Biomedical subjects

S R McCann

Publications and source records attributed to S R McCann.

At least 37 records · Page 2Linked to original sources

PubMed1998

Autologous transplantation in chronic myeloid leukaemia using peripheral blood stem cells.

Forty-three patients with chronic myeloid leukaemia in first chronic phase were recruited to study intensive chemotherapy (idarubicin plus cytarabine; IdAC) followed by collection of peripheral blood stem cells (PBSC) in the recovery phase. PBSC autografting was performed on 32 patients. One patient died during mobilization and three died following autograft. All procedural deaths occurred in patients who received IdAc more than a year from diagnosis. Nine further patients died, eight following progression of CML. 72% of transplanted patients showed a major cytogenetic response but most cases have returned to Philadelphia-positive haemopoiesis. 62% of autografted patients remain alive (median survival from diagnosis 52 months). Four of the 11 patients who did not receive a transplant remain in chronic phase.

Adult↗

PubMed1997

Cutaneous mucormycosis due to Absidia corymbifera occurring after bone marrow transplantation.

Mucormycosis is an uncommon severe life-threatening fungal infection in the immunocompromised host caused by fungi belonging to the order Mucorales, most commonly Rhizopus arrhizus (R. oryzae). We report a patient who developed a severe right atrial catheter exit site infection with Absidia corymbifera. The catheter was removed and necrotic tissue debrided. With liposomal amphotericin B and G-CSF, the infection subsided. He remains well 8 months later.

Amphotericin B↗

PubMed1997

Persistent donor chimaerism is consistent with disease-free survival following BMT for chronic myeloid leukaemia.

Chronic myeloid leukaemia (CML) can be treated successfully with allogeneic bone marrow transplantation (BMT) leading to long-term disease-free survival. Leukemia relapse, however, remains a significant clinical problem. Relapse following BMT presumably results from the expansion of small numbers of recipient leukaemic cells which have survived the conditioning therapy. In order to define patients who are at a high risk of leukaemia relapse, a variety of techniques have been employed to detect persistence of host haemopoiesis (mixed chimaerism, MC) or residual leukaemia (minimal residual disease, MRD). However, the precise relationship between the detection of MC and MRD post-BMT is unknown. We have investigated chimaerism and MRD status in 22 patients who were in clinical and haematological remission post-allogeneic BMT for chronic phase CML. Chimaerism was assessed using short tandem repeat PCR (STR-PCR) while BCR-ABL mRNA detection using reverse transcriptase polymerase chain reaction (RT-PCR) was performed to detect the presence of MRD. Seventeen patients received unmanipulated marrow (non-TCD) while in five patients a T cell-depleted transplant (TCD) was performed as additional GVHD prophylaxis. Chimaerism was evaluated in 18 patients (14 non-TCD, four TCD). Mixed chimaerism was an uncommon finding in recipients of unmanipulated BMT (21%) when compared to TCD BMT (100%). No evidence of MRD, as identified using the BCR-ABL mRNA RT-PCR assay, was detected in those patients who were donor chimaeras. Early and transient MC and MRD was detected in four patients (two non-TCD, two TCD) who have subsequently converted to a donor profile. One patient has stable low-level MC but remains MRD negative 4 years post-BMT. Late MC and MRD was observed in two patients who relapsed >6 years after TCD BMT for CML. We conclude that mixed chimaerism is a rare event in recipients of unmanipulated BMT and that donor chimaerism as detected by STR-PCR assay is consistent with disease-free survival and identifies patients with a low risk of leukaemic relapse post-BMT for CML.

Adolescent↗

PubMed1997

Treatment of chronic myeloid leukaemia in first chronic phase with idarubicin and cytarabine: mobilization of Philadelphia-negative peripheral blood stem cells.

Peripheral blood stem cell (PBSC) mobilization using idarubicin and cytarabine was investigated in 40 patients with chronic myeloid leukaemia in first chronic phase (CML CP1). Disease contamination was evaluated in harvests from 41/44 (93%) mobilization episodes. Using cytogenetics, 22/37 (59%) showed a complete or major response; Southern blot analysis demonstrated a complete or major response in 9/17 (53%). No harvests were RT-PCR negative. In the 41 evaluable episodes, more complete or major responses were seen when PBSC mobilization occurred within 24 months [17/23 (74%) versus 6/18 (33%); P = 0.02] and within 12 months of diagnosis [10/11 (91%) versus 13/30 (43%); P = 0.018]. 20 patients underwent PBSC transplantation and 18/20 successfully engrafted. Post-transplant cytogenetic analysis was available on 15 cases, of whom five achieved a major cytogenetic response at 1-3 months, with five partial cytogenetic remissions. Two of 40 patients died during mobilization therapy (5%) and three of 20 after the transplant (15%). Overall mortality was high at five of 40 patients, and the procedural mortality was 20%. This study demonstrates that Ph-negative PBSCs can be mobilized in a significant proportion of patients with CML CP1, with the best results observed within a year of diagnosis. These cells can subsequently be used for autologous transplantation, however, the impact on long-term survival requires longer follow-up, and potential benefits may be compromised by the high mortality.

Adult↗

PubMed1997

Donor chimaerism is a strong indicator of disease free survival following bone marrow transplantation for chronic myeloid leukaemia.

Although Chronic Myeloid Leukaemia (CML) can be treated successfully with allogeneic bone marrow transplantation (BMT), leukaemia relapse remains a significant clinical problem. Molecular monitoring of the post transplant marrow can be useful in predicting relapse particularly in CML patients where the Philadelphia chromosome or its molecular counterpart, the BCR-ABL fusion messenger RNA can be used as a leukaemia specific marker of minimal residual disease (MRD). We have investigated chimaerism (using polymerase chain reaction of short tandem repeat sequences (STR-PCR)) and MRD status (using reverse transcriptase PCR of the BCR-ABL fusion mRNA) in a serial fashion in 18 patients who were in clinical and haematological remission post allogeneic BMT for chronic phase CML. Eleven patients exhibited complete donor chimaerism with no evidence of minimal residual disease. Five patients had transient or low level stable MC. Late MC and MRD was observed in two patients who relapsed > 6 years after T cell depleted BMT for CML. Thus STR-PCR is an appropriate screening test in the post transplant setting for CML patients, but those patients exhibiting mixed haemopoietic chimaerism should also be monitored using a leukaemia specific sensitive molecular assay.

Adolescent↗

PubMed1997

Distribution of HLA-A, B and DR genes and haplotypes in the Irish population.

The distribution of HLA phenotypes, genes and haplotypes in the normal population is of considerable importance in, for example, disease susceptibility studies, platelet transfusion support and transplantation. HLA population genetics studies have been carried out on numerous population samples, however, no major studies have been performed on Irish Caucasoids. We have analysed the HLA-A, B and DR phenotypes of 1,910 healthy unrelated Irish blood donors recruited onto the Irish Bone Marrow Donor Panel. HLA typing was performed by a combination of serology, the polymerase chain reaction with sequence-specific primers and reverse hybridisation. We calculated Hardy-Weinberg fit, phenotype and gene frequencies and two- and three-locus haplotype frequencies, linkage disequilibrium (LD) values and their significance levels and relative LD values. Compared to many other European populations, the Irish show a high frequency of HLA-A1, B7, B8 and DR2 and a reduced frequency of HLA-A9, A30, B15 and DR4. Two- and three-locus haplotypes and the combinations of alleles in positive LD were all typical of northern European populations. However, the Irish have especially high frequencies of the common HLA-A1/B8, A2/B44, A3/B7, HLA-B8/DR3, B7/DR2, B44/DR4 and B44/DR7 haplotypes, while the frequency of other relatively common haplotypes, e.g. HLA-A2/B15, is reduced. These frequencies are of particular value for estimating the likelihood of finding bone marrow donors in patients' extended families and unrelated donor panels.

Adolescent↗

PubMed1996

Patterns of hematopoietic chimerism following bone marrow transplantation for childhood acute lymphoblastic leukemia from volunteer unrelated donors.

Hematopoietic chimerism was analyzed in serial bone marrow samples taken from 28 children following T-cell depleted unrelated donor bone marrow transplants (UD BMT) for acute lymphoblastic leukemia (ALL). Chimeric status was determined by polymerase chain reaction (PCR) of simple tandem repeat (STR) sequences (maximal sensitivity, 0.1%). At least two serial samples were examined in 23 patients. Of these, two had evidence of complete donor engraftment at all times and eight showed stable low level mixed chimerism (MC) (<1% recipient hematopoiesis). All 10 of these patients remain in remission with a minimum follow-up of 24 months. By contrast, 13 patients demonstrated a progressive return of recipient hematopoiesis. Five of these relapsed (4 to 9 months post BMT), one died of cytomegalovirus pneumonitis and seven remain in remission with a minimum follow-up of 24 months. Five children were excluded from serial analysis as two serial samples were not collected before either relapse (3) or graft rejection (2). We conclude that as with sibling transplants, ex vivo T depleted UD BMT in children with ALL is associated with a high incidence of MC. Stable donor engraftment and low level MC always correlated with continued remission. However, detection of a progressive return of recipient cells did not universally correlate with relapse, but highlighted those patients at greatest risk. Serial chimerism analysis by PCR of STRs provides a rapid and simple screening technique for the detection of relapse and the identification of patients with progressive MC who might benefit from detailed molecular analysis for minimal residual disease following matched volunteer UD BMT for childhood ALL.

Adolescent↗

PubMed1996

Effect of ultraviolet-B light on lymphocyte activity at doses at which normal bone marrow stem cells are preserved.

Ultraviolet B (UVB) light is known to be immunosuppressive, but, probably because of a small UVC component in the emission spectra of some of the UVB lamps used, reports vary on effective dose levels. To prevent potentially lethal graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation, alloreactive donor T-cell activity must be suppressed. In this study, a narrow wavelength UVB lamp (TL01, 312 nm peak emission) was used to determine what doses of UVB were required to abolish rat lymphocyte proliferation while simultaneously preserving rat bone marrow progenitor cell and primitive hematopoietic stem cell viability. Lymphocyte proliferation, as measured by 3H-Thymidine incorporation, in response to lectin stimulation was abolished below detection at doses greater than 3,500 J/m2. When T-cell clonogenicity was measured in a limiting dilution assay, a small fraction (0.6%) was maintained at doses up to 4,000 J/m2. Cytotoxic T-lymphocyte (CTL) activity was reduced after treatment with 4,000 J/m2, but a significant level of cytotoxicity was still maintained. Natural killer cell cytolytic activity was not affected by doses up to 4,000 J/m2. At 4,000 J+m2 there was a 10% survival of colony-forming units-granulocyte-macrophage; a 1% and 4% survival of day-8 and day-12 colony-forming units-spleen, respectively; and 11% survival of marrow repopulating ability cells. Up to 25% of late cobblestone area forming cells (4 to 5 weeks), reflecting the more immature hematopoietic stem cells, were preserved in bone marrow treated with 4,000 J/m2, indicating that early stem cells are less sensitive to UVB damage than are more committed progenitor cells. Thus, a potential therapeutic window was established at approximately 4,000 J/m2 using this light source, whereby the potentially GVHD-inducing T cells were suppressed, but a sufficient proportion of the cells responsible for engraftment was maintained.

Animals↗

PubMed1996

Sorting out mix-ups. The provenance of tissue sections may be confirmed by PCR using microsatellite markers.

Standard identification systems usually ensure that biopsy material is correctly associated with a given patient. Sometimes, as when a tumor is unexpectedly found, the provenance (proof of origin) of a tissue sample may be questioned; the tissue may have been mislabelled or contaminated with tissue from another patient. Techniques used to confirm tissue provenance include comparing either tissue markers of gender or ABO blood groups; however, these methods have weak confirmatory power. Recently, the use of DNA-based polymerase chain reaction (PCR) techniques has been reported. Paired, formalin-fixed, paraffin-embedded, 10 microns tissue sections were selected from 17 patients, 8 of whom had carcinoma, either by dividing a biopsy section, using sequential biopsies, or sequential biopsy and autopsy tissue. The resulting 36 samples were coded before analysis. In two additional cases, 1-mm fragments of tumor from one patient were included in the tissue block of benign tissue from another patient, the tumor fragments were identified on hematoxylin-and-eosin-stained sections, separately scraped off the glass slide, and analyzed. Tissue from two clinical cases, one of suspected mislabelling and one with a suspected carry-over of malignant tissue were also investigated. Short tandem repeat sequences (STR) or microsatellites, are 2-5 base pair repeats that vary in their repeat number between individuals. This variation (polymorphism) can be assessed using a PCR. A panel of markers of 3 STRs; ACPP, INT 2, and CYP 19 (on chromosomes 3, 11, and 15, respectively) were used. DNA was isolated from the samples after xylene deparaffinization and proteinase digestion, and was then amplified in a radioactive PCR using primers selected to give a product size ranging from 136-178 bases. Amplified products were electrophoresed on denaturing polyacrylamide gels, dried, and autoradiographed. DNA segments were successfully extracted from all samples but one, which was fixed in Bouin's fluid. By comparing allele sizes from the panel, all tissue pairs (other than the Bouin's pair) were successfully matched, the 1-mm tumor fragments were correctly assigned, and the two clinical problems were solved. STRs are highly informative and robust markers, well suited to PCR of small portions of tissue sections, and are an effective method to confirm the provenance of benign and malignant biopsy and autopsy material.

Acid Phosphatase↗

PubMed1996

Myelodysplasia and acute myeloid leukaemia following adjuvant chemotherapy for breast cancer using mitoxantrone and methotrexate with or without mitomycin.

BACKGROUND: Secondary acute myeloid leukaemia/myelodysplasia (t-AML, t-MDS) may occur following adjuvant chemotherapy for breast cancer and has been most frequently associated with alkylating agents. This complication is now being associated with an expanding list of chemotherapeutic agents including topoisomerase II poisons. Mitoxantrone is an agent with potential to cause t-AML and t-MDS and which is being used increasingly in the treatment of breast cancer. PATIENTS AND METHODS: Fifty-nine patients who received mitoxantrone as part of adjuvant chemotherapy for breast cancer between 1986 and 1992 were studied to determine the incidence of t-AML and t-MDS. RESULTS: With a median follow-up of 72 months, 2 cases of t-AML and 1 of t-MDS have occurred. CONCLUSIONS: This 5% incidence of t-AML and t-MDS is high and likely related to mitoxantrone. Whereas this agent is effective and has acceptable toxicity in advanced disease, its incorporation into adjuvant treatment regimens cannot be recommended based on this experience.

Adult↗

PubMed1996

PCR amplification of short tandem repeat sequences allows serial studies of chimaerism/engraftment following BMT in rodents.

Animal models of bone marrow transplantation (BMT) allow evaluation of new experimental treatment strategies. One potential strategy involves the treatment of donor marrow with ultra-violet B light to allow transplantation across histocompatibility boundaries without an increase in graft rejection or graft-versus-host disease. A major requirement for a new experimental protocol, particularly if it involves manipulation of the donor marrow, is that the manipulated marrow gives rise to long-term multilineage engraftment. DNA based methodologies are now routinely used by many centres to evaluate engraftment and degree of chimaerism post-BMT in humans. We report the adaptation of this methodology to the serial study of engraftment in rodents. Conditions have been defined which allow analysis of serial tail vein samples using PCR of short tandem repeat sequences (STR-PCR). These markers have been used to evaluate the contribution of ultraviolet B treated marrow to engraftment following BMT in rodents without compromising the health of the animals under study. Chimaerism data from sequential tail vein samples and bone marrow from selected sacrificed animals showed excellent correlation, thus confirming the validity of this approach in analysing haemopoietic tissue. Thus the use of this assay may facilitate experimental studies in animal BMT.

Animals↗

PubMed1996

Campath-1G in vivo confers a low incidence of graft-versus-host disease associated with a high incidence of mixed chimaerism after bone marrow transplantation for severe aplastic anaemia using HLA-identical sibling donors.

We have evaluated the effect of in vivo Campath-1G on engraftment and GVHD in 23 patients with severe aplastic anaemia transplanted from HLA-identical sibling donors. In 14 patients Campath 1g was given pre-transplant for up to 9 days in an attempt to overcome graft rejection (group 1). In nine patients Campath-1G was given pre-transplant, but also continued post-transplant until day +5 to reduce GVHD (group 2). There were three patients with late graft failure in group I following initial neutrophil engraftment, and four cases of grade II+ GVHD. In group II, two patients had early graft failure (no take), and there were no cases of acute GVHD out of seven evaluable patients. One patient in group I developed chronic GVHD of the liver, and two patients (one in each group) had transient localised chronic GVHD. PCR of short tandem repeats was used to evaluate chimaeric status in 13 patients. Of 11 patients with initial neutrophil engraftment, only one had 100% donor haemopoiesis at all times. The remaining patients had either transient mixed chimaerism or persistence of recipient (< 20%) cells. We conclude that in vivo Campath-1G is associated with a high incidence of mixed chimaerism which tips the balance away from GVHD but towards graft rejection.

Adolescent↗

PubMed1995

Studies on hemopoietic chimerism following allogeneic bone marrow transplantation in the molecular biology era.

Donor hematopoiesis or donor chimerism in the host following allogeneic bone marrow transplantation (BMT) has appeared crucial to the engraftment process. However, as molecular techniques exploiting neutral variation in human genetic material have been used in the study of chimerism, the detection of residual host cells or mixed hemopoietic chimerism has indicated that donor chimerism is not obligatory following BMT. This review focuses on the detection and significance of mixed chimerism (MC) in patients transplanted for both malignant and non-malignant hemopoietic disease and attempts to tease out the contribution of MC to engraftment, leukemia relapse, graft rejection and long-term disease-free survival.

Anemia, Aplastic↗

PubMed1995

An epidemiological study of Candida species infection in cancer patients using genetic fingerprinting and morphotyping.

During a six-week period a cluster of four cases of Candida fungaemia occurred in a mixed haematology/oncology unit of a large Dublin teaching hospital. A study was conducted to determine whether the cluster of cases was caused by a particular strain. Nine patients were studied; five who were colonized with Candida spp. and four who developed Candida fungaemia. Twenty-two clinical isolates of Candida spp. were collected and identified. Three of the patients with fungaemia yielded Candida albicans from blood cultures and C. tropicalis was isolated from the fourth patient. C. albicans isolates were serotyped, morphotyped and analysed by DNA fingerprinting of total cellular DNA using the cloned C. albicans-specific, mid-repeat sequence element 27A as a molecular probe. All C. albicans isolates were of serotype A. Eight distinguishable types were identified by both morphotyping and DNA typing from 19 C. albicans isolates recovered from seven individual patients, although there were several discrepancies. Of three patients from whom two or more isolates of C. albicans were recovered on separate occasions, two yielded recurrent isolates with different morphotype codes. However, in both cases, the recurrent isolates from individual patients yielded indistinguishable, or closely related, DNA fingerprint profiles. Both morphotyping and DNA fingerprint analysis readily distinguished the three blood culture isolates of C. albicans. We conclude that the Candida spp. infections in the unit were not due to cross-infection and were probably related to the patients' indigenous flora.

Candida↗

PubMed1995

Methylprednisolone in advanced chronic lymphocytic leukaemia: rationale for, and effectiveness of treatment suggested by DiSC assay.

The effect of methylprednisolone on fresh cells from patients with chronic lymphocytic leukaemia (CLL) has been studied using the differential staining cytotoxicity (DiSC) assay resulting in LC90s of < or = 0.2 to 2,000 micrograms/ml. Cells from previously treated patients were, on average, significantly more sensitive to methylprednisolone than those from untreated patients (mean LC90 = 5.7 micrograms/ml, n = 61 vs 31.0 micrograms/ml, n = 17, respectively; p < 0.05). Twelve patients with advanced disease were given high-dose methylprednisolone (1 g/m2/day i.v. x 5 days). In 7 cases, > or = 3 courses were given; 3 patients did not respond (2 achieved palliation) and 4 (57%) achieved a good partial response. These latter 4 patients were all clinically resistant to chlorambucil and anthracyclines and 2 were resistant to fludarabine. In 5 cases, 1 or 2 courses were given but no patients responded. The 8 nonresponders survived a median of 3.5 months whilst the responders have survived a median of 28.5+ months (3 of 4 still alive). This work suggests a rationale for why CLL patients resistant to standard chemotherapy may benefit from high-dose methylprednisolone therapy. Due to cost and toxicity associated with therapy, the decision to treat would be best made on the basis of a DiSC assay result. This pilot study requires confirmation with a well-designed controlled clinical trial.

Adult↗

PubMed1995

Bone marrow transplantation for Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is a rare disorder usually diagnosed in the first year of life. Although most cases respond to corticosteroids, > 20% are, or become, steroid-resistant. We report 10 children with DBA who received a bone marrow transplant from an HLA-identical sibling (n = 8), maternal (n = 1) or unrelated (n = 1) donor and reported to the International Bone Marrow Transplant Registry. Among eight recipients of HLA-identical sibling transplants, six are alive 5-87 months after transplant with no evidence of DBA and with Karnofsky performance scores of 90-100%. The two recipients of non-HLA-identical sibling transplants died < 2 weeks after transplant. The actuarial 2-year probability of survival for the eight sibling transplants was 72 (37-92)% (95% confidence interval).

Adolescent↗

PubMed1994

Haemopoietic growth factors in aplastic anaemia: a cautionary note. European Bone Marrow Transplant Working Party for Severe Aplastic Anaemia.

We are concerned about the inappropriate use of haemopoietic growth factors in patients with severe aplastic anaemia (SAA). The treatment of choice for this disorder is bone-marrow transplantation from an HLA-identical sibling donor if the patient is younger than 45 years, but it must be done soon after onset before the patient becomes sensitised by multiple red-cell and platelet transfusions. Other patients should receive immunosuppressive therapy with antithymocyte globulin alone or with cyclosporin or oxymetholone. Haemopoietic growth factors may have a role in stimulation of granulopoiesis after immunosuppressive therapy, but there is no evidence that they can correct the underlying stem-cell defect in SAA, and therefore no justification for their use alone in newly diagnosed SAA. Such treatment is harmful because it delays bone-marrow transplantation, or immunosuppressive therapy in older patients and those without suitable donors, thus reducing the chances of a successful outcome.

Age Factors↗

PubMed1994

Localized, late-onset, high-grade lymphoma following bone marrow transplantation: response to combination chemotherapy.

Non-Hodgkin's lymphoma is the commonest secondary cancer following bone marrow transplantation (BMT). We report the case of a 42-year-old man who developed a laryngeal high-grade B-cell lymphoma 5 years following a matched T depleted BMT for CML. Polymerase chain reaction (PCR) analysis using the microsatellite marker Cyp 19 demonstrated the donor origin of involved tissue. Epstein-Barr virus (EBV) genomic sequences were identified by PCR. Although EBV related B-cell lymphoproliferative disorders (BLPD) post BMT are difficult to treat, there was a complete remission in this patient following three courses of chemotherapy (CHOP) administered with G-CSF. This case of late-onset BLPD appears clinically distinct from the well-defined, aggressive, early post-transplant BLPD.

Adult↗