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Biomedical subjects

H Sill

Publications and source records attributed to H Sill.

At least 19 recordsLinked to original sources
PubMed2005

Evaluation of potential risk factors for early infectious complications after autologous peripheral blood stem cell transplantation in patients with lymphoproliferative diseases.

A number of risk factors for the occurrence of neutropaenic fever after haematopoietic stem cell transplantation (HSCT) have been proposed. We were interested in whether these factors remain valid for several early infection-related outcomes when applied to a homogeneous group of patients in uni- and multivariate analyses. Therefore, we analysed 144 consecutive patients with lymphoproliferative disorders receiving autologous peripheral blood HSCT. Variables tested as potential risk factors for the occurrence of fever, documented infection (DI), microbiologically documented infection (MDI) or failure of first-line antimicrobial therapy were sex, conditioning regimen, prolonged neutropaenia, low number of CD34+ cells transplanted, purging, lack of selective gut decontamination, higher age and increased body mass index. In uni- and multivariate analyses, conditioning including total body irradiation was the only risk factor for the occurrence of fever, and neutropaenia >or=10 days was the only factor associated with failure of first-line antimicrobial therapy. None of the variables tested was associated with an increased risk for DI or MDI. This analysis suggests that a number of previously proposed risk factors actually are of minor clinical relevance for early infections in the majority of patients receiving autologous HSCT.

Adolescent↗
PubMed2004

Pulmonary infiltrates in patients with haematologic malignancies: transbronchial lung biopsy increases the diagnostic yield with respect to neoplastic infiltrates and toxic pneumonitis.

We retrospectively evaluated 107 fiberoptic bronchoscopies with and without transbronchial lung biopsy (TBLB) in 98 consecutive patients with haematologic malignancies and pulmonary infiltrates. Bronchoalveolar lavage (BAL) was performed in 45 and BAL plus TBLB in 62 procedures. There was no procedure-related severe haemorrhage, pneumothorax or death. Infectious aetiology was identified in 26 of 107 (24%), toxic pneumonitis in 17 of 107 (16%) and neoplastic infiltration in 9 of 107 (8.5%) episodes. Combined BAL and TBLB was significantly superior to BAL alone with respect to the diagnosis of neoplastic infiltrates (p=0.008) and toxic pneumonitis (p<0.001) and should therefore be included in the diagnostic work-up of this patient cohort.

Adult↗
PubMed2004

High expression of the sister-chromatid separation regulator and proto-oncogene hSecurin occurs in a subset of myeloid leukaemias but is not implicated in the pathogenesis of aneuploidy.

Aneuploidy is considered to play an important role in the pathogenesis of malignancies. We were interested whether abnormalities of the sister-chromatid separation regulator and proto-oncogene hSecurin occurred in myeloid leukaemias, and whether such abnormalities correlated with aneuploidy. The expression of hSecurin was assessed by real-time quantitative PCR in samples from patients with acute myeloid leukaemia (AML, n=70), chronic myeloid leukaemia (CML) in chronic phase (CP, n=20) or blast phase (BP, n=12), and granulocytes as well as mononuclear cells (MNCs) from healthy donors (n=21). Median hSecurin expression in AML with normal karyotypes was not significantly different from AML showing aneuploidy, CML BP or cells from healthy donors. However, hSecurin expression in CML CP was significantly increased compared to AML with normal karyotypes (1.82-fold; P<0.001), CML BP (3.18-fold; P<0.001), MNCs (3.17-fold; P<0.001) and granulocytes (2.69 fold; P<0.001) from healthy donors. Mutations in the coding region of hSecurin were not detected. These results do not support a major role of hSecurin in the development of aneuploidy in myeloid leukaemias. However, high expression of hSecurin may be of pathogenetic relevance in a subset of patients with regard to its potential to stimulate angiogenesis and to interact with the DNA-damage response pathway.

Acute Disease↗
PubMed2004

RT-PCR and FISH analysis of acute myeloid leukemia with t(8;16)(p11;p13) and chimeric MOZ and CBP transcripts: breakpoint cluster region and clinical implications.

The translocation t(8;16)(p11;p13) is associated with acute myeloid leukemia displaying monocytic differentiation (AML FAB M4/5) and fuses the MOZ (also named MYST3) gene (8p11) with the CBP (also named CREBBP) gene (16p13). Detection of the chimeric RNA fusions has proven difficult; only three studies have described successful amplification of the chimeric MOZ-CBP and CBP-MOZ fusions by reverse transcriptase-polymerase chain reaction (RT-PCR). We analyzed four cases of AML M4/5 with t(8;16)(p11;p13) by RT-PCR and fluorescence in situ hybridization (FISH) and characterized the reciprocal RNA fusions from three cases. We cloned both genomic translocation breakpoints from one case by long-range PCR and successfully applied RT-PCR to monitor minimal residual disease (MRD) between clinical complete remission and relapse. In three cases, the genomic breakpoints occurred in MOZ intron 16 and CBP intron 2. In one case, no fusion transcript was detected. The available data suggest clustering of t(8;16)(p11;p13) breakpoints in these introns leading to reciprocal in-frame MOZ exon 16/CBP exon 3 and in-frame CBP exon 2/MOZ exon 17 chimeric transcripts in the majority of cases. The described RT-PCR strategy may be valuable both for the routine detection of the t(8;16)(p11;p13) as well as for monitoring of MRD in this prognostically unfavorable patient group.

Acetyltransferases↗
PubMed2003

High-risk AML complicated by pulmonary aspergillosis: successful treatment with nonmyeloablative stem cell transplantation and long-term administration of voriconazole.

Acute myeloid leukemia (AML) associated with central diabetes insipidus (DI) and chromosomal aberrations is characterised by a very poor prognosis. We present a 28-year-old female with AML FAB M0, preceding DI and cytogenetic abnormalities (monosomy 7 and inversion of chromosome 9). Complete remission was achieved with FLAG after she was refractory to two different induction regimens. Prolonged neutropenia resulted in invasive pulmonary aspergillosis. Allogeneic stem cell transplantation from a matched unrelated donor was performed using a reduced-intensity conditioning regimen. Desmopressin substitution for DI was withdrawn after transplant without recurrence of symptoms. Initial antifungal treatment, including liposomal amphotericin B, caspofungin and itraconazole, was replaced by voriconazole after deterioration of pulmonary aspergillosis, resulting in improvement, stabilisation and finally, also as the combined effect of discontinuation of the immunosuppressive therapy, in disappearance of signs and symptoms. Thirteen months after transplant, the patient is in continuous complete remission. The presented case study thus demonstrates that high-risk AML with concomitant invasive fungal infection may be safely and effectively treated by nonmyeloablative stem cell transplantation and long-term administration of voriconazole.

Adult↗
PubMed2003

Therapy-related leukemia cutis: case study of an aggressive disorder.

Therapy-related leukemia cutis has not yet been described. We report a 55-year-old male who developed aleukemic leukemia cutis 15 months after chemotherapy and radiotherapy for non-Hodgkin's lymphoma. Despite intensive therapy including allogeneic hematopoietic stem cell transplantation, the patient died of progressive disease. Sequence analysis of the TP53 gene and screening for defective DNA mismatch repair revealed no abnormalities. This case demonstrates that therapy-related aleukemic leukemia cutis is an aggressive disorder resistant to conventional antineoplastic treatment approaches. As the number of patients developing therapy-related myelodysplasia or leukemia is increasing, clinicians might be confronted more frequently with atypical, extramedullary presentations of these disorders.

Base Pair Mismatch↗
PubMed2003

Prolonged monitoring of troponin T for the detection of anthracycline cardiotoxicity in adults with hematological malignancies.

The study was performed to describe the time course of serum cardiac troponin T (cTnT) elevations for the early detection of anthracycline cardiotoxicity. cTnT was analyzed serially in 78 patients with hematological malignancies receiving 142 treatment cycles including various anthracyclines. cTnT positivity was defined as an increase in cTnT >or=0.03 ng/ml and was observed in 12 patients (15%) during 16 treatment cycles (11%). Peak cTnT levels were observed on day +21.5 (median, range: day +6 to day +35) after initiation of anthracycline therapy. cTnT positivity lasted >or=3 days in 63% of cycles and began to occur after a median of two anthracycline doses. Follow-up echocardiography in 28 patients showed a greater decrease in left ventricular ejection fraction (LVEF) in cTnT-positive patients compared to the cTnT-negative group (10% vs 2%, p=0.017). Age, gender, and pretreatment LVEF had no influence on the occurrence of cTnT positivity. Serial measurement of serum cTnT reveals delayed subclinical myocardial damage even after minor anthracycline exposure, may identify patients at risk for subsequent myocardial dysfunction, and suggests prolonged damage to the cardiac myofibrillar system.

Adult↗
PubMed2003

Acute pseudo-obstruction of the small intestine following high-dose chemotherapy and stem cell support.

BACKGROUND: Acute intestinal pseudo-obstruction is a potentially life-threatening disease which is characterized by massive dilation of the colon or small intestine without mechanical obstruction and may develop after surgery or severe illness. PATIENTS AND METHODS: We report 2 cases in which acute small intestinal pseudo-obstruction occurred after high-dose chemotherapy and autologous stem cell support. In 1 patient explorative abdominal laparoscopy was performed to rule out mechanical ileus. However, after having initiated treatment with acetylcholinesterase inhibitors a prompt small intestinal decompression was observed in both patients. CONCLUSIONS: Acetylcholinesterase inhibitors should be considered as an early conservative intervention in the treatment of acute intestinal pseudo-obstruction to avoid surgery of patients undergoing high-dose chemotherapy with autologous stem cell support.

Adult↗
PubMed2002

Infectious complications after autologous hematopoietic stem cell transplantation: comparison of patients with acute myeloid leukemia, malignant lymphoma, and multiple myeloma.

It is yet undetermined whether patients with different hematological malignancies have different propensities to infectious complications after high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (HSCT). We retrospectively analyzed 136 cycles of HDC and autologous HSCT in 114 patients with acute myeloid leukemia (AML, 24 cycles), non-Hodgkin's lymphoma/Hodgkin's disease (NHL/HD, 55 cycles), and multiple myeloma (MM, 57 cycles) with respect to early infectious complications. Median duration of neutropenia was longer in patients with AML and NHL/HD than in patients with MM (11 days vs 8 days) and after conditioning including total body irradiation (TBI) compared with chemotherapy only preparative regimens (11 days vs 7 days). Fever requiring antimicrobial therapy was observed in 88 percent of cycles, with fever of unknown origin (FUO) accounting for 60 percent of febrile episodes. There was no proven fungal infection, but one case of probable invasive pulmonary aspergillosis. Microbiologically documented infections were seen in 29 percent and clinically documented infections in 11 percent. Response to first-line empirical antibiotic therapy was better for FUO than for documented infections (70 percent vs 40 percent). Patients with TBI as part of their conditioning regimen had more overall infections than patients without TBI (96 percent vs 82 percent). There were no differences with respect to the type or incidence of infections between patients with AML, NHL/HD, and MM. Patients with different hematological malignancies have similar rates of early infectious complications after HDC and autologous HSCT. TBI may be associated with an increased risk for infections in the early post-transplant period.

Acute Disease↗
PubMed2002

Monitoring of cardiac function by serum cardiac troponin T levels, ventricular repolarisation indices, and echocardiography after conditioning with fractionated total body irradiation and high-dose cyclophosphamide.

OBJECTIVES: Highly differing rates of cardiac complications associated with high-dose cyclophosphamide (CY) have been reported, and only one clinical study has been performed on the cardiotoxic effects of CY monotherapy following total body irradiation (TBI). PATIENTS AND METHODS: We prospectively evaluated the potential cardiotoxic effects of conditioning with fractionated total body irradiation and high-dose cyclophosphamide (TBI/CY) by serial measurement of serum cardiac troponin T (cTnT), assessment of systolic and diastolic echocardiographic parameters and analysis of ventricular repolarisation indices (QT-dispersion and corrected QT-dispersion) in 30 adult patients with haematological malignancies undergoing haematopoietic stem cell transplantation. RESULTS: There was no evidence of pretreatment cardiac dysfunction in any patient. Although cTnT was determined serially for a median of 14 d after completion of conditioning, no elevated levels were observed. Echocardiographic parameters did not show any significant change at a median follow-up of 5 months except for one patient with evidence of impaired diastolic filling. No significant differences for mean values before and after high-dose CY were noted for ventricular repolarisation indices. Two patients had a significant increase in corrected QT-dispersion after CY without any other signs of cardiotoxicity. Congestive heart failure or arrhythmias were not observed. CONCLUSIONS: These data suggest that TBI/CY is safe with respect to cardiotoxicity in patients without pre-existing cardiac dysfunction. Hitherto unknown synergistic cardiotoxic effects of CY with other cytostatic drugs may constitute the major pathogenic factor of myocardial dysfunction after high-dose chemotherapy.

Adult↗
PubMed2001

BAALC, the human member of a novel mammalian neuroectoderm gene lineage, is implicated in hematopoiesis and acute leukemia.

The molecular basis of human leukemia is heterogeneous. Cytogenetic findings are increasingly associated with molecular abnormalities, some of which are being understood at the functional level. Specific therapies can be developed based on such knowledge. To search for new genes in the acute leukemias, we performed a representational difference analysis. We describe a human gene in chromosome 8q22.3, BAALC (brain and acute leukemia, cytoplasmic), that is highly conserved among mammals but evidently absent from lower organisms. We characterized BAALC on the genomic level and investigated its expression pattern in human and mouse, as well as its complex splicing behavior. In vitro studies of the protein showing its subcellular localization suggest a function in the cytoskeleton network. Two isoforms are specifically expressed in neuroectoderm-derived tissues, but not in tumors or cancer cell lines of nonneural tissue origin. We show that blasts from a subset of patients with acute leukemia greatly overexpress eight different BAALC transcripts, resulting in five protein isoforms. Among patients with acute myeloid leukemia, those overexpressing BAALC show distinctly poor prognosis, pointing to a key role of the BAALC products in leukemia. Our data suggest that BAALC is a gene implicated in both neuroectodermal and hematopoietic cell functions.

3T3 Cells↗
PubMed2001

Hepatic veno-occlusive disease in two patients with relapsed acute myeloid leukemia treated with anti-CD33 calicheamicin (CMA-676) immunoconjugate.

Monoclonal antibodies recognizing hematopoietic antigens are increasingly being used to target therapy directly at leukemic cells, with the aim of achieving sustained remission with little systemic toxicity. Administration of anti-CD33 calicheamicin immunoconjugate is commonly regarded as being safe, with only moderate systemic non-hematological side effects. We report on two cases of hepatic veno-occlusive disease in heavily pretreated patients presenting with relapsed acute myeloid leukemia (AML). Since significant liver toxicity prevented further specific therapy in both patients, we recommend that antibody therapy with anti-CD33 immunoconjugate should be applied with caution in patients presenting with risk factors for the development of hepatic veno-occlusive disease.

Acute Disease↗