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Biomedical subjects

C R Pinkerton

Publications and source records attributed to C R Pinkerton.

At least 73 records · Page 4Linked to original sources
PubMed1997

Does histology influence outcome in childhood Hodgkin's disease? Results from the United Kingdom Children's Cancer Study Group.

PURPOSE: Histology has been identified as an important prognostic factor in Hodgkin's disease (HD) in adults. Information regarding the impact of histology on outcome in childhood HD is scarce. This study determines the effect of histology on the overall survival (OS) or progression-free survival (PFS) in a national series of children treated in a standardized manner. PATIENTS AND METHODS: The results of treatment of 331 assessable patients, treated between January 1, 1982 and June 30, 1992, in the United Kingdom Children's Cancer Study Group (UKCCSG) Hodgkin's study I were reviewed to evaluate OS, PFS, and deaths according to stage and histology. Treatment was either involved-field radiation alone (stage IA) or chlorambucil, vinblastine, procarbazine, and prednisolone (ChlVPP) chemotherapy with or without mediastinal radiation. All were clinically staged at diagnosis. RESULTS: Nodular sclerosing (NS) HD was the most common histologic subtype (155 of 331 patients [47%]) and was uniformly distributed through all stages. Lymphocyte-depletion (LD) HD was extremely uncommon (< 1%). Mixed-cellularity (MC) HD had the highest relapse rate, but this was only significant (P < .05) in stage I patients who received local irradiation alone. There was no other statistically significant difference in OS and PFS between the various histologic subtypes. Multivariate analysis for PFS and OS confirmed that stage was the most important prognostic factor and that histology did not have an effect after stratification by stage. CONCLUSION: This study demonstrates that with effective multiagent chemotherapy, histologic subtype does not influence outcome. The high relapse rates in stage I MC subtype indicates that MC HD is biologically aggressive and systemic treatment with or without local irradiation may be indicated. The high relapse rate in stage IV patients appeared to be independent of histology.

Actuarial Analysis↗
PubMed1996

The molecular pathology of small round-cell tumours--relevance to diagnosis, prognosis, and classification.

Substantial improvements have been made in the treatment and survival of children with SRCT, resulting in an increased emphasis on precise histological diagnosis. Although diagnostic procedures such as electron microscopy and immunocytochemistry contribute in poorly differentiated cases, an accurate diagnosis can remain elusive in a proportion of SRCTs. The cytogenetic and molecular genetic abnormalities characteristic of the different SRCTs can now be consistently and rapidly identified from minimal quantities of tumour material, using the techniques of FISH and PCR. This, coupled with the identification of novel phenotypic characteristics, has had a major impact on SRCT diagnosis. The aim of a tumour classification is to identify disease entities which are biologically distinct and whose recognition is of clinical value. The recent advances described above demonstrate that the SRCTs are genotypically and phenotypically distinct tumour types and that the genetic abnormalities represent key alterations that influence both the morphology and the clinical behaviour of the tumour. This suggests that these advanced phenotypic and genotypic analyses should form an integral and complementary part of the laboratory assessment and clinical management of these forms of paediatric cancer.

Bone Neoplasms↗
PubMed1996

Interphase fluorescence in situ hybridization detection of t(2;13)(q35;q14) in alveolar rhabdomyosarcoma--a diagnostic tool in minimally invasive biopsies.

The identification of t(2;13)(q35;q14) is a useful aid in the accurate diagnosis of rhabdomyosarcoma, distinguishing it from other small round cell tumours and supporting the distinction between alveolar and embryonal forms. Cytogenetic analysis is difficult and with the increased use of minimally invasive biopsy methods and primary chemotherapy, adequate tumour material is not always available. To overcome these difficulties, two-colour interphase fluorescence in situ hybridization (FISH) to detect t(2;13)(q35;q14) was developed and its utility in assessing minimally invasive biopsies was investigated. Two cosmid clones which mapped proximal or distal to the breakpoint region 13q14 and one yeast artificial chromosome clone that mapped distal to the 2q35 breakpoint were identified. In interphase cells containing t(2;13)(q35;q14), the configuration of cosmid and yeast artificial chromosome signals demonstrated the presence of the translocation. Five cases of rhabdomyosarcoma were analysed by interphase FISH. The t(2;13)(q35;q14) was detected in all four alveolar tumours and was confirmed by cytogenetics in two cases, but was absent in one embryonal tumour. This sensitive detection method is applicable to minimal amounts of fresh or frozen tumour.

Adolescent↗
PubMed1996

der(16)t(1;16)(q21;q13) as a secondary change in alveolar rhabdomyosarcoma. A case report and review of the literature.

Alveolar rhabdomyosarcoma is an aggressive childhood tumor that exhibits muscle cell differentiation. Cytogenetically, it is characterized by t(2;13)(q35;q14); no consistent secondary abnormalities have been reported. Cytogenetic analysis of bone marrow in a case of alveolar rhabdomyosarcoma revealed t(2;13)(q35;q14) and der(16)t(1;16)(q21;q13). The present case and a review of the literature suggest that up to 11% of these tumors possess der(16)t(1;16)(q21;q13). This is similar to the incidence observed in the Ewing family of tumors, where unbalanced der(16)t(1;16) translocations, resulting in partial trisomy of 1q, are regarded as a consistent secondary cytogenetic change.

Child↗
PubMed1996

Response of previously untreated metastatic rhabdomyosarcoma to combination chemotherapy with carboplatin, epirubicin and vincristine.

This study aimed to assess the response to a novel combination chemotherapy containing carboplatin plus epirubicin in previously untreated children with metastatic rhabdomyosarcoma. 81 children (< or = 18 years) were treated between 1989 and 1994 with a combination of carboplatin, epirubicin and vincristine, given as initial therapy as part of a multicentre European trial (SIOP Intergroup Study of Stage IV Malignant Mesenchymal Tumours in Children). The chemotherapy regimen (CEV) was: carboplatin 500 mg/m2 plus epirubicin 150 mg/m2 administered on day 1, and vincristine 1.5 mg/m2 administered on days 1 and 7. Response was evaluated at day 21. 2 patients achieved complete remission and 41 patients partial remission, with an overall response rate of 53% (95% confidence interval 45-76%). Three patients showed progressive disease (4%). Toxicity was mainly haematological, with 52% experiencing grade IV neutropenia and 34% grade IV thrombocytopenia. Mucositis and infections were not severe. There were no toxic deaths. The combination of carboplatin, epirubicin and vincristine is effective and well tolerated in patients with metastatic rhabdomyosarcoma.

Adolescent↗
PubMed1996

Lymphoblastic leukaemia and non-Hodgkin's lymphoma.

The outcome in childhood leukaemia has shown steady improvement over the last decade and efforts are now concentrated on the stratification of patients by risk factors which may avoid overtreatment of good risk patients and limit dose escalation strategies, including those with bone marrow transplantation, to the higher risk patients. In ALL, risk stratification is based on the presenting white cell count, sex, age and cytogenetics of the tumour cells. Even in acute myeloid leukaemia, the outcome with chemotherapy alone is now sufficient to limit elective allogeneic bone marrow transplantation to those who do not have cytogenetically favourable disease. In non-Hodgkins lymphoma, a dramatic improvement in overall survival from 50% to in excess of 80% has been achieved by an escalation in dose and dose intensity of chemotherapy. With this improvement, the prognostic influence of clinical staging has become less clear and recent efforts have concentrated on determining which groups of patients would be cured by less intensive treatment. As for ALL, there is concern about the potential late sequelae in these highly curable children. There remain groups of unusual tumour types, such as anaplastic large cell and peripheral T cell lymphoma, where there remains much to be learned about the pathogenesis and clinical behaviour. The optimum treatment strategy for these subgroups remains to be clarified.

Adolescent↗
PubMed1996

Bone marrow transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia.

Between 1986 and 1995, 19 patients with Philadelphia chromosome-positive (Ph + ) acute lymphoblastic leukemia underwent 20 autologous (n = 9) or allogeneic (n = 11) blood or marrow transplant procedures in first (n = 12) or second (n = 3) remission, or in relapse (n = 5). Four patients died due to transplant-related causes, 11 relapsed at 3-39 months, one survives with disease which did not remit after transplant, and three are alive in continuous remission at 1, 26 and 65 months. Two of the relapsing patients are alive; one autografted patient after an allograft in second remission and one allografted patient after a donor leukocyte infusion. The projected overall survival is 37.5% at 3 years and 12.5% at 5 years. The 3-year probabilities of relapse and disease-free survival for autografted patients are 65.9% and 25.6% respectively, and for allografted patients, 63.4% and 21.8% respectively. The stage of the disease at the time of transplant or the type of transplant did not affect the outcome significantly, and late relapses beyond 3 years were seen after allogeneic as well as autologous transplantation. In our experience, the outcome of patients with Ph + acute lymphoblastic leukemia continues to be poor despite high-dose therapy due to high relapse rates, and the development of additional measures to enhance the antileukemic efficacy of bone marrow transplantation is necessary.

Acute Disease↗
PubMed1996

Central nervous system relapse after bone marrow transplantation for acute leukemia in first remission.

Four hundred and eighty-seven patients undergoing allogeneic or autologous BMT for acute leukemia in first remission received no prophylactic intrathecal chemotherapy after BMT. The conditioning regimen included total body irradiation in 433 (89%). Patients with acute lymphoblastic leukemia received cranial irradiation if they had no central nervous system (CNS) disease and all patients with CNS disease received craniospinal irradiation. Eleven of 311 patients examined had CNS disease at presentation, but none had active CNS disease at the time of BMT. Lumbar punctures were performed in 93 patients 1-2229 days (median 98) after BMT because of suspected CNS infection, hemorrhage or relapse (n = 65), or after systemic relapse (n = 28). CNS disease was seen in seven patients at 217-1209 days (median 340), none of whom had CNS disease pre-transplant. Systemic relapse had preceded CNS relapse by 4-207 (median 128) days in all seven and no isolated CNS relapse was seen. The actuarial risk of CNS and systemic relapse at 5 years was 2.9 and 35.9%, respectively. We conclude that CNS relapse is uncommon after BMT for acute leukemia in first remission, and that isolated CNS relapse is likely to be extremely uncommon. Therefore, routine prophylactic intrathecal chemotherapy is not warranted after BMT for acute leukemia in first remission.

Actuarial Analysis↗
PubMed1996

Long-term follow-up of patients undergoing allogeneic bone marrow transplantation for acute myeloid leukemia in first complete remission after cyclophosphamide-total body irradiation and cyclosporine.

Eighty-five patients (median age 28 years) with acute myeloid leukemia (AML) in first remission underwent allogeneic bone marrow transplantation (BMT) from HLA-identical siblings between 1978 and 1987 after cyclophosphamide and single-fraction total body irradiation with cyclosporine for graft-versus-host disease (GVHD) prophylaxis. The actuarial probabilities of development of acute and chronic GVHD were 57% and 47%, respectively. Twenty-six patients died of transplant-related complications at a median of 3.5 months, and two of unrelated causes. Seventeen patients relapsed at a median of 6.5 months. Forty patients were alive and well at 74-197 months (median 157) after BMT; seven (18%) with limited chronic GVHD requiring therapy. The actuarial 10-year probabilities of transplant-related death, relapse, and disease-free survival were 33%, 25% and 48% respectively. In multivariate analysis, infusion of a lower cell dose, development of GVHD, and age > 35 years were associated with increased transplant-related mortality, donor-recipient ABO incompatibility with a lower relapse rate, and age > 35 years and a lower cell dose with poorer disease-free survival. We conclude that with long-term follow-up, allografting in AML after cyclophosphamide-TBI and cyclosporine has resulted in disease-free survival that is comparable to most currently reported series. Patients who are alive and well 3-4 years after BMT have excellent prospects of long-term survival.

Adolescent↗
PubMed1996

Melphalan combined with a carboplatin dose based on glomerular filtration rate followed by autologous stem cell rescue for children with solid tumours.

Carboplatin and melphalan are two drugs whose toxicity profile makes them suitable for use in high doses followed by stem cell rescue. We report the use of high-dose carboplatin, with the dose based on glomerular filtration rate (GFR), combined with melphalan followed by autologous stem cell rescue in children with advanced stage or chemoresistant solid tumours. Thirty children were treated. After multiagent induction chemotherapy before BMT, 13 were in CR, five in VGPR, 11 in PR and one had progressive disease. They received melphalan, 180 mg/m2 and carboplatin, followed by autologous stem cell rescue. The dose of carboplatin was varied by GFR rather than fixed by surface area. The dose given ranged from 0.7 to 2.6 g/m2. Haematological and gastrointestinal toxicities were severe. Life-threatening or fatal toxicity was attributable to opportunistic infection in two cases and regimen-related in two cases. Of the 30 patients, 15 are alive and 13 disease-free at 4-36 months post-BMT. This simple two-drug combination has been used as consolidation of initial remission for patients with high-risk tumours. The toxicity is severe but tolerable. Use of a carboplatin dose based on GFR should optimise effectiveness in patients with good renal function and avoid excessive toxicity where renal function is impaired.

Adolescent↗
PubMed1995

Fusion of the EWS gene to a DNA segment from 9q22-31 in a human myxoid chondrosarcoma.

Southern blot analyses revealed a rearrangement of the EWS gene in a skeletal human myxoid chondrosarcoma. Interphase fluorescence in situ hybridization (FISH) studies, using cosmid clones F7 and G9 that flank the EWS locus on 22q12, confirmed the presence of this EWS gene abnormality. Cloning the rearranged EWS DNA fragment and mapping by FISH demonstrated that the EWS gene is joined to DNA sequences localised in 9q22-31. These findings are consistent with previous cytogenetic reports of a recurrent t(9;22)(q22-31;q11-12) in the myxoid variant of chondrosarcoma and reveal involvement of the EWS gene in a fourth type of human sarcoma.

Adult↗
PubMed1995

Diagnosis of Ewing's sarcoma and related tumours by detection of chromosome 22q12 translocations using fluorescence in situ hybridization on tumour touch imprints.

It is increasingly recognized that the identification of t(11;22)(q24;q12) is a useful aid in the accurate diagnosis of Ewing's sarcoma and related tumours. However, cytogenetic studies have a low success rate and adequate tumour is not always available. This study describes the use of fluorescence in situ hybridization (FISH) to detect translocations at 22q12, the site of the EWS gene involved in t(11;22)(q24;q12), on tumour touch imprints made from true cut core-needle biopsy and frozen tumour. Of the seven tumours analysed, five diagnosed as Ewing's sarcoma or primitive neuroectodermal tumour demonstrated chromosome translocation at 22q12. This is a rapid and reliable method to detect a diagnostically relevant chromosome translocation using minimal amounts of fresh or frozen tumour.

Adolescent↗
PubMed1995

Phase II study of rapid-scheduled etoposide in paediatric soft tissue sarcomas.

Twenty three patients with paediatric soft tissue sarcomas who had relapsed or refractory disease were treated with a rapid schedule of intravenous etoposide (100 mg/m2 daily on three consecutive days, weekly over 3 weeks). The regimen was well tolerated with predictable myelotoxicity. In 19 patients with rhabdomyosarcoma, there was a response rate of 42%. This appears to be better than previously reported with conventional three weekly schedules. These data indicate that for rhabdomyosarcoma, as for some other tumours, a divided dose regimen may be the optimal schedule and is worthy of further evaluation.

Adolescent↗
PubMed1995

A randomized comparison of intravenously administered granisetron versus chlorpromazine plus dexamethasone in the prevention of ifosfamide-induced emesis in children.

PURPOSE: To compare the efficacy and safety of intravenously administered granisetron with those of chlorpromazine plus dexamethosone in the prevention of ifosmamide-induced emesis in children with malignant disease. PATIENTS AND METHODS: Eighty-eight children, aged 2 to 17 years, were scheduled for ifosfamide therapy (> or = 3 gm/m2) for 2 or 3 consecutive days. On each day, children received granisetron, 20 microgram/kg intravenously, before ifosfamide therapy, plus up to two more doses within 24 hours if required, or chlorpromazine, 0.3 to 0.5 mg/kg intravenously, every 4 to 6 hours, plus dexamethasone, 2 mg/m2 intravenously every 8 hours. RESULTS: During the initial 24 hours, significantly fewer episodes of vomiting were recorded after granisetron administration (median number, 1.5 vs 7.0; p = 0.001), and the percentages of children having no more than one vomiting episode (51% granisetron vs 21% chlorpromazine-dexamethasone) and no worse than mild nausea (67% granisetron vs 38% chlorpromazine-dexamethasone) were lower after granisetron therapy (p < 0.01). Fewer children had sedation with granisetron (2 vs 19; p < 0.001); there were no extrapyramidal reactions during granisetron therapy compared with two during control therapy. CONCLUSION: Granisetron was superior to chlorpromazine-dexamethasone antiemetic therapy for children receiving ifosfamide therapy and deserves further study during other chemotherapy regimens.

Adolescent↗
PubMed1995

Continuous-infusion verapamil with etoposide in relapsed or resistant paediatric cancers.

This study evaluates the use of a multidrug resistance (MDR) modulator (verapamil) in combination with a standard dose of single-agent etoposide in relapsed or refractory paediatric malignancy. A total of 20 patients (median age 6.5 years) were treated with an infusion of verapamil (loading dose 0.1 mg kg-1, followed by continuous infusion 0.15 mg kg-1 h-1) for 72 h. Etoposide was given daily (150 mg m-2 day-1) for three doses (each over 1 h); the first dose was given 12 h into the verapamil infusion. Cardiovascular toxicity was monitored by ECG and 2 hourly blood pressure and pulse recordings. Verapamil and norverapamil plasma concentrations were measured daily. Disease response was assessed after two courses. A total of 29/35 treatment courses were given at the desired verapamil dose; five courses required a dose reduction owing to cardiovascular toxicity. No patient required intensive monitoring. All patients who developed cardiovascular toxicity were over 14 years old. There was no correlation between plasma verapamil or norverapamil concentrations and toxicity. There were six partial responses (three rhabdomyosarcoma, three neuroblastoma) after two courses, but because of variation in the dose and schedule of etoposide these cannot be unequivocally contributed to MDR reversal. In conclusion, a regimen using a continuous infusion of verapamil combined with divided-dose etoposide is tolerable in children, and this strategy may be effective in refractory neuroblastoma and rhabdomyosarcoma.

Adolescent↗
PubMed1995

Childhood T-cell lymphoblastic lymphoma--does early resolution of mediastinal mass predict for final outcome? The United Kingdom Children's Cancer Study Group (UKCCSG).

This study presents a retrospective review of chest radiography in children with Murphy stage III T-cell lymphoblastic lymphoma. All received a standard leukaemia-based protocol with intensive induction, consolidation and continuing chemotherapy. Neither initial thoracic disease bulk nor the presence of a pleural effusion predicted outcome. However a significant difference was found when the 50 patients in whom the chest radiograph returned to normal within 60 days of commencing treatment were compared with the 18 patients with persistent mediastinal abnormalities, for both event-free [hazard ratio < or = 60 days to > 60 days (HR) 3.55 (95% CI 1.33-9.48); P = 0.007] and overall survival [HR 2.95 (95% CI 1.07-8.18); P = 0.03]. It appears that this relatively simple estimate of chemosensitivity may identify a group of particularly good-risk patients in whom drugs associated with late morbidity such as anthracyclines may be reduced and conversely a higher risk group in whom further intensification of treatment would be justified.

Antineoplastic Combined Chemotherapy Protocols↗