Search PubMed⌕ Search

Biomedical subjects

J C Marsh

Publications and source records attributed to J C Marsh.

At least 91 records · Page 5Linked to original sources
PubMed1991

A phase II trial of cyclosporin A in the treatment of refractory metastatic colorectal cancer.

Cyclosporin A (CSA) is an immunosuppressive agent that in experimental models has antiproliferative activity against colon cancer and other human neoplasms. A phase II trial was conducted to evaluate CSA in refractory colorectal malignancies. CSA was administered at a starting dose of 7.0 mg/kg twice daily (total dose, 14 mg/kg/day) and escalated to tolerance. Of 18 patients with measurable disease, 17 were evaluable. All had been treated with one fluorouracil-containing regimen. The European Cooperative Oncology Group (ECOG) performance status was 0 or 1 in 17 of the 18 patients. No objective responses were seen. Four patients maintained stable disease lasting from 10 to 75+ weeks. Significant toxicity occurred in 9 of 17 (53%) patients. Dose reduction was necessary in 10 of 17 (59%). Sustained escalation beyond the initial dose was possible in only two cases. Toxicities included nausea and vomiting (71%), nephrotoxicity (41%), fatigue (35%), flu-like symptoms (29%), and neurotoxicity (18%). In the dose and schedule employed in this trial, CSA is ineffective in refractory colorectal cancer and produces significant toxicity.

Bone Neoplasms↗
PubMed1991

In vitro assessment of marrow 'stem cell' and stromal cell function in aplastic anaemia.

An in vitro model system is described that allows separate assessment of 'stem cell' and stromal cell function in aplastic anaemia (AA). Seven patients with non-severe AA, who had responded to immunosuppressive therapy and had haematological evidence of residual marrow function, were studied. Of these, three with otherwise typical AA had an acquired clonal cytogenetic marker. Purified bone marrow haemopoietic progenitors labelled with CD34 monoclonal antibody were positively selected using the fluorescence activated cell sorter (FACS) from both normal subjects and from patients with AA. The generative capacity of the CD34 positive cells was assessed by monitoring the output of granulocyte/macrophage colony forming cells (CFU-GM) in the non-adherent layer after inoculation onto irradiated performed long-term marrow culture (LTBMC) stromas. Stromal function in AA was assessed by inoculating CD34 positive cells from normal bone marrow onto performed irradiated stromas from patients with AA. Haemopoietic cell ('stem cell') function in AA was assessed by inoculating CD34 positive cells from AA patients onto confluent irradiated normal marrow stromas. Using these crossover/LTBMC experiments, all patients exhibited severe defects in haemopoietic cell function with normal functioning stroma. The proportion of CD34 positive cells present in bone marrow from these patients was reduced compared with controls, they comprised fewer small primitive 'blast-like' cells which in normal bone marrow are known to possess marrow repopulating ability, and demonstrated reduced clonogenic potential in short-term colony assays.

Adult↗
PubMed1991

The influence of drug interval on the effect of methotrexate and fluorouracil in the treatment of advanced colorectal cancer.

The importance of the interval between methotrexate (MTX) and fluorouracil (5-FU) was studied in 168 patients with previously untreated, measurable, advanced colorectal cancer. They were randomized to receive MTX 200 mg/m2, followed by 5-FU 600 mg/m2 either 24 hours (arm A) or 1 hour (arm B) after MTX. All patients received leucovorin (LV) 24 hours after MTX, 10 mg/m2 orally every 6 hours for six doses. The regimen was repeated every 2 weeks, with 5-FU escalation as tolerated. Arm A was significantly better than arm B with respect to overall response rate (29% v 14.5%, P = .026), time to progression (TTP; median, 9.9 months v 5.9 months, P = .009), and survival (median, 15.3 months v 11.4 months, P = .003). Significant differences between arms were not found in response rate, median TTP, or median survival for the subgroup of patients with rectal primaries who comprised 20% of the patients in each arm. Significant factors prognostic for survival were performance status and number of metastases, as well as treatment. Age did not influence survival. Toxicity was similar in both arms and was primarily gastrointestinal. More mucositis was seen in arm A. There were four toxic deaths secondary to neutropenia and infection (one from arm A and three from arm B) and three other deaths (two from arm A and one from arm B) that were possibly drug-related. The combination of MTX with LV rescue and 5-FU is an active regimen in advanced colorectal cancer; its efficacy is increased in colon, but not rectal cancer, when the interval between MTX and 5-FU is long (24 hours) rather than short (1 hour).

Aged↗
PubMed1990

The hematopoietic defect in aplastic anemia assessed by long-term marrow culture.

Thirty-two patients with aplastic anemia (AA) have been studied using the long-term bone marrow culture (LTBMC) system. Of these patients, 26 had been treated with immunosuppressive therapy including antilymphocyte globulin (ALG) with or without androgens or high-dose methyl prednisolone. The remaining six patients either required no treatment or were studied before therapy was begun. Thirty-one of 32 patients (96%) had defective hematopoiesis in LTBMC with little or no evidence for the generation of primitive progenitor cells. The only exception was a patient with spontaneous recovery of aplasia in whom the defect was less marked. Crossover LTBMC experiments were performed in 23 cases by inoculating (1) patient marrow hematopoietic cells that had been depleted of adherent cells onto preformed, irradiated, normal stromas to assess the proliferative capacity of the hematopoietic cells, and (2) normal marrow hematopoietic cells that were depleted of adherent cells onto preformed, irradiated stromas from patients with AA to assess stromal function. Results of these experiments demonstrated a hematopoietic defect in all patients that was independent of the degree of hematologic recovery after ALG therapy. Only one patient had a probable stromal defect and this coexisted with a defect in the regenerative capacity of hematopoietic cells. We conclude that LTBMC is a sensitive method for detecting and defining the hematopoietic failure in AA. We suggest that the defective hematopoiesis present in all patients studied may be important in the pathogenesis of clonal evolution in AA.

Adolescent↗
PubMed1990

A phase II trial of carboplatin (NSC 241240) in advanced prostate cancer, refractory to hormonal therapy. An Eastern Cooperative Oncology Group pilot study.

Twenty-nine patients with metastatic prostate cancer progressing after hormonal therapy (orchiectomy 19, diethylstilbestrol 10) and who had never received cytotoxic therapy were treated with carboplatin. Patients had good clinical performance status (66% PS 0,1) and adequate renal (creatinine less than 2.0 mg/dL) and bone marrow function. The standard dose of carboplatin administered was 400 mg/sq m. Seventeen patients received this dose and 12 either 320 mg/sq m or 250 mg/sq m based on reduced renal function or prior radiation. Five patients had bidimensionally measurable disease: one experienced a partial regression of cervical lymph node metastases of 97 days duration. Twenty-four patients had metastatic disease evaluable by clinical status, bone scan and acid phosphatase. In one patient greater than 50% reduction in number of abnormal areas of bone scan uptake occurred; 3 patients experienced improvement in clinical status; in no patient did an elevated prostate acid phosphatase return to normal. All patients entered on study have progressed and died: median time to progression was 94 days (6 to 625 days); median survival was 297 days (6-1152 days). The primary toxicity of carboplatin was myelosuppression. The median WBC and platelet nadirs after cycle one were 3150/cu mm and 93,000/cu mm, respectively. Dose escalations to grade 2 or greater myelosuppression were mandated. Twenty-six achieved at least grade 2 myelosuppression during carboplatin treatment. We conclude that carboplatin administered at this dose and schedule has no important activity in hormone refractory prostate cancer.

Bone Neoplasms↗
PubMed1989

Phase II trial of spirogermanium and vindesine in malignant glioma.

Fifty-four adults with recurrent malignant glioma were treated on an Eastern Cooperative Oncology Group (ECOG) trial. All had previous radiation therapy, and 70% had previous chemotherapy. They were assigned to either vindesine 3 mg/m2 weekly or spirogermanium 80 mg/m2 three times weekly with escalation to 120 mg/m2. The response was 4% to vindesine, and 8% to spirogermanium. The duration of response was 53 days for a patient who had clinical improvement only, but greater than 151 days and greater than 1066 days for two patients who had achieved a greater than 50% reduction in tumor size by computed tomography (CT). The toxicities were hematologic for vindesine and neurologic for spirogermanium. Neither agent seems to have sufficient efficacy to warrant further trials in previously treated glioma patients.

Adult↗
PubMed1989

Pregnancy associated aplastic anaemia: a report of five cases and review of current management.

The occurrence of aplastic anaemia in pregnancy has been long recognized but its rarity has made it difficult to establish the relationship between the two conditions and the optimal management. We now report five cases of aplastic anaemia in pregnancy and offer some recommendations for treatment. In two patients the pregnancy was allowed to continue to term and the disease persisted post-partum leading to death in one case. The other three patients had their pregnancies terminated; one subsequently deteriorated and died, two had spontaneous remissions of their aplasia. We suggest that patients presenting with severe aplastic anaemia in early pregnancy should be offered termination because this may be followed by haematological improvement. If haematological improvement does not occur allogeneic bone marrow transplantation (BMT) may be considered. Aplastic anaemia presenting in late pregnancy should be treated with supportive care until delivery. On the basis of our experience, antilymphocyte globulin may safely be given during pregnancy.

Abortion, Induced↗
PubMed1989

Bone marrow transplantation for severe aplastic anaemia using cyclosporin: long-term follow-up.

Between 1980 and 1986 we transplanted 49 patients from genotypically identical sibling donors for severe aplastic anaemia (SAA). Patients were predominantly adults, median age 22 years (3-47). Forty-six were multiply transfused prior to referral. The median pre-transplant disease duration was 4 months (1-72). Pre-transplant conditioning was with cyclophosphamide (CY) 200 mg/kg. Cyclosporin A (CSA) was given from 1 day before the transplant and continued for 9-12 months. Eight of 48 evaluable patients did not achieve initial engraftment (early graft failure). Six of these episodes occurred in the eight cases transplanted more than 1 year after diagnosis, four of whom died. Thirteen of 44 (30%) evaluable patients (with stable engraftment after one or two transplants) had grade III-IV acute graft-versus-host disease (GVHD). Only three of 35 patients surviving more than 100 days with sustained engraftment developed generalized chronic GVHD; two died. An additional 10 patients developed localized chronic GVHD, which was very mild, transient and related to CSA withdrawal. Four long-term survivors are known to have autologous marrow function. All survivors have Karnofsky scores of greater than 90%. We conclude that the use of CSA after bone marrow transplantation for SAA is associated with good long-term survival and minimal on-going chronic GVHD. Early graft failure was frequent when transplantation was delayed beyond 1 year from diagnosis.

Anemia, Aplastic↗
PubMed1989

Bone marrow transplantation for Fanconi's anaemia: the Hammersmith experience 1977-89.

Twenty-one patients with Fanconi's anaemia (FA) were treated by allogeneic bone marrow transplantation (BMT). Two, transplanted before 1980, received high dose cyclophosphamide conditioning and both died. Subsequently 19 patients received conditioning with low dose cyclophosphamide 5 mg/kg x 4 and total body irradiation 200 cGy x 3. Ten of 19 received HLA identical sibling marrow (ID-BMT) and nine marrow from alternative donors (MM-BMT). Marrow was T cell depleted in 9/19 cases. Sustained engraftment was observed in 13 cases (eight ID-BMT, five MM-BMT). Nine patients developed greater than or equal to grade II acute graft-versus-host disease (GVHD) (six ID-BMT, nine MM-BMT). Chronic GVHD occurred in 5/11 evaluable patients. Overall survival of the low dose cyclophosphamide group was 9/19 (47%) at a median follow-up of 1257 days post-BMT (110-1825). Six of 10 (60%) survived after ID-BMT compared with two of nine (22%) after MM-BMT. We conclude that allogeneic BMT using a low dose cyclophosphamide protocol is a satisfactory treatment for FA patients who have a normal HLA identical sibling. The results of MM-BMT have been poor, and must improve before these transplants can be generally recommended for treatment of FA.

Adolescent↗
PubMed1989

Recurrent graft failure following syngeneic bone marrow transplantation for aplastic anaemia.

We present the case of a 60-year-old woman with drug-induced aplastic anaemia with a healthy monozygotic twin. Proof of monozygosity was confirmed by studies using the hypervariable minisatellite probe to obtain identical DNA fingerprints in donor and recipient. In vitro co-culture studies performed showed no evidence of a recipient-derived cellular or humoral inhibitor of donor haemopoiesis. Despite this, there was no engraftment following simple marrow infusion without preconditioning. A second syngeneic transplant following high dose cyclophosphamide therapy produced trilineage engraftment but severe thrombocytopenia developed at 3 months, followed later by pancytopenia with generalized marrow failure. Following a third syngeneic transplant with cyclophosphamide and total lymphoid irradiation there was good initial engraftment but graft failure occurred at 14 weeks. A fourth transplant using Campath 1G as preconditioning resulted in no engraftment and the patient died of septicaemia 8 weeks following her fourth transplant. We suggest that the cause of the recurrent aplastic anaemia in this case was a defect of marrow stroma as neither an inhibitor of donor haemopoiesis nor an intrinsic defect of donor stem cell growth could be demonstrated in vitro.

Anemia, Aplastic↗
PubMed1988

Relationship between in vitro tumor stem cell assay and in vivo antitumor activity using the P388 leukemia.

The relationship between in vitro tumor stem cell sensitivity and in vivo antitumor efficacy using 13 active antineoplastic agents was examined by means of the intraperitoneal P388 mouse leukemia system. The doses, which produced a 50% increase in life span after one, five and nine days of treatment, were all significantly correlated with the in vitro concentration producing a 70% reduction in colony formation during a seven-day continuous drug exposure. The five-day correlation was the best, followed by nine days and one day. Correlations were not improved by corrections for either in vitro drug stability or toxicity (LD50). The highly significant correlations observed in this simple retrospective analysis provide a basis for the development of more sophisticated models for the prediction of in vivo results from in vitro data.

Animals↗
PubMed1988

The role of antilymphocyte globulin in the treatment of chronic acquired bone marrow failure.

Antilymphocyte globulin is an immunoglobulin preparation prepared from heterologous serum after the animal (horse or rabbit) has been immunised with human lymphocytes, obtained from the thymus (antithymocyte globulin, ATG) or thoracic duct (antilymphocyte globulin, ALG). The rationale for the use of ALG in the treatment of chronic acquired marrow failure is based on its immunosuppressive activity and the fact that a proportion of cases of bone marrow failure, whether affecting single or multiple haemopoietic cell lines are due to immune-mediated suppression of haemopoiesis. In addition, in vitro studies have shown that ALG also has an immunostimulatory effect on lymphokine and haemopoietic growth factor production, and may therefore directly stimulate haemopoietic progenitor cells. ALG has been used for the treatment of aplastic anaemia and acquired chronic marrow failure affecting single cell lines namely pure red cell aplasia (PRCA), amegakaryocytic thrombocytopenia and chronic neutropenia due to immune inhibition of granulopoiesis ('acquired white cell aplasia'). ALG is used for treatment of non-severe aplastic anaemia (NSAA) and in those cases of severe aplastic anaemia (SAA) where allogeneic transplantation is not possible or is not indicated. Treatment with ALG results in 75% long term survival for NSAA and 40-50% for SAA although there is a very severe subgroup of SAA defined by peripheral blood neutrophils of less than 0.2 x 10(9)/l who rarely benefit from ALG therapy. For those patients who do not respond a second course of ALG can be given later using ALG from a different animal source.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗