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1.  Extramedullary plasmacytoma of the head and neck region: clinicopathological correlation in 25 cases. 
British Journal of Cancer  1997;75(6):921-927.
Extramedullary plasmacytomas (EMP) of head and neck are rare tumours. Between 1972 and 1993, 25 cases of EMP of head and neck were seen at our institute. The clinical and pathological features and response to treatment are presented. At initial presentation, 23 (92%) patients presented with disease confined to a single extramedullary site only and two patients had in addition clinical involvement of cervical lymph nodes. All except these two patients received radiotherapy to the primary site only as initial treatment. Initial primary control of local disease was obtained in 16 of 24 (67%) patients treated with radical intent. With salvage treatment of further radiotherapy and/or chemotherapy, local disease control was achieved in 21 of 24 (88%) patients. One patient was treated with palliative intent. Conversion to multiple myeloma was seen in two patients (8%). Pathologically, the tumours were classified into low, intermediate and high grade, which correlated closely with outcome. This classification has been used for the first time in extramedullary plasmacytomas and is based on the multiple myeloma grading criteria devised by Bartl et al (1987). Fifteen of eighteen (83%) low-grade tumours and only one of six (17%) intermediate- and high-grade tumours were locally controlled after primary radiotherapy. This is statistically significant for local control (P= 0.0019) but not for overall survival (P= 0.12). The median survival and 5-year overall survival is 68 months and 58.9% respectively. We recommend consideration of adjuvant chemotherapy in patients with higher grade disease.
PMCID: PMC2063399  PMID: 9062417
2.  PCR-ELISA for the early diagnosis of invasive pulmonary aspergillus infection in neutropenic patients. 
Journal of Clinical Pathology  1998;51(9):652-656.
AIM: To evaluate a newly developed aspergillus mitochondrial gene PCR-ELISA assay for the early diagnosis of invasive pulmonary aspergillosis (IPA) in neutropenic patients. METHODS: The aspergillus mitochondrial gene was chosen for the amplification target for use with a solution hybridisation assay with colorimetric end stage detection in microtitre plate format (PCR-ELISA). The study group comprised neutropenic patients undergoing febrile episodes not responding to standard antibacterial antibiotics. Patients underwent computed tomography and bronchoscopy. Bronchoalveolar lavage (BAL) fluids were examined by culture and PCR. RESULTS: The aspergillus mitochondrial gene PCR-ELISA was both sensitive (100%) and specific (100%) for IPA in neutropenic patients. All 12 patients with definite or probable IPA had PCR positive BAL fluids. None of the patients with undiagnosed or confirmed infections of other aetiologies were mitochondrial PCR positive. Speciation based upon amplicon size difference was possible. CONCLUSIONS: Aspergillus mitochondrial DNA PCR-ELISA on BAL fluid is useful in the early diagnosis of IPA in neutropenic patients alone or, potentially, as an indication for thoracic computed tomography.
PMCID: PMC500900  PMID: 9930067
3.  Relationship between the pretreatment proliferative activity of marrow blast cells and prognosis of acute lymphoblastic leukaemia of childhood 
British Journal of Cancer  1980;41(5):764-771.
Pretreatment marrow blast cells were studied in 38 boys and 27 girls (aged 1-14) with acute lymphoblastic leukaemia by flow cytometry after staining with propidium iodide.
The percentage of blast cells in the S phase of the cell cycle ranged from 1% to 40% (median 6%). A correlation was found between the percentage of cells in S and the morphological classification of the French American British Cooperative Group (FAB), presence of T or B cell markers, haemoglobin concentration, blast size, bone pain, platelet count, and an inverse correlation with coarse granule and block staining with Periodic-acid-Schiff (PAS).
63 of the 65 children attained complete remission. During the first 24 months of follow up there were fewer relapses (P = 0·054), and deaths (P = 0·004) in those children with 6% or fewer blasts in S phase. The difference was most marked in the first 12 months with 4 relapses out of 33 in the group with 6% or fewer cells in S compared with 13/30 in the group with > 6% cells in S.
In order to investigate the prognostic significance of the pretreatment proliferative studies in greater detail, remission duration was correlated with 17 presenting features. Each feature was correlated individually and then the simultaneous effect of all the features was assessed by stepwise multiple regression.
Only 3 features of the disease at diagnosis were individually correlated with duration of remission. These were% cells in S (P < 0·001), log white cell blood count (WBC) (P < 0·01) and the presence of T- or B-cell surface markers (P < 0·05). However, the multiple regression analysis showed that cell markers were not an independent prognostic feature, whereas the percentage cells in S and log WBC were independently and significantly correlated with duration of first remission (P < 0·001 in each case).
PMCID: PMC2010298  PMID: 7000111
4.  Colchicine ultrasensitivity of peripheral-blood lymphocytes from patients with non-Hodgkin's lymphoma. 
British Journal of Cancer  1980;41(4):593-601.
Incubation for 20 h in low concentrations of colchicine has been shown to kill the peripheral blood lymphocytes (PBL) of patients with chronic lymphocytic leukaemia (CLL), whereas at least a 10,000 x higher concentration of colchicine is required to kill lymphocytes from a normal donor. This ultrasensitivity of CLL lymphocytes to low doses of colchicine was confirmed in 19/20 PBL samples, 5/6 lymph nodes, and in the one totally replaced marrow studied. PBL from 75 patients with non-Hodgkin's lymphoma (NHDL) were examined for colchicine ultrasensitive (CUS) cells similar to those found in CLL. All the patients had less than 5 x 10(9)/1 morphologically normal circulating lymphocytes. PBL from 45 healthy donors and 39 patients with diseases other than leukaemia or lymphoma were used as controls. CUS cells were detected in 24 (32%) of the 75 patients. The CUS cells were considered to represent blood involvement with malignant lymphocytes for three reasons. First, there was an association with marrow involvement (P less than 0.05) which usually accompanies involvement of the blood with morphologically abnormal cells. Secondly, 23 (77%) of the 30 involved lymph nodes, marrows and spleens studied were CUS. Thirdly, there was a close correlation with the presence of a monoclone of B lymphocytes demonstrated by surface markers (P less than 0.01).
PMCID: PMC2010294  PMID: 7387857
5.  Treatment of inoperable hepatocellular carcinoma with pegylated liposomal doxorubicin (PLD): results of a phase II study 
British Journal of Cancer  2005;92(4):628-630.
Monthly intravenous pegylated liposomal doxorubicin (PLD) 50 mg m−2, although well tolerated, showed almost no activity in this phase II study of 16 patients with advanced hepatocellular carcinoma with a response rate of 0%, stable disease 19%, median time to progression of 2.4 months, 1-year survival of 25% and median survival of 6.5 months.
PMCID: PMC2361887  PMID: 15700038
pegylated liposomal doxorubicin; hepatocellular carcinoma; phase II
7.  Recombinant human interleukin 4 (IL-4) given as daily subcutaneous injections--a phase I dose toxicity trial. 
British Journal of Cancer  1992;66(1):204-210.
Recombinant Interleukin 4 was administered by subcutaneous injection at daily doses of 0.5, 1.0 or 5.0 micrograms kg-1 to nine patients as part of a Phase I Dose Toxicity Study. Dose limiting toxicity was reached at 5 micrograms kg-1 day-1. Symptoms of toxicity included fatigue, 'flu like symptoms and elevated liver enzymes. Modest but significant elevations of neutrophil and platelet counts occurred. No clear evidence of antitumour effects emerged although pain in metastatic lymph nodes and a small fall in myeloma paraprotein levels during dosing were observed. In vitro and murine in vivo studies indicate that patients with lymphoproliferative disease should be selected for Phase II trials.
PMCID: PMC1977892  PMID: 1637669
8.  Failure of balloon dilatation of the pulmonary valve in carcinoid pulmonary stenosis. 
British Heart Journal  1992;67(6):450-453.
BACKGROUND--Carcinoid heart disease typically results in pulmonary stenosis and tricuspid incompetence. Percutaneous balloon dilatation is an effective treatment for congenital pulmonary stenosis and has been applied successfully to tricuspid stenosis caused by carcinoid heart disease. The value of balloon dilatation of the pulmonary valve in carcinoid pulmonary stenosis was assessed. METHODS--Two patients with severe congestive heart failure secondary to carcinoid heart disease and with documented pulmonary stenosis had balloon dilatation of the pulmonary valve. In both cases tricuspid regurgitation was also present together with reduced cardiac output. RESULTS--The procedure was technically successful in both patients. One patient experienced symptomatic benefit for two months and the other experienced no improvement. Both patients subsequently required combined tricuspid and pulmonary valve replacement from which good results and symptomatic improvement were obtained. CONCLUSION--Though balloon dilatation of the pulmonary valve is technically feasible it is unlikely to provide useful palliation in carcinoid heart disease. Valve surgery should be considered in patients in whom the malignancy is controlled but carcinoid heart disease is producing drug resistant congestive heart failure.
PMCID: PMC1024885  PMID: 1622693
9.  Cancer Therapy 
British Journal of Cancer  1983;47(4):576-577.
PMCID: PMC2011327
10.  Cancer Medicine 
British Journal of Cancer  1982;46(6):1007-1008.
PMCID: PMC2011205
12.  Cancer Treatment 
British Journal of Cancer  1980;42(5):805.
PMCID: PMC2010546
18.  Hodgkin's Disease 
British Journal of Cancer  1976;34(4):458.
PMCID: PMC2025263
19.  Immunogenicity of vaccination against influenza, Streptococcus pneumoniae and Haemophilus influenzae type B in patients with multiple myeloma 
British Journal of Cancer  2000;82(7):1261-1265.
Vaccination against influenza and Streptococcus pneumoniae is recommended for elderly and immunocompromised individuals. However, there is little information concerning the efficacy of vaccination in specific groups of patients. In this study, 52 patients underwent vaccination against influenza, S. pneumoniae and Haemophilus influenzae type b (Hib) as they attended hospital outpatient clinics. Serum was analysed prior to vaccination and 4–6 weeks afterwards. Antibody titres against S. pneumoniae and Hib were compared with reference values corresponding to the geometric mean titres of a healthy UK population. For influenza vaccination, haemagglutination inhibition (HI) titres were measured against three inactivated strains; a titre of ≥ 1/40 was considered protective. No patient had protective titres to all three antigens prior to vaccination and 41 patients (85%) had titres < 1/40 to all 3 strains. Post vaccination only 9/48 patients (19%) achieved protective antibody titres. Resistance to S. pneumoniae and response to Pneumovax II was also poor: prevaccination, 45 patients (93%) had suboptimal antibody titres and in 26/43 patients (61%) titres remained low post vaccination. Resistance to Hib and response to vaccination was comparable with the healthy adult UK population. These results question the practice of routine influenza and pneumococcal vaccination in myeloma patients. © 2000 Cancer Research Campaign
PMCID: PMC2374477  PMID: 10755398
myeloma; influenza; Streptococcus pneumoniae; Haemophilus influenzae; vaccination
20.  Cyclophosphamide decreases O6-alkylguanine-DNA alkyltransferase activity in peripheral lymphocytes of patients undergoing bone marrow transplantation. 
British Journal of Cancer  1992;66(2):331-336.
O6-alkylguanine-DNA-alkyltransferase (ATase) levels were measured in extracts of peripheral blood lymphocytes taken at various times during chemotherapy from 19 patients with various haematological malignancies. Seven patients with advanced Hodgkin's disease received preparative treatment consisting of cyclophosphamide (1.5 g m-2, daily) administered on days 1 to 4 and BCNU (600 mg m-2) on day 5 prior to autologous bone marrow rescue (ABMR) delivered on day 7. Treatment in the remaining 12 patients consisted of cyclophosphamide (1.8 g m-2, daily) given on days 1 and 2 followed at day 4 with total body irradiation (TBI) administered in six fractions over the subsequent 3 days to a total dose of 1200 cGy prior to bone marrow transplantation. In the Hodgkin's group, significant decreases in ATase activity were seen during the cyclophosphamide treatment, and the median ATase nadir was 32% (range 0% to 57%) of pretreatment levels following 4 days of cyclophosphamide. In one patient, no ATase activity was detectable following the 4th cyclophosphamide treatment. ATase activities decreased further after BCNU administration to a median of 19% (range 0% to 32%) of pretreatment levels. Extensive cyclophosphamide-induced reduction of lymphocyte ATase levels was also seen in the other group of 12 patients treated with cyclophosphamide/TBI: postcyclophosphamide median ATase nadir was 35% (range 12% to 78%) of the pretreatment levels. No ATase depletion was seen when cyclophosphamide (up to 10 mM) was incubated for 2 h with pure recombinant human ATase in vitro whereas ATase activity was reduced by 90% on preincubation with 100 microns acrolein or with greater than 1 mM phosphoramide mustard. This suggests that a cyclophosphamide-induced decrease in ATase levels in human peripheral lymphocytes in vivo may be due to depletion mediated by the production of intracellular acrolein. Since ATase appears to be a principal mechanism in cellular resistance to the cytotoxic effects of BCNU and related alkylating agents, these observations suggest that a cyclophosphamide-induced reduction in ATase activity may be an additional factor in the effectiveness of the combined sequential therapy.
PMCID: PMC1977821  PMID: 1387001
21.  Granulocyte-macrophage colony stimulating factor (GM-CSF) after high-dose melphalan in patients with advanced colon cancer. 
British Journal of Cancer  1990;61(5):749-754.
Nine patients with progressive, metastatic disease from primary carcinoma of the colon were entered into a phase I/II study using continuous intravenous infusions of granulocyte-macrophage colony-stimulating factor (GM-CSF) and high dose melphalan (120 mg m-2). GM-CSF was given alone to six patients during the first part of the study to determine a dose that would produce a peripheral leucocyte count (WCC) greater than or equal to 50 X 10(9) 1(-1) and was initially given at 3 micrograms kg-1 day-1 and escalated to 10 micrograms kg-1 day-1 after 10 days. The infusion was discontinued when the WCC exceeded 50 X 10(9) 1(-1) and after a gap of one week, melphalan was given over 30 min. GM-CSF was recommenced 8 h later and was continued until the neutrophil count had exceeded 0.5 X 10(9) 1(-1) for greater than 1 week. One patient achieved a WCC greater than 50 X 10(9) 1(-1) with GM-CSF 3 micrograms kg-1 day-1, but the other five who entered this phase of the study required dose escalation to 10 micrograms kg-1. No toxicity attributed to GM-CSF was seen. After melphalan, the median times to severe neutropenia (less than 0.5 X 10(9) 1(-1] and thrombocytopenia (greater than 20 X 10(9) 1(-1] were 6 and 9 days respectively. The median durations of neutropenia and thrombocytopenia were 14 and 10 days respectively. All patients required intensive support with a median duration of inpatient stay of 24 days. There was one treatment related death due to renal failure. One complete and two partial remissions (33% response rate) were seen but these were of short duration (median of 10 weeks). This study demonstrates that GM-CSF given by continuous intravenous infusion produces significant increments of peripheral granulocyte counts at 3 and 10 micrograms kg-1 day-1 and is not associated with any toxicity. The duration of neutropenia and thrombocytopenia induced by high-dose melphalan appears to be reduced by the subsequent administration of GM-CSF to times which are at least as short as have been reported in historical series which have used autologous bone marrow rescue.
PMCID: PMC1971606  PMID: 1692472
22.  Recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF) given as daily short infusions--a phase I dose-toxicity study. 
British Journal of Cancer  1989;59(1):142-145.
Twenty patients with progressive metastatic solid tumours were entered into a study to evaluate the biological effects and toxicity of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF was given as half-hour intravenous infusions during two 10-day phases of daily treatments (separated by 10 days without GM-CSF) and over a final phase of 20 days of alternate day infusions. Doses were escalated in steps from 0.3 to 60 micrograms kg-1 day-1 between successive patient groups. Significant increases (P less than 0.005) of total leucocyte, neutrophil and eosinophil polymorph counts were seen over the periods of daily infusions (up to four-fold rises of total white count) at dose levels of 10 micrograms kg-1 and above. Counts produced at 30 micrograms kg-1 were significantly higher than at 10 micrograms kg-1 (P less than 0.025). Toxic side effects of GM-CSF included mild transient pyrexias, bone pain and pruritus. The maximum tolerated dose was 60 micrograms kg-1, which produced severe toxicity in 80% of patients. The toxicity at this dose included pericarditis and dyspnoea ascribed to a 'capillary-leak' syndrome. One patient receiving 60 micrograms kg-1 died as a result of a pulmonary embolus. Seven patients with previously rapidly progressive metastatic tumours experienced stabilisation of disease while receiving GM-CSF and one patient with a previously heavily pretreated metastatic soft tissue sarcoma underwent a greater than 50% reduction of tumour volume. Patients undergoing chemotherapy may benefit both from a reduction of the myelosuppressive effects of cytotoxic agents and from an antitumour effect if GM-CSF is incorporated into future regimens.
PMCID: PMC2246969  PMID: 2667607
23.  In vitro and in vivo analysis of the effects of recombinant human granulocyte colony-stimulating factor in patients. 
British Journal of Cancer  1988;58(1):64-69.
Twelve patients with small cell lung cancer were treated with recombinant human granulocyte colony-stimulating factor, rhG-CSF, given by continuous infusion at doses ranging from 1 to 40 micrograms kg-1 day-1. Patients received the rhG-CSF before the start of intensive chemotherapy and after alternate cycles of chemotherapy. Several in vitro assays were performed using peripheral blood neutrophils and marrow progenitor cells collected from patients prior to and after infusion of the growth factor. Peripheral blood neutrophils were tested for mobility and phagocytic activity. In addition, in vitro clonogenic assays of marrow haemopoietic progenitor cells and analysis of bone marrow trephines and aspirates were carried out. We found that rhG-CSF in vivo has at least two main effects: (a) an early fall in peripheral neutrophils, within the first hour, followed by a rapid influx of mature neutrophils into the circulatory pool; (b) stimulation of proliferation and differentiation of neutrophil precursors in the bone marrow. Neutrophils released into the circulation were normal in tests of their mobility and phagocytic activity.
PMCID: PMC2246501  PMID: 2458748
24.  A phase I and pharmacokinetic study of amphethinile. 
British Journal of Cancer  1988;57(6):623-627.
Amphethinile is a new spindle poison with a novel structure that has shown activity in the L1210, ADJ/PC6 and Walker carcinoma rodent tumours. In addition the agent appeared to have an improved therapeutic ratio compared to existing spindle poisons and is well absorbed when administered orally. The starting dose for the phase I study was 40 mg m-2 (1/10th mouse LD10) and further patients were studied at 200, 400, 800 and 1200 mg m-2, dose escalation being based on pharmacological monitoring. Significant toxic effects were seen only at 800 and 1200 mg m-2. At these doses patients experienced nausea and vomiting, light headedness during the infusion and varying degrees of lethargy following therapy. Two of six patients at 800 mg m-2 developed severe pain in the tumour bearing area 1-2 h after treatment and one experienced colicky abdominal pain. At 1200 mg m-2 two patients died within 48 h of treatment from what appeared to be vascular causes. Following these episodes the trial was discontinued. Neutropenia and alopecia occurred in two patients, one at 800 and one at 1200 mg m-2. These patients achieved the highest drug exposure in terms of area under the concentration x time curve. It was not possible to achieve an AUC consistently high enough to produce cytotoxic effects due to the occurrence of dose limiting toxicities thus amphethinile cannot at present be recommended for phase II testing by the i.v. route. The dose escalation scheme based on pharmacological monitoring resulted in a considerable saving in the duration of the trial. Further evaluation of this methodology is recommended.
PMCID: PMC2246468  PMID: 3408647
25.  Phase I/II study of recombinant human granulocyte colony-stimulating factor in patients receiving intensive chemotherapy for small cell lung cancer. 
British Journal of Cancer  1987;56(6):809-813.
Twelve patients with advanced small cell carcinoma of the bronchus were treated by continuous infusion of recombinant human granulocyte colony-stimulating factor (rhG-CSF) at the following dose levels: 1 microgram, 5 micrograms, 10 micrograms, 20 micrograms and 40 micrograms kg-1 day-1 for 5 days. No toxicities resulted from the treatment and in all 12 patients the number of peripheral neutrophils increased rapidly to a maximum of 100 x 10(9) l-1 at 10 micrograms kg-1 day-1. The neutrophils were shown to be functionally normal in tests of their mobility and bactericidal activity. During the phase II part of the study the patients were treated by a combination of intravenous adriamycin 50 mg m-2, ifosfamide 5 g m-2 by i.v. infusion with mesna 8 g m-2 on day 1, and etoposide 120 mg m-2 on days 1, 2 and 3 also intravenously. The chemotherapy regime was repeated every 3 weeks. RhG-CSF was given to each patient for 14 days on alternate cycles of chemotherapy and reduced the period of absolute neutropenia considerably (median of 80%), with a return to normal, or above normal, neutrophil counts within 2 weeks after day 1 of chemotherapy. Six severe infective episodes were observed during the cycles of chemotherapy which did not include rhG-CSF, while no infective episodes occurred when patients were treated with rhG-CSF. These results demonstrate the utility of rhG-CSF in restoring functional neutrophils to patients undergoing intensive chemotherapy.
PMCID: PMC2002403  PMID: 2829955

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