Myelodysplastic syndromes, from French-American-British to World Health Organization: comparison of classifications on 431 unselected patients from a single institution.

In 1999 a working group of the World Health Organization (WHO) published a revised classification for myelodysplastic syndromes (MDS): RA, RARS, refractory cytopenia with multilineage dysplasia (RC+Dys), RAEB I and II, del (5q) syndrome, and MDS unclassifiable. Chronic myelomonocytic leukemia (CMML) and RAEB-t were excluded. Standard French-American-British (FAB) and new WHO classifications have been compared in a series of patients (n = 431) from a single center, analyzing morphologic, clinical, and cytogenetic data. According to the WHO findings, dysgranulocytopoiesis or dysmegakaryocytopoiesis only were found in 26% of patients with less than 5% medullary blasts. These patients are thus unclassified and should remain in the subgroups RA and RARS. Splitting of heterogeneous RAEB into 2 subgroups according to blast count was supported by a trend to a statistically significant difference in the single-center study population. Patients with CMML whose white blood cell counts are above 13 000/microL may be excluded from the MDS classification, as warranted by WHO, but a redistribution of patients with dysplastic CMML according to medullary blast count leads to more heterogeneity in other WHO subgroups. Although the natural courses of RAEB-T and acute myeloid leukemia (AML) with dysplasia are different, comparable median survival durations after treatment in patients with RAEB-T and AML were in favor of the proposed 20% medullary blast threshold for AML. The homogeneity of subgroups was studied by evaluating prognostic scores. A significant shift into lower IPSS risk groups was evident in the new classification. These data cannot provide evidence for the new WHO proposal, which should not be adopted for routine clinical use at present. Some of its aspects can provide a starting point for further studies involving refined cytogenetics and clinical results.     

Induced luteolysis in the primate: rapid loss of luteinizing hormone receptors

The molecular mechanisms involved in luteolysis are still unclear in the primate. This study aimed to investigate the effect of induced luteolysis on the ovarian luteinizing hormone (LH) receptor and the steroidogenic enzyme, 3beta-hydroxysteroid dehydrogenase (3beta-HSD) in the marmoset monkey. Luteolysis was induced in the mid-luteal phase either directly by systemic prostaglandin F2alpha (PGF2alpha), or indirectly by LH withdrawal using systemic gonadotrophin releasing hormone antagonist (GnRHant) treatment. The LH receptor was studied by isotopic mRNA in-situ hybridization and in-situ ligand binding and 3beta-HSD expression was studied using isotopic mRNA in-situ hybridization and immunohistochemistry. Induced luteolysis was associated with a reduction in the expression of LH receptor (P < 0.0001) and 3beta-HSD mRNA, closely followed by a reduction in the LH receptor (P < 0.05) and 3beta-HSD protein concentrations within 24 h. There were no differences in the findings whether luteolysis was induced with PGF2alpha or GnRHant. This study shows that disparate mechanisms to induce luteolysis in the primate result in an identical rapid loss of the LH receptor and 3beta-HSD. In conclusion, induced luteolysis leads to rapid loss of the steroidogenic pathway in luteal cells.      

Trastuzumab-induced cardiotoxicity in elderly women with HER-2-positive breast cancer: a meta-analysis of real-world data

Background: We conducted a meta-analysis to assess the overall risk of cardiac toxicity associated with trastuzumab treatment in elderly breast cancer patients.

Methods: We searched databases from PubMed, EMBASE and Cochrane Central Registry of Controlled Trials to identify relevant studies. Statistical analyses were conducted to calculate the incidence rate, overall hazard ratio (HR) and 95% CIs using a fixed effects model.

Results: A total of 116,342 and 360 elderly patients from five cohort studies and two randomized clinical trials (RCTs) were included for analysis. The pooled incidences of symptomatic congestive heart failure (CHF) and CHF/HF/CM were 6.4% (95% CI 4.1% – 9.4) and 16.4% (95% CI 16.19% – 16.61) in patients with median age of 67.5 years from two RCTs and in patients with median age of 67.5 (60 – 75), 71 (66 – 80+), 74.5 (65 – 89), 75 (66 – 81+) and 79.5 (60 – 99) from five cohort studies, respectively. Trastuzumab was significantly correlated with an increased risk of defined cardiac toxicities in five cohort studies (HR = 1.89, 95% CI 1.72 – 2.07, p < 0.00001) and two RCTs (HR = 3.00, 95% CI 1.71, 5.26, p < 0.00001). Sub-group analysis showed that the anthracycline-based chemotherapy increased the risk of CHF/HF and CM in patients among five cohort studies (HR = 2.16, 95% CI: 1.8 – 1.87, p < 0.00001).

Conclusion: Trastuzumab is likely associated with an increased risk of cardiac toxicity in elderly patients with HER-2-positive breast cancer. Carefully monitoring cardiac function in elderly patients receiving trastuzumab, particularly with concurrent use of anthracycline, is warranted.     

Recognition of beta 2-microglobulin-negative (beta 2m-) T-cell blasts by natural killer cells from normal but not from beta 2m- mice: nonresponsiveness controlled by beta 2m- bone marrow in chimeric mice.

The role of major histocompatibility complex (MHC) class I expression in control of the sensitivity of normal cells to natural killer (NK) cells was studied by the use of mutant mice made deficient for expression of beta 2-microglobulin (beta 2m) through homologous recombination in embryonal stem cells. T-cell blasts from beta 2m-deficient (beta 2m -/-) mice were killed by NK cells from normal mice in vitro, while beta 2m +/- blasts were resistant. The beta 2m defect also affected the NK effector cell repertoire: NK cells from beta 2m -/- mice failed to kill beta 2m -/- blasts, while they retained the ability to kill the prototype NK cell target lymphoma YAC-1, although at reduced levels. The inability to recognize beta 2m -/- blasts could be transferred with beta 2m -/- bone marrow to irradiated beta 2m-expressing mice. In contrast, the development of CD8+ T cells (deficient in beta 2m -/- mice) was restored in such chimera. These results indicate that loss of MHC class I/beta 2m expression is sufficient to render normal cells sensitive to NK cells, and that the same defect in the hemopoietic system of a mouse renders its NK cells tolerant to beta 2m-deficient but otherwise normal cells. In the beta 2m -/- mice, NK cells may be selected or educated by other bone marrow cells to tolerate the MHC class I deficiency. Alternatively, the specificity may be controlled directly by the class I molecules on the NK cells themselves.     

Success,complications, and restenosis following rotational and transluminal extraction atherectomy of ostial stenoses

Our objectives were to determine procedural success, clinical complications, and follow-up restenosis rates after rotational burr and transluminal extraction atherectomy of coronary artery and saphenous vein graft ostial stenoses. Balloon angioplasty of ostial lesions has been associated with low rates of success and high rates of clinical complications and restenosis compared to nonostial lesions. Atherectomy, due to its ability to excise (extraction atherectomy) or pulverize (rotational atherectomy) atheroma and the internal elastic lamina, may result in improved procedural outcome. We retrospectively studied 101 patients with ostial stenoses treated by rotational burr and transluminal extraction atherectomy over a 3-yr period. Quantitative angiography and clinical follow-up were reviewed to determine success, complication, and restenosis rates. Rotational burr (n = 29) and transluminal extraction (n = 72) atherectomy were associated with high procedural success (93% and 90%, respectively) and a low incidence of complications (6.9% and 4.2%, respectively). Postatherectomy angiographic success was low (52% and 69%, respectively) and required adjunctive balloon angioplasty in 85% of patients overall. This lower success rate likely reflects device undersizing as the overall postatherectomy artery to device ratio was near unity (0.95). The rates of angiographic ostial restenosis remain high (39.1% and 65.9%, respectively, P < 0.05). The high rate of restenosis after transluminal extraction atherectomy was due to the higher rate of restenosis in saphenous vein grafts (80%) compared to TEC treated coronary arteries (59%). When only coronary artery lesions were compared, there was no significant difference between atherectomy device groups with respect to restenosis rates or late loss. Rotational or transluminal extraction atherectomy of ostial stenoses is associated with high procedural success rates and a low incidence of complications; however, the rates of restenosis in these lesions remain high.     

Percutaneous implantation of permanent pacemakers (author's transl)

2 methods for the implantation of permanent pacemakers with percutaneous puncture of the subclavian vein are described. The first one was used in 44 patients with the aid of an introducing catheter-set Desilets-Hoffman consisting of guide-wire, inner Teflon dummy catheter and outer thin-walled sheath; through this a shoulder-less electrode catheter no. 8 could be inserted for permanent pacing. The other technique was applied to 20 patients and used thinner special electrodes no. 6F, which could be introduced directly through a plastic cannula inserted with a puncture-needle. The advantages are: diminished risk of infections, local anesthesia instead of general anesthesia, applicability by the cardiologist in the catheterization-laboratory or under a simple fluoroscopy-unit, short stay of patients in the hospital without transfers to other departments, few personnel (1 scrubbed doctor, 1 non-scrubbed nurse), recognition of venous anomalies (singular left superior caval vein) without useless incisions for the patient. Complications such as pneumothorax, puncture of the subclavian artery, and dislocations of the electrodes have also been encountered.