50% PR). Toxicity consisted of nausea and vomiting which was maximal in the 3 d after therapy, infections and haematological suppression which was prolonged in some patients. This combination, which is based on a rational prediction of synergistic activity, is highly effective but associated with significant problems with tolerance.

Relationship of endotoxin to tumor necrosis factor-alpha and interleukin-1 beta in children with otitis media with effusion.

Sixty-five middle ear effusions and paired sera from 41 children with chronic otitis media with effusion were assayed for endotoxin and for tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) in order to establish whether a correlation exists between the concentrations of endotoxin and of these cytokines. Endotoxin concentration was determined by means of a chromogenic limulus amebocyte lysate assay, and the cytokine concentration by means of a quantitative enzyme-linked immunosorbent assay. Forty percent of the effusions had detectable levels of endotoxin, with a mean concentration of 2.9 +/- 7.8 endotoxin units per milligram of total protein. The mean concentration of TNF-alpha was 1.24 +/- 3.1 pg/mg total protein, and that of IL-1 beta was 18.79 pg/mg total protein. A strong, statistically significant correlation exists between the concentrations of endotoxin and TNF-alpha (r = .89) and IL-1 beta (r = .72). The data indicate that endotoxin may contribute to the pathogenesis of chronic otitis media with effusion by stimulating the sustained production of TNF-alpha and IL-1 beta in the middle ear.

Vinorelbine in the treatment of lymphoma.

Seventeen patients with previously treated Hodgkin's disease or non-Hodgkin's lymphoma (NHL) were treated with single-agent vinorelbine (Navelbine Pierre-Fabre Medicament) in an open study to assess the activity of this new-generation vinca alkaloid. Responses were obtained in four out of eight patients with Hodgkin's disease and four out of nine patients with NHL, including four patients who had been previously treated with high-dose therapies. Toxicity was very mild. The study demonstrates worthwhile activity and justifies the inclusion of vinorelbine in combination therapies for lymphoma.

Early evaluation of liposomal daunorubicin (DaunoXome, Nexstar) in the treatment of relapsed and refractory lymphoma.

We have treated 19 patients with relapsed or refractory lymphoma with liposomally encapsulated daunorubicin (DaunoXome) at two dose schedules; 40 mg/m2 repeated every 14 days and 120 mg/m2 repeated every 21 days. Non-haematological toxicity was mild, in particular, no patient treated with the higher dose schedule showed clinical deterioration in cardiac function. At the lower dose (10 patients) no objective responses were seen but at the higher dose (9 patients) one complete response and two partial responses were achieved. Liposomal daunorubicin at 120 mg/m2 appears to have some activity against refractory lymphoma and we suggest that further studies with this agent are required.