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We report the results of non-myeloablative (NM) and myeloablative (MA) conditioning for haematopoietic cell transplantation in 207 consecutive AML patients at a single institution. A total of 122 patients were transplanted in first CR (CR1) and 67 in second CR (CR2). MA conditioning was given to 60 patients in CR1 and 50 in CR2. NM conditioning was given to 62 patients in CR1 and 17 patients in CR2. MA patients in CR1 experienced more acute GVHD than NM patients, 60.5% versus 22.9%, but the 5-year post transplant cumulative TRM was not different. Relapse incidence at 5 years in CR1 patients was 23.7% which is not statistically different from 28.5% in NM patients. Leukaemia-free survival at 5 years in CR1 patients was 57.7% after MA conditioning and 58.3% after NM conditioning. No statistical difference in overall 5-year survival after MA or NM conditioning was observed in CR1 patients (63.9 versus 64%) and CR2 patients (51.2 versus 64.7%). Durable remission can be obtained in older patients with AML in remission after NM conditioning, which may also be applicable to younger patients.

Allogeneic hematopoietic cell transplantation (allo-HCT) has been proposed as treatment for multiple sclerosis (MS) and other autoimmune diseases.

SUMMARY: We present a unique case of a bone marrow stem cell transplanted (BMT) patient with cutaneous chronic Graft versus Host Disease (cGvHD) who underwent successful allogeneic split-thickness skin graft (STSG) transplantation. BMT had previously been carried out due to myelodysplasia and non-Hodgkin's lymphoma of the patient. Pre-BMT human leucocyte antigen (HLA)-typing had revealed identity between the donor and the recipient, who were siblings (not twins). Complete donor chimaerism was achieved. The recipient developed severe cGvHD with ichthyosis-like dryness and scleroderma. A folliculitis evolved to a full thickness ulceration on the entire scalp. From the femoral region of the donating sister a STSG was harvested under local analgesia and transplanted without analgesia to the prepared scalp ulcer of the recipient. The result was full and permanent take of the allogeneic STSG (follow up: three years). Allogeneic skin grafts are known to be acutely rejected. Successful allogeneic STSG has only been reported in sporadic cases of identical twins (isotransplantation). This case is the first to demonstrate what works in theory: the immune system of a stem cell transplanted patient with 100% or mixed stable donor chimaerism will not recognise skin from the stem cell donor as foreign. Due to advances in haematology, the number of BMT patients and their long-term survival is expected to increase. cGvHD, predisposing to skin problems and ulcerations, complicates up to 70% of cases of BMT. In BMT patients with cGvHD and large skin defects, allogeneic STSC from the BMT donor seems to be a safe alternative for permanent coverage Udgivelsesdato: 2008/12, SUMMARY: We present a unique case of a bone marrow stem cell transplanted (BMT) patient with cutaneous chronic Graft versus Host Disease (cGvHD) who underwent successful allogeneic split-thickness skin graft (STSG) transplantation. BMT had previously been carried out due to myelodysplasia and non-Hodgkin's lymphoma of the patient. Pre-BMT human leucocyte antigen (HLA)-typing had revealed identity between the donor and the recipient, who were siblings (not twins). Complete donor chimaerism was achieved. The recipient developed severe cGvHD with ichthyosis-like dryness and scleroderma. A folliculitis evolved to a full thickness ulceration on the entire scalp. From the femoral region of the donating sister a STSG was harvested under local analgesia and transplanted without analgesia to the prepared scalp ulcer of the recipient. The result was full and permanent take of the allogeneic STSG (follow up: three years). Allogeneic skin grafts are known to be acutely rejected. Successful allogeneic STSG has only been reported in sporadic cases of identical twins (isotransplantation). This case is the first to demonstrate what works in theory: the immune system of a stem cell transplanted patient with 100% or mixed stable donor chimaerism will not recognise skin from the stem cell donor as foreign. Due to advances in haematology, the number of BMT patients and their long-term survival is expected to increase. cGvHD, predisposing to skin problems and ulcerations, complicates up to 70% of cases of BMT. In BMT patients with cGvHD and large skin defects, allogeneic STSC from the BMT donor seems to be a safe alternative for permanent coverage.

Udgivelsesdato: 1997-Dec, A cDNA encoding the human transmembrane 140 kDa isoform of the neural cell adhesion molecule (NCAM) was transfected into the highly invasive MDA-MB-231 human breast cancer cell line. Transfectants with a homogeneous expression of NCAM showed a restricted capacity for penetration of an artificial basement membrane. However, when injected into nude mice, both control and NCAM-expressing cell lines produced equally invasive tumors. Tumors generated from NCAM-transfected cells were heterogeneous, containing NCAM-positive as well as NCAM-negative areas, indicating the existence of host factors capable of modulating NCAM expression in vivo. In nude mice, NCAM-transfected cells developed tumors with longer latency periods and slower growth rates than tumors induced by NCAM-negative control cells, implying that NCAM may be involved not only in adhesive and motile behavior of tumor cells but also in their growth regulation. There was no indication of differences in cell proliferative characteristics between the different NCAM-transfected and the control transfected cells as determined by flow cytometric DNA analysis, suggesting an increased cell loss as the reason for decreased in vivo growth rate of the NCAM-transfected cells. The fact that NCAM expression influences growth regulation attributes a pivotal role to this cell adhesion molecule during ontogenesis and tumor development.

Udgivelsesdato: 1995-null, Clonal evolution of neoplastic cells during solid tumour growth leads to the emergence of new tumour cell subpopulations with diverging phenotypic characteristics which may alter the behaviour of a malignant disease. Cellular interaction was studied in mixed xenografts in nude mice and during in vitro growth of two sets of small cell lung cancer (SCLC) subpopulations (54A, 54B and NYH, NYH2). The tumour cell lines differed in cellular DNA content enabling flow cytometric DNA analysis (FCM) to be used to monitor changes in the fractional composition of the mixed cell populations. The progeny clone 54B was found to dominate the parent 54A clone when grown as mixed subcutaneous xenografts in nude mice, whereas no dominance was exerted during in vitro growth. The in vivo dominance could not be explained by differences in growth kinetics between the two tumour cell lines, and the interaction was not dependent on 54B being in excess in mixed tumours. The dominance was dependent on close in vivo contact as no remote effect on the growth of 54A was found when the dominating 54B cells were growing in the opposite flank of tumour-bearing mice. Irradiation inactivated 54B cells were unable to exert the dominating effect, indicating that the interaction required viable and proliferating cells. Clonal dominance was not found in mixed NYH-NYH2 tumours indicating that the dominance mechanism(s) may not always be operational between subpopulations in heterogeneous tumours. Recognition of interaction between tumour cell populations may result in a better understanding of the behaviour of heterogeneous human malignancies.

Udgivelsesdato: 1994-Jul, Clonal interaction between three subpopulations of Ehrlich carcinoma were studied during growth as mixed solid tumours and as ascites tumours in immune-incompetent nude NMRI mice. The tumour cell lines differed in DNA content as determined by DNA flow cytometry (FCM). Tumour growth was evaluated by tumour growth curves including calculation of tumour volume doubling times, tumour weight on day 14, cell cycle times (per cent labelled mitoses) and cell cycle distributions (FCM). Two subpopulations (E1.15 and E1.95) showed nearly identical growth characteristics during both solid and ascites tumour growth. The third subpopulation (E1.80) grew more slowly. FCM on fine-needle tumour aspirates was used to determine the relative proportions of the cell populations in mixed solid tumours in which E1.95 showed a growth-dominating effect on E1.15. No such effect was demonstrated during single-cell tumour growth in ascitic fluid in which the cells had no intimate contact. Ascitic fluid from E1.95-bearing animals or radiation-killed E1.95 cells had no effect on the growth of E1.15, and no remote effect was seen when the two cell lines were growing in opposite flanks. This indicates that only viable E1.95 cells in close in vivo contact were able to induce growth inhibition of the E1.15 subpopulation. Both the E1.95 and the E1.15 cells dominated the E1.80 cells, but in these cases cell kinetic differences may have played a role as the E1.95 and the E1.15 lines grew faster than the E1.80. The E1.80 cell line had no dominating effect on the E1.15 or E1.95. It is concluded that non-immunologically mediated cellular dominance in heterogeneous tumours may contribute to the evolution of these tumours and may be involved in fundamental tumour biological phenomena.

Udgivelsesdato: 1994-Jun-15, In order to address the question of the influence of a primarily chemoresistant tumor cell subpopulation on the progression of a heterogeneous tumor after cytotoxic therapy, in vitro established human small cell lung cancer cell lines of a 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)-sensitive (592) and a resistant (NYH) tumor were used to produce mixed solid tumors in nude mice. Mixtures of 592/NYH (9:1 and 1:1) were inoculated s.c. After 3-4 weeks of tumor growth, the mice were stratified according to tumor size and randomized to treatment with BCNU 40 mg/kg i.p. (10% of lethal dose) or no treatment. Tumor growth curves were used to calculate the effect of the treatment, and changes in the relative proportions of 592 and NYH in the mixed tumors were monitored by flow cytometric DNA analysis by which the two cell lines were distinguishable due to differences in DNA content. A significant response was demonstrated in the 9:1 mixed tumors in which only 592 cells were detectable at the start of the treatment. The response was short and less pronounced compared with tumors containing only 592. In the regrowing tumors after treatment, only NYH was detected. In untreated 9:1 mixed control tumors, only 592 cells were detectable throughout the entire observation period. It is substantiated that the 592 cells were able to inhibit the growth of the NYH cells completely when grown together in 9:1 mixed tumors. This was not the case in the 1:1 mixed tumors. The 1:1 mixed tumors did not respond to BCNU, although 592 was eradicated. These results indicate that resistant and undetectable (dominated) subpopulations in heterogeneous tumors may be responsible for relapse and that the fractional size and the growth characteristics of the resistant subpopulation may determine the magnitude of the clinical response to cytotoxic treatment.

Udgivelsesdato: 1994-Nov-1, We investigated the influence of cellular heterogeneity on the response to low-dose BCNU chemotherapy of an artificially mixed human small-cell lung cancer (SCLC) xenograft in nude mice containing a BCNU-sensitive and dominating sub-population and a BCNU-resistant and undetectable (dominated) sub-population. The cell lines differed in DNA content, making them distinguishable by DNA flow cytometry (FCM). After 3 weeks of tumor growth, the mice were stratified according to tumor size and randomized to 2 different low-dose treatments with BCNU or no treatment. After a further 3 to 4 weeks, a high-dose treatment (LD10) was given to both groups of treated tumors. Changes in the relative proportions of and cell lines in the tumors were measured by FCM on fine-needle tumor aspirates. At the time of low-dose treatment, all the tumors were totally dominated by the sensitive cells. A temporary response was seen after low-dose treatment. After the high-dose treatment, a similar short response was seen. In the non-treated group, the sensitive cells continued to dominate. At the time of tumor regrowth after the low-dose treatment, most of the tumors continued to be dominated by the sensitive population. At the time of progression after the response to the high-dose treatment, the resistant cell line was the predominant population. If compared with a single high-dose BCNU treatment, the response of tumors treated with a low dose was superior, indicating that the presence of a dominating and slower growing sub-population influenced the outcome of the treatment.

Udgivelsesdato: 1993-Apr-22, A number of genes have altered activity in small-cell lung cancer (SCLC), but especially genes of the myc family (c-myc, L-myc and N-myc) are expressed at high levels in SCLC. Most studies have explored expression at the mRNA level, whereas studies of myc family oncoprotein expression are sparse. WE examined the expression of myc proto-oncogenes at the mRNA and protein level in 23 cell lines or xenografts. In the cell lines, the doubling time and the cell-cycle distribution, as determined by flow-cytometric DNA analysis, were examined to establish whether the level of myc-gene-family expression correlated with proliferative parameters. All tumours expressed at least one myc family member at the mRNA level. Exclusive c-myc mRNA expression was demonstrated in 8 tumours, L-myc in 7 and N-myc in I. Five tumours expressed both c-myc and L-myc, and 2 tumours expressed both c-myc and N-myc. In general, the level of expression of c-myc and N-myc was similar at the mRNA and the protein level. Expression of c-myc was positively correlated with the proliferative index (sum of S and G2+M phases) of cell lines, but not with the population doubling time. In general, L-myc-expressing cell lines had a low proliferative index. There was no systematic difference in myc expression between cell lines and xenografts of individual tumours.

Biokemi

Biokemi

Udgivelsesdato: 1990-null, The epipodophyllotoxines VP-16 and VM-26 are chemically closely related. VM-26 has been found to be considerably more potent than VP-16 in vitro in a number of investigations. Although the drugs have been known for greater than 20 years, they have not been compared at clearly defined equitoxic doses on an optimal schedule in vivo and it has not been clarified as to whether a therapeutic difference exists between them. A prolonged schedule is optimal for both drugs; accordingly we determined the toxicity in mice using a 5-day schedule. The dose killing 10% of the mice (LD10) was 9.4 mg/kg daily (95% confidence limits, 7.4-11.8) for VP-16 and 3.4 (2.5-4.5) mg/kg daily for VM-26. In vitro, we found VM-26 to be 6-10 times more potent than VP-16 in a clonogenic assay on murine tumors P388 and L1210 leukemia and Ehrlich ascites. This pattern was also demonstrated in a multidrug-resistant subline of Ehrlich selected for resistance to daunorubicin (Ehrlich/DNR+), as it was 30 times less sensitive than Ehrlich cells to both VP-16 and VM-26. Using 90%, 45%, and 22% of the LD10 on the same murine tumors in vivo, we found that the effect of the two drugs was equal as evaluated by both the increase in life span and the number of cures. The drugs were also compared in nude mice inoculated with human small-cell lung cancer lines OC-TOL and CPH-SCCL-123; however, they were more toxic to the nude mice and only a limited therapeutic effect was observed. In conclusion, the complete cross-resistance between the two drugs suggests that they have an identical antineoplastic spectrum. VM-26 was more potent than VP-16 in vitro; however, this was not correlated to a therapeutic advantage for VM-26 over VP-16 in vivo.