Efficient reduction of loco-regional recurrences but no effect on mortality twenty years after postmastectomy radiation in premenopausal women with stage II breast cancer – A randomized trial from the South Sweden Breast Cancer Group

PurposeTo study long term loco-regional and distant recurrence rate and survival after post-mastectomy radiotherapy in combination with oral cyclophosphamide in premenopausal women with stage II breast cancer.Study designA three-armed randomized multicenter phase III trial comparing 1) Radiotherapy (RT) 2) RT+ oral cyclophosphamide for one year (RT + C) and 3) Oral cyclophosphamide only (C).Radiotherapy was administered, in 20 fractions, to 48 Gy to the axilla and parasternal lymph nodes, 45 Gy to infra- and supraclavicular fossae and 38 Gy to the chest wall. Cyclophosphamide was prescribed as 12 courses of 130 mg/m² od for14 days every 4 weeks.Patients and methods367 patients from 15 surgical departments in Southern Sweden, representing 80% of all eligible patients, were included in the trial between 1978–1983. Median age was 47 years, median tumour size was 25 mm, and 33% of the patients were lymph node negative. Median follow-up time was 24 years.ResultsRT reduced the risk at twenty years for loco-regional recurrence in C-treated patients at twenty years with 75% (13.9% vs. 3.5%). The risk reduction was highly significant in both N0 and N+ patients. No reduction in systemic disease or mortality was observed.ConclusionPost-mastectomy radiotherapy reduced loco-regional recurrences in this premenopausal population, but no effect was seen on mortality with 20 years follow-up.     

Bleeding times in rats treated with heparin, heparin fragments of high and low anticoagulant activity and chemically modified heparin fragments of low anticoagulant activity

A template bleeding time study in the rat was undertaken to see if it is possible to correlate bleeding times with the molecular weight, anticoagulant activity or chemical composition of heparin or heparin-derived compounds. Heparin from porcine intestinal mucosa (PM-heparin) and from bovine lung (BL-heparin) as well as heparin fragments from these sources were compared. Heparin fragments of low anticoagulant activity were prepared by affinity chromatography on immobilized antithrombin as well as by chemical modification. A heparin fragment of high affinity for antithrombin (HA-fragment) caused a marked and dose-dependent increase in bleeding time while the corresponding heparin fragment with low affinity for antithrombin (LA-fragment) had a marginal and non-dose dependent effect on the bleeding time. Similar results were also obtained with PM-heparin with high and low affinity for antithrombin. A high anti-FXa activity was not always correlated with a marked bleeding tendency. Provided that a fragment was devoid of activated partial thromboplastin time (APTT) activity, it was not possible to provoke a bleeding time of 20 min or longer, although the compound was administered at a dose of 1,088 U/kg (anti-FXa activity). On the other hand, a N-acetylated chemically oversulphated heparin fragment, with a very low anti-FXa activity (1 U/mg) and with an APTT activity of 34 U/mg, caused a bleeding time of 20 min or longer in 70% of the animals after injection of the same number of APTT units, 1,088 U/kg. These data indicate that the APTT activity is a better and more sensitive indicator of the bleeding than is the anti-FXa activity.     

Ultrastructural characterization of tooth–biomaterial interfaces prepared with broad and focused ion beams

Current available techniques for transmission electron microscopy (TEM) of tooth–biomaterial interfaces are mostly ineffective for brittle phases and impair integrated chemical and morphological characterization.ObjectivesThe aims of this study were (1) to determine the applicability of new focused ion beam (FIB) and broad ion beam (BIB) techniques for TEM preparation of tooth–biomaterial interfaces; (2) to characterize the interfacial interaction with enamel and dentin of a conventional glass-ionomer (Chemfil Superior, DeTrey Dentsply, Germany), a 2-step self-etch (Clearfil SE, Kuraray, Japan) and a 3-step etch-and-rinse (OptiBond FL, Kerr, USA) adhesives; and (3) to characterize clinically relevant interfaces obtained from actual Class-I cavities.MethodsAfter bonding to freshly extracted human third molars, non-demineralized and non-stained sections were obtained using the FIB/BIB techniques and examined under TEM.ResultsThe main structures generally disclosed in conventional ultramicrotomy samples were recognized in FIB/BIB-based ones. There were not any major differences between FIB and BIB concerning the resulting ultrastructural morphology. FIB/BIB-sections enabled to clearly resolve sub-micron hydroxyapatite crystals on top of hard tissues and the interface between matrix and filler in all materials, even at nano-scale. Some investigated interfaces disclosed areas with a distinct “fog” or “melted look”, which is probably an artifact due to surface damage caused by the high-energy beam. Interfaces with enamel clearly disclosed the distinct “keyhole” shape of enamel rods sectioned at 90°, delimited by a thin electron-lucent layer of inter-rod enamel. At regions where enamel crystals ran parallel with the interface, we observed a lack of interaction and some de-bonding along with interfacial void formation.SignificanceThe FIB/BIB methods are viable and reliable alternatives to conventional ultramicrotomy for preparation of thin sections of brittle and thus difficult to cut biomaterial–hard tissue interfaces. They disclose additional ultrastructural information about both substrates and are more suitable for advanced analytic procedures.     

An evaluation of automated indirect blood pressure measurement during pregnancy

An automatic microcomputer-assisted instrument (Dinamap) for indirect determination of blood pressure was evaluated in 10 healthy women in the last trimester of pregnancy. Blood pressure determined intra-arterially was significantly (p less than 0.001) higher than indirect blood pressure determined with the Dinamap instrument or by manual sphygmomanometry. However, there was no significant difference in the mean change in blood pressure determined by the three techniques under investigation. A close correlation was recorded between systolic and diastolic blood pressure determined intra-arterially and with the Dinamap instrument (r = 0.92, r = 0.90), and between blood pressure determined intra-arterially and indirectly by auscultation (r = 0.93, r = 0.81). There was no significant difference in the reproducability of individual blood pressure values determined intra-arterially (systolic, 2.4 mmHg, diastolic, 3.7 mmHg) or by the Dinamap instrument (systolic, 2.8 mmHg, diastolic, 3.4 mmHg) or by auscultation (systolic, 5.0 mmHg, diastolic, 4.9 mm Hg). The Dinamap instrument proved reliable for the measurement of changes in blood pressure during late pregnancy. The technique eliminates the problem of inter-observer error which otherwise becomes evident when checking blood pressure antenatally.     

Fludarabine-based disease-specific conditioning or conventional myeloablative conditioning in hematopoietic stem cell transplantation for treatment of non-malignant diseases

Fludarabine-based conditioning (FBC) was given to 24 patients and conventional myeloablative conditioning (MC) to 33 patients, most children, before hematopoietic stem cell transplantation (HSCT) for non-malignant diseases. The donors were human leukocyte antigen (HLA)-A, -B, -DRbeta1-identical related (33%) or unrelated (67%). In the FBC group, two grafts failed versus three in the MC group; all were successfully regrafted. Fever was more common in the MC patients (P=0.003). Bacteremia occurred in 25% of the FBC group and 50% in the MC group (P=0.1). In the FBC group, platelet engraftment was faster and transfusions were fewer (P<0.05). Mucositis and renal function were similar in the two groups. The MC group had higher maximum bilirubin (P=0.03) and less often normal spirometry (P=0.04) after HSCT. A 7-year-old girl in the MC group had permanent alopecia. No patients had severe acute graft-versus-host disease (GVHD). Chronic GVHD was rare. Complete donor CD3+ chimerism was more common in the MC group (P=0.01), but CD33+ engraftment was better with FBS (P=0.03). Treatment-related mortality was 4 and 15%, and 5-year survival was 89 and 85% in the FBC and MC groups. Although survival was similar, FBC is a promising alternative to MC in non-malignant disorders.     

Human Fanconi A cells are susceptible to TRAIL-induced apoptosis

Tumour necrosis factor (TNF) contributes to the pathogenesis of bone marrow failure in Fanconi anaemia (FA) patients. The sensitivity of haematopoietic cells from FA, complementation group A (FANCA) subjects, who represent the majority of FA patients, to TNF-related apoptosis-inducing ligand (TRAIL) is unknown. The human lymphoblastoid FANCA HSC072 cell line and the genetically corrected counterpart HSC072FANCA-neo were tested for apoptoptic response to TRAIL using flow cytometry and Western blotting. FANCA cells were more sensitive to TRAIL-induced apoptosis than their corrected counterparts, indicating that TRAIL negatively regulates haematopoietic FANCA cell lines. This effect involved poly(ADP-ribose) polymerase-1 cleavage and caspase-8 activation.     

Breast tomosynthesis and digital mammography: a comparison of breast cancer visibility and BIRADS classification in a population of cancers with subtle mammographic findings

The main purpose was to compare breast cancer visibility in one-view breast tomosynthesis (BT) to cancer visibility in one- or two-view digital mammography (DM). Thirty-six patients were selected on the basis of subtle signs of breast cancer on DM. One-view BT was performed with the same compression angle as the DM image in which the finding was least/not visible. On BT, 25 projections images were acquired over an angular range of 50 degrees, with double the dose of one-view DM. Two expert breast imagers classified one- and two-view DM, and BT findings for cancer visibility and BIRADS cancer probability in a non-blinded consensus study. Forty breast cancers were found in 37 breasts. The cancers were rated more visible on BT compared to one-view and two-view DM in 22 and 11 cases, respectively, (p < 0.01 for both comparisons). Comparing one-view DM to one-view BT, 21 patients were upgraded on BIRADS classification (p < 0.01). Comparing two-view DM to one-view BT, 12 patients were upgraded on BIRADS classification (p < 0.01). The results indicate that the cancer visibility on BT is superior to DM, which suggests that BT may have a higher sensitivity for breast cancer detection.     

Genomic tissue typing and optimal antithymocyte globuline dose using unrelated donors results in similar survival and relapse as HLA-identical siblings in haematopoietic stem-cell transplantation for leukaemia

Sixty-one leukaemia patients treated with haematopoietic stem cell transplantation (HSCT) from a genomic human leucocyte antigen (HLA)-A, -B and -DRbeta1 matched unrelated donor (MUD) were compared with 121 patients with an HLA-identical sibling donor. All patients received conventional conditioning. We selected all patients with unrelated donors who received optimal antithymocyte globuline (ATG) dose, 6 mg/kg. One hundred and seven patients received stem cells from peripheral blood and 75 patients received bone marrow (BM) cells. The incidences of acute graft-versus-host disease (GVHD) grades II-IV were 33.4% and 34.7% in the MUD and sibling group, respectively. After year 2001, the incidence of chronic GVHD was similar in the two groups (27.8% vs. 25.8%). There was no difference in overall survival (60% vs. 60%), transplant-related mortality (18.6% vs. 16.6%) and relapse (23% vs. 26.4%) between the two groups. Conclusion: Haematopoietic stem cell transplantation with unrelated donors results in similar GVHD, relapse and survival as compared to using sibling donors. Reasons for this may be improved tissue-typing techniques and supportive care and optimisation of the ATG dose.     

A prospective randomized study using N-acetyl-L-cysteine for early liver toxicity after allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (ASCT) and its conditioning with chemoradiotherapy often results in liver toxicity, the most severe form being veno-occlusive liver disease (VOD). N-acetyl-L-cysteine (NAC), an antioxidant glutathione precursor, may provide protection from liver toxicity. Patients with elevated bilirubin (>26 mmol/l) and/or elevated (ALT) (>1.4 microkat/l) and/or aspartate aminotransferase (AST) (>1.4 microkat/l) levels were randomized to treatment with NAC or no treatment. Among 522 transplanted patients, 160 were included in the trial. NAC was given, 100 mg/kg per day, as a 6-h i.v. infusion until normalization of bilirubin, ALT and AST values. Maximum bilirubin level was the same in patients randomized to NAC (n=72) or controls (n=88). Increase and recovery of ALT and AST were the same in patients randomized to NAC or controls. There were two patients in the NAC group who developed VOD, as compared to three of the controls. To conclude, NAC does not improve liver toxicity after ASCT.