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Biomedical subjects

C R Pinkerton

Publications and source records attributed to C R Pinkerton.

At least 37 records · Page 2Linked to original sources
PubMed2001

Outcome of relapsed or refractory childhood B-cell acute lymphoblastic leukaemia and B-cell non-Hodgkin's lymphoma treated with the UKCCSG 9003/9002 protocols.

Twenty-six children with B-cell acute lymphoblastic leukaemia (B-ALL) or Murphy Stage III or IV B-cell non-Hodgkin's lymphoma (B-NHL) progressed or relapsed after first-line therapy with a short, intensive multiagent chemotherapy regimen [United Kingdom Childhood Cancer Study Group (UKCCSG) 9003] (n = 62) or a slightly less intensive regimen (UKCCSG 9002) (n = 112). Eight patients (4.6%) never achieved complete remission (CR) and 18 (10.3%) relapsed. Second-line therapy resulted in remission for eight patients (30%). All patients initially treated with the 9003 protocol died. Three patients (11.5%) in the 9002 group, including one who never achieved CR in the primary site, are alive after second-line therapy. This study confirms that the prognosis of relapsed or refractory B-ALL/B-NHL is poor and exceptionally so if relapse occurred less than 6 months from diagnosis. High-dose therapy with stem cell rescue was used in only seven patients; its role needs to be studied further.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Response to influenza immunisation during treatment for cancer.

AIMS: To assess the annual risk of influenza infection in children with cancer and the immunogenicity of a trivalent split virus influenza vaccine in these children. METHODS: Eighty four children with cancer were tested for susceptibility to the circulating strains of influenza virus in autumn 1995 and 1996. Non-immunised children were reassessed the following spring for serological evidence of natural infection. Forty two patients received two doses of influenza vaccine. These children were receiving continuing chemotherapy for acute lymphoblastic leukaemia or were within six months of completing chemotherapy. RESULTS: Among the 84 children tested for influenza virus susceptibility only 8% of patients were fully protected (antibody titres >/= 40) against all three of the prevalent influenza virus strains; 33% were susceptible to all three viruses. Evidence of acquired natural infection was seen in 30% of unimmunised patients. Among immunised susceptible patients, 66% made some protective response to the vaccine and 55% showed protective antibody titres to all three viral strains following vaccination. Older age was associated with increased response to the H1N1 and H3N2 vaccine components, but total white cell count or neutrophil count at immunisation, type of cancer, or length of time on treatment for acute lymphoblastic leukaemia did not affect response. CONCLUSIONS: Most children with cancer studied were at risk of influenza infection. A significant response to immunisation was seen, supporting annual influenza vaccination for children being treated for cancer.

Acute Disease↗
PubMed2001

In vitro prevention of the emergence of multidrug resistance in a pediatric rhabdomyosarcoma cell line.

We have established preclinical models for the development of drug resistance to vincristine (a major drug used in the treatment of pediatric rhabdomyosarcoma) using cell lines. The RD cell line has a mutant P53 phenotype and does not have detectable P-glycoprotein (P-gp) or multidrug resistance-related protein (MRP) despite expressing low levels of mdr-1 mRNA, which encodes P-gp and mrp1 mRNA. Resistant variants of RD were derived by exposure to increasing concentrations of vincristine. This was repeated on six occasions, resulting in three cell lines which could tolerate 64 x the IC(50) concentration. Six independent agents were tested for their ability to prevent the development of resistance in this model. Despite at least 10 attempts, resistance did not develop in the presence of the multidrug resistance (MDR) modulators PSC833, VX710, and XR9576. This strongly suggests that these agents may delay or even prevent the development of resistance to vincristine. This was also confirmed in a second rhabdomyosarcoma cell line, Rh30. In contrast, the agents indomethacin (MRP1 modulator), CGP41251 (protein kinase C inhibitor), and dexrazoxane (putative MDR prevention agent) did not affect the development of resistance in the RD model. Characterization of the resistant cell lines indicated the presence of increased mdr-1 and P-gp expression, which resulted in resistance to the agents doxorubicin, etoposide, and vincristine but not cisplatin. The resistance could be modulated using PSC833 or VX710, confirming that functional P-gp is present. No apparent differences were seen between the resistant cell lines derived in the absence and presence of the various agents. These experiments strongly suggest that the development of MDR may be preventable using modulators of MDR and merit clinical studies to test this hypothesis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Interventions for early stage Hodgkin's disease in children.

BACKGROUND: Hodgkin's Disease is one of the most curable cancers in children, particularly at the early stages. The debate rests now more with retention of high cures and eliminating treatment sequelae. OBJECTIVES: To assess relapse free survival and overall survival rates in children with Stage l-llA Hodgkin's Disease treated with radiotherapy, chemotherapy or a combination of the two treatments. SEARCH STRATEGY: MEDLINE, EMBASE, CINAHL, Cancer-CD and the Cochrane Library were searched for randomised controlled trials. Key words included 'Hodgkin's Disease', 'Reed-Sternberg cells' and variations of 'child'. SELECTION CRITERIA: Treatments with a combination of the following therapies; involved field radiotherapy, extended field radiotherapy, anthracycline based chemotherapy regimens, or alkylating chemotherapy agents. Patients included children to 19 years of age. DATA COLLECTION AND ANALYSIS: Seven papers were identified as meeting the selection criteria. Of these four were usable, though one only covered a small section of the paper. It was not possible to combine the outcomes as they covered different treatment regimens and the numbers in one study were inaccurate. MAIN RESULTS: The results comparing IF with EF radiotherapy for children are based on one large multi-centred trial. Although the study is substantial and methodologically rigorous, the evidence for efficacy rests simply on this one trial. The results from the other three studies are not generalizable. The outcomes could not be combined as the studies assessed different treatment regimens. In addition there is little evidence to suggest that the methodological quality, particularly in terms of randomisation and simple arithmetic, is of a sufficiently robust nature in two of the studies. REVIEWER'S CONCLUSIONS: The treatment of Hodgkin's Disease Stage l -llA for children has undergone considerable evolution and development in the previous three decades with the introduction and refinement of combined modality treatments. There is now overall consensus that the prognosis for these patients following a short course of chemotherapy and low dose local radiotherapy is very good with a large percentage achieving long-term survival or relapse free survival. The main issues and problems facing practitioners in the field is the reduction and management of late effects and sequelae of treatment. The evidence for this overall agreement is based on a mass of cohort studies that have influenced changes in practice and significantly improved outcomes. However, apart from the collaborative study looking at radiotherapy alone, there is little evidence from randomised controlled trials to support this consensus.

Antineoplastic Agents↗
PubMed2000

Initial measurements of ifosfamide and cyclophosphamide in patients using (31)P MRS: pulse-and-acquire, decoupling, and polarization transfer.

Ifosfamide and cyclophosphamide are (31)P-containing alkylating agents used widely in the treatment of cancer. In this communication it is demonstrated that signals from these agents may be detected in the livers of patients undergoing treatment using (31)P MRS at 1.5 T. In vitro, signals are enhanced 4-fold by use of (1)H-decoupling, with a B(1) field of 100 Hz at -150 Hz relative to water. Polarization transfer (BINEPT) enhances signals in vitro by a further factor of 5.5. Preliminary results using the double-resonance methods in vivo show that the technique is practicable although enhancements may be less than observed in vitro. Factors affecting signal enhancement in vivo are evaluated. Magn Reson Med 44:180-184, 2000.

Antineoplastic Agents, Alkylating↗
PubMed2000

Induction chemotherapy in metastatic neuroblastoma--does dose influence response? A critical review of published data standards, options and recommendations (SOR) project of the National Federation of French Cancer Centres (FNCLCC).

The purpose of this study was to determine, from a review of published data, whether in stage 4 neuroblastoma in children over 1 year of age, the dose or scheduling of induction chemotherapy influenced the response rate in distant metastases. Publications relating to induction chemotherapy since the introduction of cisplatin/epipodophyllotoxin combinations were identified using Medline, Current Contents and personal reference lists. Thirteen publications were identified which described 17 regimens involving 948 children. The doses and the scheduling of the various regimens were compared with a standard regimen OPEC (vincristine, cisplatin, teniposide, cyclophosphamide). These were correlated with the reported response rates in the bone marrow. Due to a lack of standardisation in the nature of restaging investigations, timing of restaging and definitions of response it was difficult to compare all studies. The complete response rate at distant metastases ranged from less than 40% to over 90%. For individual drugs; the comparative doses given in each course ranged up to 4.2 g/m(2) for cyclophosphamide, 280 mg/m(2) for cisplatin, 600 mg/m(2) for etoposide and 4.5 mg/m(2) for vincristine. There was no evidence of any positive correlation between response rate in the marrow and either the dose of any individual drug or the schedule used. In contrast to a previous study which included a number of older studies where disease assessment was even more variable, this analysis has failed to show any justification for the routine use of very intensive induction regimens in this disease. Such an approach should only be taken in the context of randomised trials in which timing and methods of reassessment can be standardised. Until such studies demonstrate superiority either in terms of response rate or progression-free survival lower morbidity regimens should remain the standard therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Autologous bone marrow transplantation for childhood acute lymphoblastic leukaemia in second remission - long-term follow-up.

From 1984 to 1996, 31 consecutive children without sibling donors, aged 5-19 years (median 8) with acute lymphoblastic leukaemia (ALL) in second complete remission (CR), received unpurged autologous bone marrow transplantation (ABMT) after melphalan and single fraction total body irradiation (TBI). ABMT was performed using fresh unmanipulated marrow harvested after standard reinduction and consolidation therapy 2-11 months (median 5) after relapse. With a median survival of 2.9 years the probability of survival for all patients in continuing second CR was 45.1% (95% CI, 24%-62%) after 5 years. Regimen-related and non-leukaemia mortality was 7% (95% CI, 2%-26%). The longest time to second relapse from ABMT was 3.1 years. Pituitary and gonadal dysfunction requiring hormonal replacement therapy occurred in the majority of long-term survivors. Twelve patients developed cataracts. ABMT with melphalan/single fraction TBI has proved an effective anti-leukaemia treatment with low regimen-related mortality but significant long-term morbidity. The current approach of allogeneic BMT from an unrelated donor when no sibling donor is available, following conditioning with cyclophosphamide/ fractionated TBI has resulted in a reduced relapse rate and improved short-term overall survival in the treatment of relapsed childhood ALL. However, long-term results are awaited.

Adolescent↗
PubMed2000

Improved outcome in children with advanced stage B-cell non-Hodgkin's lymphoma (B-NHL): results of the United Kingdom Children Cancer Study Group (UKCCSG) 9002 protocol.

From July 1990 to March 1996, 112 children with stage III or IV B-cell non-Hodgkin's lymphoma (B-NHL) with up to 70% FAB L3-type blasts (n = 42) in the bone marrow without central nervous system (CNS) disease were treated on the United Kingdom Children Cancer Study Group (UKCCSG) 9002 protocol (identical to the French LMB 84). The median age was 8.3 years. There were 81 boys and 31 girls. According to the extent of the primary disease, patients were sub-staged into three groups: IIIA with unresectable abdominal tumour (n = 39); IIIB with abdominal multiorgan involvement (n = 57) and IIIX with extra-abdominal primary lymphoma often presenting as pleural effusion (n = 16). Univariate and multivariate analyses were carried out to evaluate the prognostic significance of lactate dehydrogenase (LDH) level at diagnosis, the sub-stage and the time to achieve complete remission (CR). With a median follow up of 48 months (range 12-92), the overall and event free survival (EFS) is 87% (95% confidence interval (CI) 79.2-92.1 %) and 83.7% (95% CI 76.3-89.2%) respectively. Six patients (5.4%) never achieved CR, of whom one is alive following high-dose therapy. Eight patients (7.1%) relapsed after achieving CR, three are alive after second-line therapy. There were three early toxic deaths (2.7%), mainly from infection, and one late death from a second cancer. There was no significant difference in EFS according to LDH level at diagnosis, the sub-stage or the time to CR. This study confirms the overall good prognosis and low rate of toxic deaths in patients with advanced B-NHL treated with this intensive regimen. No significant difference in EFS according to the sub-stage, the time to achieve CR or LDH level at diagnosis making it difficult to identify a group that should not receive intensive therapy.

Adolescent↗
PubMed2000

Characterization and modulation of drug resistance of human paediatric rhabdomyosarcoma cell lines.

The role of multidrug resistance (MDR) and p53 functional status in the treatment of paediatric rhabdomyosarcoma is unclear. We have characterized a panel of seven human rhabdomyosarcoma cell lines for MDR and p53 phenotype. None of the cell lines had P-glycoprotein (P-gp) or multidrug resistance-related protein (MRP) detectable by Western blotting, whereas immunohistochemistry suggested that very low levels of MDR proteins may be present in some of the lines. RT-PCR studies indicated that mdr-1, mrp-1 and Irp mRNA was present in 5/7, 7/7 and 5/7 lines respectively. The function of p53 is compromised in six of the lines, either through mutation of the p53 gene or by overexpression of mdm-2. The sensitivity of many of the cell lines to vincristine could be modulated above 2-fold and as high as 16-fold using two modulating agents, PSC833 and VX710 (with VX710 being a significantly more potent modulator of the rhabdomyosarcoma lines). PSC833 also increased vincristine accumulation in all of the lines from 1.2- to 2.2-fold. These results suggest that some of these cell lines have low levels of multidrug resistance. The level of MDR proteins is very low and therefore difficult to detect, but may be sufficient to confer low-level, but clinically relevant, resistance to some cytotoxic agents, especially vincristine. These cell lines will therefore provide a suitable model to test new strategies in treatment and for further understanding relationships between protein expression and drug resistance.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Treatment of nondysgerminomatous ovarian germ cell tumors: an analysis of 69 cases.

BACKGROUND: Combination chemotherapy has dramatically improved the prognosis of patients with nondysgerminomatous ovarian germ cell tumors (NDOGCT). However, guidelines are needed for the identification of patients at risk of relapse. METHODS: The authors performed a retrospective analysis of women with NDOGCT managed during the period 1970-1994 at the Royal Marsden Hospital and other hospitals of the London Gynaecological Oncology Group. RESULTS: Sixty-nine women were included; their median follow-up was 5.7 years (minimum, 12 months). The median age was 21 years (range, 4-44 years), with a histology of immature teratoma (IT) for 17 patients, endodermal sinus tumor (EST) for 20 patients, and mixed tumors for 32 patients. Thirty-five patients (51%) had Stage I disease. Nine patients with Stage I tumors were observed without further therapy (six with IT and three with mixed tumors), and one relapsed. Seven patients received non-platinum-based chemotherapy, and four relapsed. A total of 52 patients were treated with platinum-based chemotherapy, with relapse free and overall survival rates of 87% (95% confidence interval [CI], 73-93%) and 84% (95% CI, 70-91%), respectively. Of these patients, relapse was seen in 0 of 9 IT patients, 1 of 25 patients with mixed tumors, and 6 of 18 EST patients. With alpha-fetoprotein (AFP) > 1000 kU/L, relapse was seen in 6 of 18 patients compared with 1 of 33 relapses with lower AFP levels. In multivariate analysis, including all patients who received chemotherapy, AFP >1000 kU/L (P = 0.001) and non-platinum-based chemotherapy (P = 0.005) were associated with relapse. When only patients given platinum-based treatment were considered, EST histology (P = 0.003) and AFP >1000 kU/L (P = 0.003) were associated with relapse in univariate analysis; however, these factors were linked. No malignant tumor was found at second-look surgery performed on 24 patients. Of 26 women assessable for fertility, 24 subsequently recommenced regular menstrual function, and 11 patients had pregnancies. CONCLUSIONS: Platinum-based chemotherapy has been confirmed to be effective in the management of patients with NDOGCT. Relapses were principally seen among patients with AFP >1000 kU/L or pure EST histology. Efforts to improve outcome need to focus on patients with EST, whereas less intensive management strategies may be appropriate for some patients with IT.

Adolescent↗
PubMed1999

Local therapy and other factors influencing site of relapse in patients with localised Ewing's sarcoma. United Kingdom Children's Cancer Study Group (UKCCSG).

Relapse patterns have been documented in 191 children with localised Ewing's sarcoma treated with the United Kingdom Children's Cancer Group (UKCCSG) Ewing's Tumour regimen ET2. All received chemotherapy comprising ifosfamide, vincristine, doxorubicin and actinomycin D. Local treatment modality was excision and or radiotherapy depending on tumour site and response to primary chemotherapy. Although not strictly comparable, due to the clinical indications used for each modality, local relapse rates were very low and were similar, irrespective of the type of local treatment modality: radiotherapy (3/56), surgery (7/114) or a combination (0/20). Combined relapse (local + distant) rates were similarly low irrespective of the type of local therapy: radiotherapy (4/56), surgery (4/114) or a combination (0/20). Overall survival was lower in females (P = < 0.04), older children (P = < 0.002) and those with primaries at sites other than long bones (P = < 0.02). It is concluded that with effective intensive chemotherapy combined with either radiotherapy or surgery, local control in this study was excellent at sites other than the pelvis. Preventing distant relapse, predominantly to lung and bone, remains the major challenge.

Adolescent↗
PubMed1999

BIRICODAR (VX-710; Incel): an effective chemosensitizer in neuroblastoma.

Clinical studies have suggested that both MDR1 and MRP may play a significant role in the chemosensitivity and outcome of neuroblastoma. To clarify the nature of multidrug resistance (MDR) in this tumour a series of six neuroblastoma cell lines have been characterized with regard to P-glycoprotein, MRP and LRP expression using immunocytochemistry and expression of MDR1, MRP, LRP and topoisomerase II genes using reverse transcription polymerase chain reaction (RT-PCR). By RT-PCR, all lines expressed MRP, five expressed LRP and four expressed MDR1, but protein levels of each of these were variable. Chemosensitization to a range of MDR-associated drugs (vincristine, doxorubicin, etoposide, taxotere, topotecan) and non-MDR-associated drugs (cisplatin, melphalan) by three modulating agents, cyclosporin A, PSC 833 and the novel Biricodar (VX-710; Incel), was evaluated using a colourimetric cytotoxicity assay (MTS). Alteration of daunorubicin efflux by these agents was evaluated using FACS analysis. Clonogenic assay was used to study the influence of these chemosensitizers on vincristine cytotoxicity. Marked sensitization to vincristine was observed in MDR1-positive lines, and a similar but less consistent effect was seen with taxotere, doxorubicin and etoposide. With MRP-positive, MDR-negative lines, only VX-710 caused consistent sensitization. These data confirm MDR1 and MRP expression as contributory factors in chemoresistance in neuroblastoma and indicate that VX-710 may be a useful modulator of both mechanisms and worthy of clinical evaluation in this tumour.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Morphine and morphine-6-glucuronide in the plasma and cerebrospinal fluid of children.

AIMS: To measure morphine and morphine-6-glucuronide in the plasma and cerebrospinal fluid of children following a single intravenous dose of morphine. METHODS: Twenty-nine paired samples of cerebrospinal fluid and plasma were collected from children with leukaemia undergoing therapeutic lumbar puncture. An intravenous dose of morphine was administered at selected intervals before the procedure. Concentrations of morphine and morphine-6-glucuronide (M6G) were measured in each sample. Morphine was measured using a specific radioimmunoassay (r.i.a.) and M6G was measured using a novel enzyme-linked immunosorbent assay (ELISA). RESULTS: The ELISA for measuring M6G was highly sensitive. The intra-and interassay variations were less than 15%. Using a two-compartment model for plasma morphine, the area under the curve to infinity (AUC, 7143 ng ml-1 min), volume of distribution (3.6 l kg-1 ) and elimination half-life (88 min) were comparable with those reported in adults. Clearance (35 ml min-1 ) was higher than that in adults. Morphine-6-glucuronide was readily synthesized by the children in this study. The elimination half-life (321 min) and AUC (35507 ng ml-1 min) of plasma M6G were much greater than those of morphine. CONCLUSIONS: Extensive metabolism of morphine to M6G in children with cancer has been demonstrated. These data provide further evidence to support the importance of M6G accumulation after multiple doses. There was no evidence that morphine passed more easily into the CSF of children than adults.

Area Under Curve↗
PubMed1999

High-dose melphalan with autologous stem-cell rescue in metastatic rhabdomyosarcoma.

PURPOSE: The European Collaborative MMT4-91 trial was conducted as a prospective nonrandomized study to evaluate the potential benefit of high-dose melphalan as consolidation of first complete remission in children with stage IV rhabdomyosarcoma. PATIENTS AND METHODS: Fifty-two patients in complete remission after six courses of chemotherapy received "megatherapy": 42 received melphalan alone, whereas 10 received melphalan in combination with etoposide, carboplatin/etoposide, or thiotepa/busulfan and etoposide. The outcome of this group of patients was compared with that observed in 44 patients who were also in complete remission after six courses of identical chemotherapy (plus surgery or radiotherapy) but went on to receive a total of up to 12 courses of conventional chemotherapy (four cycles). No differences were found between the two groups regarding clinical characteristics, chemotherapy received before complete remission, or response to chemotherapy. In particular, there was no significant difference between the groups for site of primary tumor, histologic subtype, age at presentation, presence of bone or bone marrow metastases, or number of metastases. RESULTS: The 3-year event-free survival (EFS) and overall survival (OS) rates were 29.7% and 40%, respectively, for those receiving high-dose melphalan or other multiagent high-dose regimens and 19.2% and 27.7%, respectively, for those receiving standard chemotherapy. The difference was not statistically significant (P =.3 and P =.2 for EFS and OS, respectively). There was a significant prolongation in the time from the last day of high-dose chemotherapy or the end of chemotherapy cycle 4 to the time of relapse in those receiving megatherapy (168 days for patients receiving megatherapy v 104 days for those receiving standard therapy; P =.05). CONCLUSION: The addition of a high-dose alkylating agent to consolidation therapy may have prolonged progression-free survival in this poor-risk patient group, but it did not significantly improve the ultimate outcome.

Adolescent↗