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1.  A study to investigate dose escalation of doxorubicin in ABVD chemotherapy for Hodgkin lymphoma incorporating biomarkers of response and toxicity 
British Journal of Cancer  2013;109(10):2560-2565.
Background:
Myelotoxicity during initial cycles of chemotherapy for Hodgkin lymphoma is associated with better outcome, supporting the concept of individualised dosing based on pharmacodynamic end points to optimise results. This study was performed to identify the maximum tolerated dose (MTD) of doxorubicin within cycles 1–3 ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). Circulating biomarkers of response (nucleosomal DNA, nDNA) and epithelial toxicity (Cytokeratin 18, CK18) were also measured.
Methods:
Dose escalation of doxorubicin in cycles 1–3 ABVD supported by pegfilgrastim was performed on a six-patient cohort basis (35, 45 and 55 mg m–2) with doxorubicin reduced to 25 mg m–2 or omitted in cycles 4–6 to maintain cumulative exposure of 103–130% standard ABVD. BVD was given at standard doses throughout. Six additional subjects were recruited at the MTD.
Results:
Twenty-four subjects were recruited. Dose-limiting toxicities (DLTs) of grade 3 neuropathy, pneumonitis, palmar-plantar erythema and neutropenic infection were observed at 55 mg m–2, so 45 mg m–2 was declared the MTD. In patients who subsequently experienced DLT at any time, large increases in CK18 were seen on day 3 of cycle 1 ABVD.
Conclusion:
Escalated ABVD incorporating doxorubicin at 45 mg m–2 in cycles 1–3 can be delivered safely with pegfilgrastim support. Circulating cell death biomarkers may assist in the development of future individualised dosing strategies.
doi:10.1038/bjc.2013.605
PMCID: PMC3833204  PMID: 24136151
Hodgkin lymphoma; ABVD chemotherapy; cell death biomarkers; phase I
2.  Breast cancer risk following Hodgkin lymphoma radiotherapy in relation to menstrual and reproductive factors 
British Journal of Cancer  2013;108(11):2399-2406.
Background:
Women treated with supradiaphragmatic radiotherapy (sRT) for Hodgkin lymphoma (HL) at young ages have a substantially increased breast cancer risk. Little is known about how menarcheal and reproductive factors modify this risk.
Methods:
We examined the effects of menarcheal age, pregnancy, and menopausal age on breast cancer risk following sRT in case–control data from questionnaires completed by 2497 women from a cohort of 5002 treated with sRT for HL at ages <36 during 1956–2003.
Results:
Two-hundred and sixty women had been diagnosed with breast cancer. Breast cancer risk was significantly increased in patients treated within 6 months of menarche (odds ratio (OR) 5.52, 95% confidence interval (CI) (1.97–15.46)), and increased significantly with proximity of sRT to menarche (Ptrend<0.001). It was greatest when sRT was close to a late menarche, but based on small numbers and needing reexamination elsewhere. Risk was not significantly affected by full-term pregnancies before or after treatment. Risk was significantly reduced by early menopause (OR 0.55, 95% CI (0.35–0.85)), and increased with number of premenopausal years after treatment (Ptrend=0.003).
Conclusion:
In summary, this paper shows for the first time that sRT close to menarche substantially increases breast cancer risk. Careful consideration should be given to follow-up of these women, and to measures that might reduce their future breast cancer risk.
doi:10.1038/bjc.2013.219
PMCID: PMC3681009  PMID: 23652303
Hodgkin lymphoma; breast cancer; supradiaphragmatic radiotherapy
3.  Assessment of circulating biomarkers for potential pharmacodynamic utility in patients with lymphoma 
British Journal of Cancer  2011;104(4):719-725.
Purpose:
Treatment efficacy and toxicity are difficult to predict in lymphoma patients. In this study, the utility of circulating biomarkers in predicting and/or monitoring treatment efficacy/toxicity were investigated.
Patients and methods
Circulating biomarkers of cell death (nucleosomal DNA (nDNA) and cytokeratin 18 (CK18)), and circulating FLT3 ligand, a potential biomarker of myelosuppression, were assessed before and serially after standard chemotherapy in 49 patients with Hodgkin and non-Hodgkin lymphoma. Cytokeratin 18 is not expressed in lymphoma cells so is a potential biomarker of epithelial toxicity in this setting. Tumour response was assessed before and after completion of chemotherapy by 2D and 3D computed tomography radiological response.
Results:
Baseline nDNA level was significantly higher in all lymphoma subtypes compared with 61 healthy controls and was prognostic for progression-free survival in diffuse large B-cell lymphoma (DLBCL). Decreases in nDNA levels were observed in the first week after chemotherapy; in FL, early falls in nDNA predicted for long remission following therapy. In DLBCL, elevations in nDNA occurred in cases with progressive disease. Circulating CK18 increased within 48 h of chemotherapy and was significantly higher in patients experiencing epithelial toxicity graded >3 by Common Terminology for Classification of Adverse Events criteria. FLT3 ligand was elevated within 3–8 days of chemotherapy initiation and predicted those patients who subsequently developed neutropenic sepsis.
Conclusion:
These data suggest circulating biomarkers contribute useful information regarding tumour response and toxicity in patients receiving standard chemotherapy and have potential utility in the development of individualised treatment approaches in lymphoma. These biomarkers are now being tested within multicentre phase III trials to progress their qualification.
doi:10.1038/sj.bjc.6606082
PMCID: PMC3049589  PMID: 21245866
Hodgkin and non-Hodgkin lymphoma; biomarkers; nucleosomal DNA; cytokeratin 18; FLT3 ligand
4.  The UK national breast cancer screening programme for survivors of Hodgkin lymphoma detects breast cancer at an early stage 
British Journal of Cancer  2009;101(4):582-588.
Background:
Supradiaphragmatic radiotherapy (SRT) to treat Hodgkin's lymphoma (HL) at a young age increases the risk of breast cancer (BC). A national notification risk assessment and screening programme (NRASP) for women who were treated with SRT before the age of 36 years was instituted in the United Kingdom in 2003. In this study, we report the implementation and screening results from the largest English Cancer Network.
Methods:
A total of 417 eligible women were identified through cancer registry/hospital databases and from follow-up (FU) clinics. Screening results were collated retrospectively, and registry searches were used to capture BC cases.
Results:
Of the 417 women invited for clinical review, 243 (58%) attended. Of these 417 women, 23 (5.5%) have been diagnosed with BC, a standardised incidence ratio of 2.9 compared with the age-matched general population. Of five invasive BCs diagnosed within the NRASP, none involved axillary lymph nodes compared with 7 of 13 (54%) diagnosed outside the programme (P<0.10). The mean latency for BC cases was 19.5±8.35 years and the mean FU duration for those unaffected by BC was 14.6±9.11 years (P<0.01), suggesting that those unaffected by BC remain at high risk. Recall and negative biopsy rates were acceptable (10.5 and 0.8%, respectively).
Conclusions:
The NRASP appears to detect BC at an early stage with acceptable biopsy rates, although numbers are small. Determination of NRASP results on a national basis is required for the accurate evaluation of screening efficacy in women previously treated with SRT.
doi:10.1038/sj.bjc.6605215
PMCID: PMC2736813  PMID: 19672261
breast; cancer; Hodgkin; lymphoma; supradiaphragmatic; radiotherapy
5.  Does stretching increase ankle dorsiflexion range of motion? A systematic review 
British Journal of Sports Medicine  2006;40(10):870-875.
Background
Many lower limb disorders are related to calf muscle tightness and reduced dorsiflexion of the ankle. To treat such disorders, stretches of the calf muscles are commonly prescribed to increase available dorsiflexion of the ankle joint.
Hypothesis
To determine the effect of static calf muscle stretching on ankle joint dorsiflexion range of motion.
Study design
A systematic review with meta‐analyses.
Methods
A systematic review of randomised trials examining static calf muscle stretches compared with no stretching. Trials were identified by searching Cinahl, Embase, Medline, SportDiscus, and Central and by recursive checking of bibliographies. Data were extracted from trial publications, and meta‐analyses performed that calculated a weighted mean difference (WMD) for the continuous outcome of ankle dorsiflexion. Sensitivity analyses excluded poorer quality trials. Statistical heterogeneity was assessed using the quantity I2.
Results
Five trials met inclusion criteria and reported sufficient data on ankle dorsiflexion to be included in the meta‐analyses. The meta‐analyses showed that calf muscle stretching increases ankle dorsiflexion after stretching for ⩽15 minutes (WMD 2.07°; 95% confidence interval 0.86 to 3.27), >15–30 minutes (WMD 3.03°; 95% confidence interval 0.31 to 5.75), and >30 minutes (WMD 2.49°; 95% confidence interval 0.16 to 4.82). There was a very low to moderate statistical heterogeneity between trials. The meta‐analysis results for ⩽15 minutes and >15–30 minutes of stretching were considered robust when compared with sensitivity analyses that excluded lower quality trials.
Conclusions
Calf muscle stretching provides a small and statistically significant increase in ankle dorsiflexion. However, it is unclear whether the change is clinically important.
doi:10.1136/bjsm.2006.029348
PMCID: PMC2465055  PMID: 16926259
stretching; dorsiflexion; Achilles tendon; gastrocnemius; soleus
6.  Whole blood IFN‐γ assay for detecting TB in children 
Thorax  2006;61(10):919-920.
PMCID: PMC2104750  PMID: 17008485
tuberculosis; children; interferon gamma; tuberculin skin test; diagnosis
8.  Patterns of mortality after prolonged follow-up of a randomised controlled trial using granulocyte colony-stimulating factor to maintain chemotherapy dose intensity in non-Hodgkin's lymphoma 
British Journal of Cancer  2008;99(2):253-258.
The effect of utilising granulocyte colony-stimulating factor (G-CSF) to maintain chemotherapy dose intensity in non-Hodgkin's lymphoma (NHL) on long-term mortality patterns has not been formally evaluated. We analysed prolonged follow-up data from the first randomised controlled trial investigating this approach. Data on 10-year overall survival (OS), progression-free survival (PFS), freedom from progression (FFP) and incidence of second malignancies were collected for 80 patients with aggressive subtypes of NHL, who had been randomised to receive either VAPEC-B chemotherapy or VAPEC-B+G-CSF. Median follow-up was 15.7 years for surviving patients. No significant differences were found in PFS or OS. However, 10-year FFP was better in the G-CSF arm (68 vs 47%, P=0.037). Eleven deaths from causes unrelated to NHL or its treatment occurred in the G-CSF arm compared to five in controls. More deaths occurred from second malignancies (4 vs 2) and cardiovascular causes (5 vs 0) in the G-CSF arm. Although this pharmacovigilance study has insufficient statistical power to draw conclusions and is limited by the lack of data on smoking history and other cardiovascular risk factors, these unique long-term outcome data generate hypotheses that warrant further investigation.
doi:10.1038/sj.bjc.6604468
PMCID: PMC2480980  PMID: 18594529
non-Hodgkin's lymphoma; granulocyte colony-stimulating factor; mortality pattern; dose intensity; pharmacovigilance; second malignancy
9.  Acquisition of biologically relevant gene expression data by Affymetrix microarray analysis of archival formalin-fixed paraffin-embedded tumours 
British Journal of Cancer  2008;98(8):1403-1414.
Robust protocols for microarray gene expression profiling of archival formalin-fixed paraffin-embedded tissue (FFPET) are needed to facilitate research when availability of fresh-frozen tissue is limited. Recent reports attest to the feasibility of this approach, but the clinical value of these data is poorly understood. We employed state-of-the-art RNA extraction and Affymetrix microarray technology to examine 34 archival FFPET primary extremity soft tissue sarcomas. Nineteen arrays met stringent QC criteria and were used to model prognostic signatures for metastatic recurrence. Arrays from two paired frozen and FFPET samples were compared: although FFPET sensitivity was low (∼50%), high specificity (95%) and positive predictive value (92%) suggest that transcript detection is reliable. Good agreement between arrays and real time (RT)–PCR was confirmed, especially for abundant transcripts, and RT–PCR validated the regulation pattern for 19 of 24 candidate genes (overall R2=0.4662). RT–PCR and immunohistochemistry on independent cases validated prognostic significance for several genes including RECQL4, FRRS1, CFH and MET – whose combined expression carried greater prognostic value than tumour grade – and cmet and TRKB proteins. These molecules warrant further evaluation in larger series. Reliable clinically relevant data can be obtained from archival FFPET, but protocol amendments are needed to improve the sensitivity and broad application of this approach.
doi:10.1038/sj.bjc.6604316
PMCID: PMC2361698  PMID: 18382428
archival formalin-fixed paraffin-embedded tissue; gene expression profiling; Affymetrix U133 Plus 2.0 array; extremity soft tissue sarcoma; prognostic markers
10.  PILOMATRIXOMA OF THE FOREARM: A CASE REPORT 
The Iowa Orthopaedic Journal  2009;29:121-123.
Pilomatrixoma is a benign neoplasm derived from hair follicle matrix cells. Involvement of the upper extremities is relatively uncommon and can be mistaken for malignancy. We present the case of a 52-year-old woman with a pilomatrixoma of the forearm, and we review the literature regarding pilomatrixomas in the upper extremity.
PMCID: PMC2723706  PMID: 19742099
12.  Semen cryopreservation, utilisation and reproductive outcome in men treated for Hodgkin's disease 
British Journal of Cancer  2002;87(4):381-384.
Between 1978 and 1990, 122 men underwent semen analysis before starting sterilising chemotherapy for Hodgkin's disease. Eighty-one (66%) had semen quality within the normal range, 25 were oligospermic (<20×106 sperm per ml) and five were azoospermic (no sperm in the ejaculate). Semen from 115 men was cryopreserved and after a median follow-up time of 10.1 years, 33 men have utilised stored semen (actuarial rate 27%) and nine partners have become pregnant resulting in 11 live births and one termination for foetal malformation. Actuarial 10 year rates of destruction of semen before death or utilisation and death before utilisation are 19% and 13% respectively. This retrospective cohort study demonstrates that approximately one-quarter of men utilising cryopreserved semen after treatment for Hodgkin's disease obtain a live birth. The high non-utilisation rate is intriguing and warrants further investigation.
British Journal of Cancer (2002) 87, 381–384. doi:10.1038/sj.bjc.6600483 www.bjcancer.com
© 2002 Cancer Research UK
doi:10.1038/sj.bjc.6600483
PMCID: PMC2376135  PMID: 12177773
semen cryopreservation; reproductive outcome; Hodgkin's disease
13.  A randomized controlled trial to evaluate the role of interferon as initial and maintenance therapy in patients with follicular lymphoma 
British Journal of Cancer  2001;85(1):29-35.
The purpose of this study was to evaluate the role of interferon as initial and maintenance therapy in patients with newly diagnosed follicular lymphoma. Between 1984 and 1994, 204 patients with newly diagnosed Stage III or Stage IV follicular lymphoma were randomized to receive either, Chlorambucil (CB): 10 mg daily for 6 weeks, followed by a 2-week interval, with 3 subsequent 2-week treatment periods at the same dose, separated by 2-week intervals, or, CB given concurrently with interferon (IFN). IFN was given at a dose of 3 × 106units thrice weekly, subcutaneously, throughout the 18-week treatment period. Responding patients were subsequently randomized to receive maintenance IFN at the dose and schedule described above, or to expectant management. The overall response rate was 161/204 (78%), complete remission being achieved in 24% of patients. Neither the addition of IFN to the initial treatment, nor the use of maintenance IFN influenced response rate, remission duration or survival. This study was undertaken to determine whether IFN, given in combination with, and then subsequent to, CB would alter the clinical course of patients with follicular lymphoma. Disappointingly, this objective was not achieved, no advantage having been demonstrated for the addition of IFN. © 2001 Cancer Research Campaign http://www.bjcancer.com
doi:10.1054/bjoc.2001.1822
PMCID: PMC2363909  PMID: 11437398
interferon; initial therapy; maintenance; follicular lymphoma
14.  A phase II trial of bryostatin 1 in patients with non-Hodgkin's lymphoma 
British Journal of Cancer  2001;84(4):465-469.
Bryostatin 1 is a naturally occurring macrocyclic lactone with promising antitumour and immunomodulatory function in preclinical and phase I clinical investigations. In this phase II study, 17 patients with progressive non-Hodgkin's lymphoma of indolent type (NHL), previously treated with chemotherapy, received a median of 6 (range 1–9) intravenous infusions of 25 μg/m2bryostatin 1 given once weekly over 24 hours. In 14 evaluable patients no responses were seen. Stable disease was attained in one patient for 9 months. The principal toxicities were myalgia and phlebitis. Treatment was discontinued early because of toxicity alone (phlebitis) in 2 patients, toxicity in addition to progressive disease in 3 patients (myalgia and phlebitis n = 2; thrombocytopenia n = 1) and progressive disease in 5 patients. The results fail to demonstrate efficacy of this regimen of bryostatin 1 in the treatment of NHL. In light of preclinical data that demonstrate synergy between bryostatin 1 and several cytotoxic agents and cytokines, clinical studies to investigate bryostatin 1 in combination are warranted. We also present data to demonstrate that central venous lines may be used in future studies to avoid phlebitis. © 2001 Cancer Research Campaign http://www.bjcancer.com
doi:10.1054/bjoc.2000.1624
PMCID: PMC2363763  PMID: 11263437
bryostatin 1; non-Hodgkin's lymphoma; protein kinase C inhibitors
15.  Fatigue, sexual function and mood following treatment for haematological malignancy: the impact of mild Leydig cell dysfunction 
British Journal of Cancer  2000;82(4):789-793.
Fatigue, sexual dysfunction, anxiety and depression are all more common in patients who have previously been treated with cytotoxic chemotherapy and radiotherapy (XRT) for haematological malignancies. Following therapy, a significant proportion of men have biochemical evidence of Leydig cell dysfunction, defined by a raised luteinizing hormone level in the presence of a low/normal testosterone level. We postulated that mild testosterone deficiency may account for some of the long-term side-effects of treatment, and we have therefore assessed fatigue, mood and sexual function by questionnaire in 36 patients with Leydig cell dysfunction (group 1), and also in a group of 30 patients (group 2) with normal hormone levels who underwent the same treatment for cancer. There was no significant difference in anxiety and depression scores between the two groups although anxiety scores were higher than those previously reported for normal men. Eighty-seven per cent of group 2 were sexually active compared with only 69% of group 1 (P = 0.1), and patients in group 1 engaged less in sexual activity than those in group 2 (mean of 1.8 times per week compared with 3.2 times per week;P = 0.02) Fatigue scores were significantly higher in both groups compared with normal men, but there were no significant differences in any of the fatigue subscales between the two groups. We conclude that mild Leydig cell insufficiency following treatment with cytotoxic chemotherapy ± XRT is not associated with higher levels of fatigue and anxiety but may result in reduced sexual function. These results do not provide a convincing argument that androgen replacement therapy is mandatory to improve quality of life in the majority of these patients, although it may be beneficial in a minority. To establish criteria for selection of patients for a trial of androgen therapy a randomized placebo-controlled study will be necessary. © 2000 Cancer Research Campaign
doi:10.1054/bjoc.1999.1000
PMCID: PMC2374403  PMID: 10732747
Leydig cell; testosterone; fatigue; sexual; mood
16.  Further investigation of the role of HLA-DPB1 in adult Hodgkin's disease (HD) suggests an influence on susceptibility to different HD subtypes 
British Journal of Cancer  1999;80(9):1405-1411.
It has been suggested in a number of studies that susceptibility to adult Hodgkin's disease (HD) is influenced by the HLA class II region, and specifically by alleles at the HLA-DPB1 locus. Since HD is diagnostically complex, it is not clear whether different HLA-DPB1 alleles confer susceptibility to different HD subtypes. To clarify this we have extended a previous study to type DPB1 alleles in 147 adult HD patients from a single centre. We have analysed patients with nodular sclerosing (NS), mixed cellularity (MC) or lymphocyte predominant (LP) HD, and gender in relation to HLA-DPBI type, in comparison with 183 adult controls. The results confirmed previously reported associations of DPB1*0301 with HD susceptibility (relative risk (RR) = 1.42; 95% confidence interval (CI) 0.86–2.36) and DPB1*0201 with resistance to HD (RR = 0.49; CI 0.27–0.90). However, analysis by HD subtype and gender showed that *0301-associated susceptibility was confined to females with HD (RR = 2.46; CI 1.02–5.92), and *0201-associated resistance to females with NS-HD (RR = 0.28; CI 0.10–0.79). Susceptibility to NS-HD was also associated in females with *1001 (RR = 11.73; CI 1.32–104.36), and resistance with *1101 (RR = 0.08; CI 0.01–0.65). In contrast, susceptibility to LP-HD was associated in males with *2001 (RR = 32.14; CI 3.17–326.17), and to MC-HD with *3401 (RR = 16.78; CI 2.84–99.17). Comparison of DPB1-encoded polymorphic amino-acid frequencies in patients and controls showed that susceptibility to MC-HD was associated with Leucine at position 35 of DPB1 (RR = 8.85; CI 3.04–25.77), Alanine-55 (RR = 15.17; CI 2.00–115.20) and Valine-84 (RR = 15.94; CI 3.55–71.49). In contrast, Glutamic acid 69 was significantly associated with resistance to MC-HD (RR = 0.14; CI 0.03–0.60). Certain DPB1 alleles and individual DPβ1 polymorphic amino acid residues may thus affect susceptibility and resistance to specific HD subtypes. This may be through their influence on the binding of peptides derived from an HD-associated infectious agent, and the consequent effect on immune responses to the agent. © 1999 Cancer Research Campaign
doi:10.1038/sj.bjc.6690536
PMCID: PMC2363076  PMID: 10424743
Hodgkin's disease; HLA-DPB1; HVR; susceptibility; resistance; polymorphic amino acid
18.  Recombinant human granulocyte colony-stimulating factor (filgrastim) following high-dose chemotherapy and peripheral blood progenitor cell rescue in high-grade non-Hodgkin's lymphoma: clinical benefits at no extra cost. 
British Journal of Cancer  1998;77(8):1294-1299.
In order to evaluate the potential clinical and economic benefits of granulocyte colony-stimulating factor (G-CSF, filgrastim) following peripheral blood progenitor cells (PBPC) rescue after high-dose chemotherapy (HDCT), 23 consecutive patients aged less than 60 years with poor-prognosis, high-grade non-Hodgkin's lymphoma (NHL) were entered into a prospective randomized trial between May 1993 and September 1995. Patients were randomized to receive either PBPC alone (n = 12) or PBPC+G-CSF (n = 11) after HDCT with busulphan and cyclophosphamide. G-CSF (300 microg day[-1]) was given from day +5 until recovery of granulocyte count to greater than 1.0 x 10(9) l(-1) for 2 consecutive days. The mean time to achieve a granulocyte count > 0.5 x 10(9) l(-1) was significantly shorter in the G-CSF arm (9.7 vs 13.2 days; P<0.0001) as was the median duration of hospital stay (12 vs 15 days; P = 0.001). In addition the recovery periods (range 9-12 vs 11-17 days to achieve a count of 1.0 x 10(9) l[-1]) and hospital stays (range 11-14 vs 13-22 days) were significantly less variable in patients receiving G-CSF in whom the values clustered around the median. There were no statistically significant differences between the study arms in terms of days of fever, documented episodes of bacteraemia, antimicrobial drug usage and platelet/red cell transfusion requirements. Taking into account the costs of total occupied-bed days, drugs, growth factor usage and haematological support, the mean expenditure per inpatient stay was pound sterling 6500 (range pound sterling 5465-pound sterling 8101) in the G-CSF group compared with pound sterling 8316 (range pound sterling 5953-pound sterling 15,801) in the group not receiving G-CSF, with an observed mean saving of 1816 per patient (or 22% of the total cost) in the G-CSF group. This study suggests that after HDCT and PBPC rescue, the use of G-CSF leads to more rapid haematological recovery periods and is associated with a more predictable and shorter hospital stay. Furthermore, and despite the additional costs for G-CSF, these clinical benefits are not translated into increased health care expenditure.
PMCID: PMC2150159  PMID: 9579836
19.  Follow up policy after treatment for Hodgkin's disease: too many clinic visits and routine tests? A review of hospital records. 
BMJ : British Medical Journal  1997;314(7077):343-346.
OBJECTIVE: To examine the effectiveness of routine clinic review in detecting relapse after treatment for Hodgkin's disease. DESIGN: Review of hospital records. SETTING: Regional centre for cancer treatment and research. SUBJECTS: 210 patients with Hodgkin's disease recruited to a chemotherapy trial protocol between 1984 and the end of 1990 who had achieved a complete or partial remission after treatment. MAIN OUTCOME MEASURES: The number of clinic visits made by patients over the period of observation, the number of relapses occurring during that time, and the route by which relapse was detected. RESULTS: The 210 patients generated 2512 outpatient reviews, and 37 relapses were detected. Thirty relapses (81%) were diagnosed in patients who described symptoms, which in 15 cases had resulted in an earlier appointment being arranged. In only four cases (11%; 95% confidence interval 4% to 25%) was relapse detected as a result of routine physical examination on investigation of a patient who did not have symptoms. CONCLUSIONS: Relapse of Hodgkin's disease after treatment is usually detected as a result of the investigation of symptoms rather than by routine screening of asymptomatic patients. It is therefore proposed that the frequency of routine follow up visits should be reduced and greater emphasis placed on patient education. This should underline the importance of symptoms and encourage patients to arrange an earlier appointment if these develop.
PMCID: PMC2125852  PMID: 9040326
20.  Prognostic factors for disease progression in advanced Hodgkin's disease: an analysis of patients aged under 60 years showing no progression in the first 6 months after starting primary chemotherapy. 
British Journal of Cancer  1997;75(1):110-115.
The aim of this study was to determine whether a very high-risk group based on presenting characteristics could be identified in patients with advanced Hodgkin's disease who may benefit from high-dose chemotherapy (HDCT). Between 1975 and 1992, 453 previously untreated patients aged under 60 years who did not progress in the first 6 months after the start of standard chemotherapy had their hospital notes reviewed. The outcomes analysed were early disease progression (in the 6- to 18-month window following the start of chemotherapy) and disease progression in the whole of the follow-up period. A Cox regression analysis was used to investigate the combined effects of a number of presenting characteristics on these outcomes. Despite the presence of factors with significant effects on the relative rate of progression, the absolute effects in a group identified as having the poorest prognosis were not especially poor. No group could be defined with a freedom from progression rate of less than 70% over 6-18 months, and the worst prognostic group, which included only 53 patients, had an overall freedom from progression rate of 57% at 5 years. Four other reported prognostic indices were evaluated using our data set, but none of the indices was more successful in identifying a very high-risk group. It has not been possible to define a sufficiently high-risk group of patients with Hodgkin's disease based on presenting characteristics for whom HDCT could be advised as part of primary treatment. The search for more discriminating prognostic factors identifying vulnerable patients with a high risk of relapse must continue before a role can be found for HDCT following conventional chemotherapy in patients without disease progression.
PMCID: PMC2222699  PMID: 9000607
21.  Immunogenicity and protection studies with recombinant mycobacteria and vaccinia vectors coexpressing the 18-kilodalton protein of Mycobacterium leprae. 
Infection and Immunity  1996;64(6):2274-2281.
The activation of antigen-specific T lymphocytes is essential for the control of leprosy infection in humans and experimental animals. T cells recognize a variety of protein antigens from Mycobacterium leprae, including the 18-kDa protein, which is limited in distribution among mycobacteria and which is absent from Mycobacterium tuberculosis and the vaccine strain, Mycobacterium bovis BCG. Adjuvant preparations of mycobacterial protein antigens have had limited protective efficacy for experimental infections in animals. Since recombinant vectors may elicit more effective T-cell responses than adjuvant preparations, recombinant vaccinia virus (VV18) and M. bovis BCG (BCG18) vectors expressing the 18-kDa protein of M. leprae were prepared. Both VV18 and BCG18 stimulated anti-18-kDa protein antibody and lymphocyte proliferative responses. Sequential immunization with VV18 followed by BCG18 induced higher levels of specific immunoglobulin G2a antibodies than immunoglobulin G1 antibodies, in contrast to immunization with VV18 or BCG18 alone. The protective efficacy of immunization with VV18 from a challenge with BCG18 was examined in two murine models of mycobacterial infection. After intravenous challenge, mice immunized with recombinant vaccinia virus exhibited lower initial levels of replication and earlier clearance of BCG18 from their spleens than mice immunized with vaccinia virus expressing an unrelated protein. After footpad infection in a dissemination model, there was earlier clearance of BCG18 from specifically immunized mice. However, immunization of mice with VV18 did not prevent a productive mycobacterial infection.
PMCID: PMC174066  PMID: 8675337
22.  Protection of sheep against caseous lymphadenitis by use of a single oral dose of live recombinant Corynebacterium pseudotuberculosis. 
Infection and Immunity  1994;62(12):5275-5280.
An inactive form of the Corynebacterium pseudotuberculosis phospholipase D (PLD) gene was constructed and expressed in a PLD-negative strain (designated Toxminus) of C. pseudotuberculosis. Antibody responses specific to Toxminus and both Toxminus and PLD proteins were detected in sheep following oral administration of Toxminus or Toxminus expressing the PLD toxoid, respectively. However, only those sheep vaccinated with Toxminus expressing PLD toxoid were protected against wild-type challenge. These results confirm the importance of PLD as a protective antigen and demonstrate both the potential for developing an oral caseous lymphadenitis vaccine and C. pseudotuberculosis Toxminus as a live vaccine vector.
Images
PMCID: PMC303265  PMID: 7960105
23.  Expression of ovine gamma interferon in Escherichia coli and Corynebacterium glutamicum. 
Bacteria of two species, Escherichia coli and Corynebacterium glutamicum, were used as hosts to express recombinant ovine gamma interferon as a fusion protein with glutathione S-transferase. The recombinant gamma interferon produced by both bacteria was biologically active in vitro and was recognized by anti-gamma interferon monoclonal antibodies. E. coli produced large amounts of soluble recombinant protein which could be purified by a simple affinity chromatography method. Only a small fraction of the recombinant protein made by C. glutamicum was recovered by this method. Expression of recombinant protein in C. glutamicum was unstable but could be controlled by increased regulation of the tac promoter. Both hosts expressed ovine gamma interferon at high levels, with the recombinant protein making up a significant proportion of the cellular protein content.
Images
PMCID: PMC201530  PMID: 8017943
24.  Male fertility after VAPEC-B chemotherapy for Hodgkin's disease and non-Hodgkin's lymphoma. 
British Journal of Cancer  1994;69(2):379-381.
Semen analysis was performed in 14 men a median of 13.5 months after completion of VAPEC-B chemotherapy for Hodgkin's disease or non-Hodgkin's lymphoma. Semen from 12 patients contained motile spermatozoa, and in nine cases the count was > 20 million ml-1. One patient was azoospermic (VAPEC-B followed by pelvic radiotherapy) and another had a count of 21 million ml-1 but sperm were non-motile. These findings suggest that, in the majority of cases, VAPEC-B chemotherapy does not cause permanent damage to the male germinal epithelium. A more detailed study of gonadal function in males and females before and after treatment with VAPEC-B for Hodgkin's disease is currently in progress.
PMCID: PMC1968681  PMID: 7507693
25.  Monocytoid B cell lymphoma. 
Journal of Clinical Pathology  1991;44(1):39-44.
The clinical, light microscopic, ultrastructural, immunocytochemical and cytogenetic features of a case of monocytoid B cell lymphoma were investigated. The tumour initially affected the cervical and supraclavicular nodes, but 33 months later affected the left parotid salivary gland. The patient had subclinical Sjögren's syndrome. The neoplastic cells showed characteristic morphological features and had peri- and interfollicular distribution in the node. Immunocytochemically the tumour cells were L26, 4KB5, MB2, CD19, CD20, CD22 and IgM/kappa positive. Prominent plasmablastic plasmacytoid differentiation was present in the recurrent tumour, suggesting an origin from post-follicular B cells. The lymphoma cells showed unusual cytogenetic abnormalities.
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PMCID: PMC497012  PMID: 1997532

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