Gender differences in the anatomy of the distal femur.

Recently, gender-specific designs of total knee replacement have been developed to accommodate anatomical differences between males and females. We examined a group of male and female distal femora matched for age and height, to determine if there was a difference in the aspect ratio (mediolateral distance versus anteroposterior distance) and the height of the anterior flange between the genders. The Hamann-Todd Collection provided 1207 skeletally mature cadaver femora. The femoral length, the anteroposterior height, height of the lateral and medial flanges and the mediolateral width were measured in all the specimens. The mechanical axis of the femur, the cut articular width and the aspect ratio were assessed. Statistical analysis of the effect of gender upon the aspect ratio and the lateral and medial flanges was undertaken, controlling for age, height and race. The mean aspect ratio of male femora was 1.21 (SD 0.07) and of female femora it was 1.16 (SD 0.06) (p < 0.001). There was no significant difference between male and female specimens in the mean size of the lateral flange (6.57 mm (SD 2.57) and 7.02 mm (SD 2.36), respectively; p = 0.099) or of the medial flange (3.03 mm (SD 2.47) and 3.56 mm (SD 2.32), respectively; p = 0.67). Future work in the design of knee prostheses should take into account the overall variability of the anatomy of the distal femur.

Donor CD31 genotype and its association with acute graft-versus-host disease in HLA identical sibling stem cell transplantation.

CD31 gene polymorphisms are implicated in the pathogenesis of graft-versus-host disease (GvHD) following haematopoietic stem cell transplantation (HST). We investigated the influence of CD31 genotype on the incidence of GvHD following HST from an human leukocyte antigen (HLA)-identical sibling donor. Donor and recipient CD31 codons 125, 563 and 670 DNA polymorphisms were determined in 85 cases of HLA identical sibling HST from two transplant centres. A correlation between CD31 genotype and acute GvHD was considered significant if observed in patients from both transplant centres independently. A strong correlation was identified between donor CD31 codon 125 genotype and the incidence of acute GvHD. Acute GvHD grades II-IV occurred in 27 of 46 (59%) recipients with a CD31 codon 125 leucine / valine heterozygous donor compared to nine of 39 (23%) recipients with a CD31 codon 125 homozygous donor (P=0.0019, relative-risk 2.45, 95% confidence interval 1.3-4.5). This correlation was significant in patients from both transplant centres (P=0.015 and P=0.019). We suggest that CD31 genotype may influence the function of donor-derived leukocytes and may be informative when there is a choice of comparable donors.

Primary central nervous system lymphoma: a single-centre experience of 55 unselected cases.

AIMS: Current treatment for primary central nervous system lymphoma (PCNSL) involves high-dose methotrexate (HDMTX) with or without radiotherapy. Many published studies describing this approach include a highly selected group of patients. We report a single-centre experience of unselected cases of PCNSL. MATERIALS AND METHODS: We retrospectively reviewed the case notes of 55 consecutive patients diagnosed with biopsy-proven PCNSL between 1995 and 2003 at Addenbrooke's Hospital Cambridge, UK. We describe the treatment and outcome, including survival, treatment-related toxicity and long-term functional disability. RESULTS: At diagnosis, 45% of patients were considered unfit to receive treatment with HDMTX, owing to poor performance status or comorbidity. These patients had a median survival of 46 days and may not have been included in other published studies. The remaining patients were treated with a chemotherapy regimen, which included HDMTX. Patients who received at least one cycle of a chemotherapy containing HDMTX had a median survival of 31 months. Forty per cent did not complete planned chemotherapy owing to toxicity, disease progression or death. The median survival of patients treated with HDMTX aged 60 years compared with patients aged under 60 years was 26 months vs 41 months (P = 0.07), respectively. Younger patients treated with HDMTX, who achieved complete remission with chemotherapy, had a median survival of 56 months. We identified a high incidence of functional disability among survivors, resulting from a combination of the tumour itself, the neurosurgical procedure required for diagnosis and the late neurotoxicity of combined chemoradiotherapy. CONCLUSION: The treatment of PCNSL is associated with significant early and late toxicity. Further attempts to improve treatment should address mechanisms to reduce this toxicity. In particular, the benefit of radiotherapy in patients who achieve complete remission with HDMTX will remain uncertain until it is addressed in a multicentre, randomised trial.

Efficacy and safety of oral fludarabine phosphate in previously untreated patients with chronic lymphocytic leukemia.

PURPOSE: A prospective, multicenter, open-label, phase II clinical trial to assess oral fludarabine phosphate treatment in terms of safety, efficacy, and quality of life. Reference to a historical group of patients treated with the intravenous (IV) formulation allowed the two formulations to be compared. PATIENTS AND METHODS: Patients with previously untreated B-cell chronic lymphocytic leukemia received 10-mg tablets of fludarabine phosphate to a dose of 40 mg/m(2)/d for 5 days, repeated every 4 weeks, for a total of six to eight cycles. Efficacy was assessed using International Workshop on Chronic Lymphocytic Leukemia and National Cancer Institute criteria for response. Safety monitoring included WHO toxicity grading for adverse events. Quality of life was also assessed. RESULTS: Eighty-one patients received treatment. According to International Workshop on Chronic Lymphocytic Leukemia criteria, the overall response rate was 71.6% (complete remission, 37.0%; partial remission, 34.6%). The response rate using National Cancer Institute criteria was 80.2% (complete remission, 12.3%; partial remission, 67.9%). Median time to progression was 841 days (range, 28 to 1,146 days). The most frequently reported grade 3/4 toxicity was myelosuppression. WHO grade 3/4 hematological toxicities included granulocytopenia (32.1%), anemia (9.9%), and thrombocytopenia (4.9%). Gastrointestinal toxicity was more common with the oral formulation than with IV fludarabine phosphate, but was generally mild to moderate and did not require treatment. Statistically significant improvements in mean emotional and insomnia quality-of-life scores were seen after treatment. CONCLUSION: This study demonstrates that oral fludarabine phosphate is clinically effective and generally well tolerated by patients with previously untreated B-cell chronic lymphocytic leukemia. Oral fludarabine phosphate has a similar clinical efficacy and safety profile to the IV formulation. Oral fludarabine phosphate does not adversely affect quality of life and may improve emotional and insomnia scores.

Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial.

BACKGROUND: Neither chemotherapy with a single-alkylating agent nor aggressive combination chemotherapy cures advanced stage low-grade non-Hodgkin lymphomas, even when combined with radiotherapy. Our aim was to compare administration of immediate chlorambucil treatment with a policy of delaying chlorambucil until clinical progression necessitated its use, in asymptomatic patients with advanced-stage, low-grade non-Hodgkin lymphoma. METHODS: 309 patients with asymptomatic, advanced-stage, low-grade non-Hodgkin lymphomas were recruited from 44 UK centres between Feb 1, 1981, and July 31, 1990. 158 patients were randomised to receive immediate systemic therapy with oral chlorambucil 10 mg per day continuously. The remaining 151 were randomised to an initial policy of observation, with systemic therapy delayed until disease progression. In both groups, local radiotherapy to symptomatic nodes was allowed. FINDINGS: Median length of follow-up was 16 years. Overall survival or cause-specific survival did not differ between the two groups (median overall survival for oral chlorambucil 5.9 [range 0-17.8] years and for observation 6.7 [0.5-18.9] years, p=0.84; median cause-specific survival 9 [0-17.8] years and 9.1 [0.67-18.9] years, respectively p=0.44). In a multivariate analysis, age younger than 60 years, erythrocyte sedimentation rate (ESR) 20 mm/h or less, and stage III disease, conferred significant advantages in both overall survival (p<0.0001, 0.03, and 0.03, respectively) and cause-specific survival (p=0.002, 0.008, and 0.001, respectively). In the observation group, at 10 years' follow-up, 19 patients were alive and had not received chemotherapy. The actuarial chance of not needing chemotherapy (non-lymphoma deaths censored) at 10 years was 19% (40% if older than 70 years). INTERPRETATION: An initial policy of watchful waiting in patients with asymptomatic, advanced stage low-grade non-Hodgkin lymphoma is appropriate, especially in patients older than age 70 years.

Stem cell transplantation after salvage therapy with high-dose cytarabine and amsacrine in adults with high-risk leukaemia.

Stem cell transplantation (SCT) may be the only curative option for patients with relapsed or refractory leukaemia, that is, high-risk (HR) leukaemia. Several salvage regimens have been used to cytoreduce disease before SCT, but disease progression or treatment toxicity limits numbers of patients receiving SCT. Here, we report our experience with high-dose cytarabine and amsacrine (Ara-amsa) to salvage patients with HR-leukaemia in the context of SCT. A total of 34 patients with HR-leukaemia (20 AML, 12 ALL, two advanced CML) received 3 g/m(2)/day cytarabine for 5 days and amsacrine 200 mg/m(2)/day for 3 days. Disease response was observed in 62% of patients. Toxicity was limited to neutropenic fever, one patient developed cerebellar toxicity and there was one treatment-related death. A total of 17 patients proceeded to SCT (12 allografts and five autografts). Median survival (OS) of all patients was 10.8 months (95% CI 7.8-21). Patients who were consolidated with SCT after salvage therapy had a superior median OS of 29.4 months (95% CI 12.5-upper limit not reached, n=17) than those who did not receive SCT (6.7 months, CI 1.5-8.6, P<0.0001). Median disease-free survival with SCT (23 months) was higher than after treatment with salvage chemotherapy alone (6.7 months, P=0.0002). Thus Ara-amsa can be used effectively to salvage HR-leukaemia, enabling further consolidation with SCT.

Total body irradiation using a modified standing technique: a single institution 7 year experience.

We describe a simple standing technique for delivering total body irradiation (TBI) using large horizontal fields, made possible by the off-centre installation of a non-dedicated treatment unit in a pre-existing bunker. Patients are treated using anterior and posterior fields with customized lung compensators. This technique enables the dose to the lung to be accurately calculated and modified to avoid overdose and to minimize the risk of pneumonitis. From February 1991 to December 1997, 94 patients with a variety of haematological malignancies were given fractionated TBI using this technique prior to allogenic or autologous bone marrow transplantation. Patients received a total dose of 14.4 Gy given in eight fractions over 4 days, with at least 6 h between fractions. The prescribed dose to the lungs was reduced to 12 Gy in eight fractions. The technique was well tolerated, took less than 10 min to set up and did not disrupt the daily routine use of the machine. Doses to all measured points on the trunk and head were within +/-6% of the prescribed dose. Doses to the lungs were within +/-5% of the prescribed dose. There were no early respiratory deaths in the 37 autologous transplant patients. There were 10 (17%) respiratory deaths in the 57 allogeneic transplant patients, 3 of confirmed infectious aetiology.

Large-cell lymphoma. An unusual late relapse.

We report a case of a 40-year-old man with a stage 4, anaplastic, large-cell lymphoma. He had been diagnosed 13 years before as having a liposarcoma, at which point he was treated with combination chemotherapy, which included anthracycline. On review of the histopathology from 13 years before, the original diagnosis of liposarcoma was revised to that of an anaplastic large-cell lymphoma. A diagnosis of relapsed anaplastic large-cell lymphoma was made. A MUGA scan showed a reduced ejection fraction of 46%. Our patient responded initially to combination chemotherapy, which included anthracycline, without further reduction in his ejection fraction. This was followed by high-dose chemotherapy and peripheral blood stem-cell transplantation. Twenty months later he is well and remains in complete remission.

Age-based outcomes of cheilectomy for the treatment of hallux rigidus.

The results of cheilectomy, performed on 67 consecutive patients with hallux rigidus resulting in primary extraarticular symptoms are presented. Four patients who underwent subsequent fusion were rated as failures. Follow-up evaluation, averaging 65 months (28-117) on 53 additional patients available for follow-up, revealed an average AOFAS score of 80. with 91% of the patients stating that they were currently better than before surgery. There was a statistically significant higher mean score (89) in patients over 60 years of age at the time of surgery. There were no differences between other age groups, preoperative grade, duration of symptoms, or length of follow-up. Cheilectomy should be the treatment of choice for hallux rigidus with predominantly extra-articular symptoms, especially in patients over 60 years of age.

Antibody responses to vaccinations given within the first two years after transplant are similar between autologous peripheral blood stem cell and bone marrow transplant recipients.

As a consequence of the significantly larger inoculum of lymphoid cells present in peripheral blood stem cell (PBSC) harvests compared to bone marrow (BM), it is possible that autoPBSCT recipients may have an earlier and*or enhanced response to vaccines. Until data to confirm this become available, the European Blood and Marrow Transplantation Association (EBMT) recommend that all transplant recipients be immunized in the same way regardless of stem cell source. We performed a prospective study comparing serological responses to influenza, pneumococcal polysaccharide and tetanus toxoid vaccines between autoPBSCT with autoBMT recipients. Antibody responses in sibling HLA-matched allogeneic BMT (alloBMT) survivors were also evaluated. All vaccines were administered within the first 2 years after stem cell transplantation. Fifty patients were enrolled. The time of vaccination after transplant was similar between autoPBSCT (mean 11 months for each vaccine) and autoBMT recipients (mean 12 months except 13 months for tetanus toxoid) (P = NS). Serological responses were poor and no significant difference in response to any of the vaccines used was seen between the three transplant cohorts. We provide no evidence that current EBMT guidelines be modified. Large prospective vaccine studies are needed to address the issue more fully.

Comparison of three PCR techniques for detecting cytomegalovirus (CMV) DNA in serum, detection of early antigen fluorescent foci and culture for the diagnosis of CMV infection.

Three PCR assays were developed for detection of cytomegalovirus (CMV) DNA in serum and were evaluated with samples from organ transplant recipients. The Qiamp Blood Kit was efficient for extraction of DNA from sera. Single-round PCR of a 293-bp region of CMV DNA was sensitive and highly specific for CMV targets and was more sensitive than detection of early antigen fluorescent foci (DEAFF) testing or isolation of CMV from buffy coat by cell culture. The results of a significant proportion of buffy coat samples were not interpretable because of toxicity in conventional culture or DEAFF tests. A non-competitive quantitative PCR test and semi-quantitative PCR test for the detection of CMV DNA in serum yielded comparable results for samples taken serially from three bone marrow transplant recipients. Single-round PCR was superior to conventional techniques for the diagnosis of CMV infection, was simple to perform and was completed rapidly. The semi-quantitative technique has added advantages where quantification is important.

The minimum CD34 threshold depends on prior chemotherapy in autologous peripheral blood stem cell recipients.

We analysed 57 patients with non-myeloid malignancies who received a non-purged autologous PBSCT. All had similar mobilisation and conditioning regimens. A high prior chemotherapy score and the number of chemotherapy lines used (P = 0.015 and P = 0.01, respectively) were adverse predictors of CD34 cell yields. Lower CD34 values (P = 0.002) were seen in patients treated with potent stem cell toxins (BCNU, melphalan, CCNU and mustine), designated toxicity factor 4 agents (TF4). All patients infused with grafts containing CD34 cell doses between 1.0 and 2.0 x 10(6)/kg (range 1.25-1.90) engrafted by day 51. The only variable associated with slow platelet recovery was exposure to TF4 (P = 0.007). The majority of patients with CD34 >1.0 x 10(6)/kg achieved rapid and sustained engraftment and the only predictive factor of delayed recovery is prior exposure to stem cell toxins. Potential PBSCT candidates should if possible avoid first line and salvage chemotherapy containing TF4 drugs. We therefore advocate a minimum CD34 threshold of >1.0 x 10(6)/kg in patients without extensive prior chemoradiotherapy, and > or = 2.0 x 10(6)/kg in all other patients.

Erythropoiesis in patients stimulated with erythropoietin: the relevance of storage iron.

BACKGROUND AND OBJECTIVES: The clinical importance of iron-restricted erythropoiesis in erythropoietin (EPO)-stimulated patients is controversial. MATERIALS AND METHODS: We therefore reviewed 70 patients randomized into clinical trials of aggressive autologous donation and oral iron supplementation, with or without recombinant human EPO therapy. RESULTS: Nineteen (27%) iron-depleted patients produced 5.4+/-2.8 ml RBC/kg compared to 4.8+/-2.3 ml RBC/kg (nonsignificant) in iron-replete patients due to endogenous EPO (placebo group) stimulation. EPO-treated iron-depleted patients produced 20% less RBC than iron-replete patients (8.23+/-3.3 vs. 10. 2+/-4.0, p = 0.066). RBC volume expansion correlated with initial storage iron only in iron-replete patients who received EPO therapy. CONCLUSION: Initial storage iron status is a marginally important limitation to EPO-mediated erythropoiesis in the setting of oral iron supplementation. Strategies to maintain plasma transferrin saturation with intravenous iron therapy may be desirable to improve the erythropoietic response to EPO in this setting.

A trend towards an increased incidence of chronic graft-versus-host disease following allogeneic peripheral blood progenitor cell transplantation: a case controlled study.

Allogeneic peripheral blood progenitor cell transplantation (alloPBPCT) is increasingly used as an alternative to bone marrow transplantation (alloBMT). Early data suggest that the incidence and severity of acute graft-versus-host disease (GVHD) following alloPBPCT is no higher than that seen with alloBMT, despite the increased number of cytotoxic T cells infused with mobilised blood. We compared 12 patients undergoing alloPBPCT with 12 well-matched alloBMT controls. All patients received identical GVHD prophylaxis. No T cell depletion or CD34 purification was performed. Median engraftment times for neutrophils >0.5 x 10(9)/l and platelets >20 x 10(9)/l were 14 and 12 (alloPBPCT) and 21 and 23 days (alloBMT), respectively (P = 0.0035 and P = 0.002). There was no difference in antibiotic requirements (P = 0.83), platelet support (P = 0.59) or days in hospital (P = 0.51). After alloPBPCT, five patients developed > or =grade II acute GVHD vs five patients after alloBMT (P = 0.99). There was one death (alloBMT) at 100 days and three at 1 year (all due to relapse). There was one death at 100 days with alloPBPCT, and 11 patients remain alive (range 9-21 months) to date. Chronic GVHD occurred in five patients in the PBPC arm and one patient in the BM arm (P = 0.14). This case-controlled analysis indicates that alloPBPCT results in more rapid engraftment kinetics but in no significant difference in transplant-related morbidity or mortality. There is no difference in the incidence of acute GVHD. However, there is a trend towards increased incidence of chronic GVHD in patients allografted with PBPC. Prospective randomised trials are required to determine further the role of alloPBPCT.

Two cases of fatal bleomycin pneumonitis complicating the treatment of non-Hodgkin's lymphoma.

We present two cases of fatal bleomycin pneumonitis complicating the treatment of non-Hodgkin's lymphoma. Pneumonitis is a well recognized side effect of this drug, but occurs at low doses in the treatment of NHL. Early intervention with high dose corticosteroids may be curative, indicating that clinicians should have a low threshold for investigation and treatment.

Achievement of complete cytogenetic remission after two very low-dose donor leucocyte infusions in a patient with extensive cGVHD relapsing in accelerated phase post allogeneic BMT for CML.

We report the case of a 55-year-old female who despite having developed extensive chronic graft-versus-host disease (GVHD), relapsed 35 months after a T cell-replete sibling donor bone marrow transplant for Philadelphia-positive chronic myeloid leukaemia (Ph CML). She achieved complete cytogenetic remission after discontinuation of cyclosporin A and administration of two low-dose donor leucocyte infusions (DLI 1 x 10(6) and 5 x 10(6) CD3+ cells/kg). Eighteen months after the first infusion she remains well and in complete cytogenetic remission with a normocellular marrow and no exacerbation of GVHD.

The erythropoietic response to erythropoietin in patients with rheumatoid arthritis.

We studied whether orthopedic surgical patients with rheumatoid arthritis (RA) can generate an erythropoietic response to either endogenous erythropoietin or to recombinant human erythropoietin (EPO) therapy to the same extent as patients without rheumatoid arthritis (non-RA). Seventy patients (10 RA, 60 non-RA) were entered into clinical trials of aggressive autologous blood donation before elective orthopedic surgery at one institution, randomized to receive EPO (600 U/kg, iv, 6 times over 3 weeks) or placebo. RA patients given EPO had red blood cell (RBC) production that was enhanced by 624 +/- 137 ml (mean +/- SD) as compared with 271 +/- 174 ml (p = 0.02) for RA patients given placebo treatment. Preoperative RBC volume expansion in 10 RA patients was 5.9 +/- 3.7 ml/kg as compared with 7.4 +/- 3.9 ml/kg for 60 non-RA patients (p = 0.13). RA patients can benefit to the same extent as non-RA patients from aggressive blood conservation programs that incorporate erythropoietin-modulated erythropoiesis.

Biological properties of peripheral blood progenitor cells mobilized by cyclophosphamide and granulocyte colony-stimulating factor.

Patients transplanted with mobilized blood progenitor cells (PBPC) recover their neutrophil counts more rapidly than patients transplanted with bone marrow even when they receive the same dose/kg of granulocyte-macrophage colony-forming cells (CFU-GM). Here we have sought a biological explanation for this phenomenon. Most CD34-positive PBPC are quiescent (<1% in S phase) when they are collected from the bloodstream of patients treated with cyclophosphamide and granulocyte colony-stimulating factor (G-CSF), but we have shown that they are able to resume proliferation rapidly in vitro by measuring the kinetics of CFU-GM production by primitive plastic-adherent (Pdelta) cells. Also, Pdelta cells in PBPC harvests, unlike normal marrow Pdelta cells, were insensitive to cell-cycle restraint imposed by contact with marrow-derived stromal cells. We found that Pdelta cells in PBPC collections produce relatively more CFU-GM and relatively fewer BFU-E than Pdelta cells in bone marrow, indicating that granulopoiesis might occur at the expense of erythropoiesis, but we were unable to find any differences in the kinetics of granulocytic maturation between PBPC and bone marrow. Our interpretation of these findings is that transplanted PBPC rapidly enter the cell cycle and contact with stromal cells in the marrow does not reduce the proportion of progenitors participating in neutrophil production. Consequently. neutrophil recovery after PBPC infusion is more rapid than neutrophil recovery after marrow infusion. Granulopoiesis at the expense of erythropoiesis may also contribute to this effect.