Dose reduction and its influence on diagnostic accuracy and radiation risk in digital mammography: an observer performance study using an anthropomorphic breast phantom

This study aimed to investigate the effect of dose reduction on diagnostic accuracy and radiation risk in digital mammography. Simulated masses and microcalcifications were positioned in an anthropomorphic breast phantom. Thirty digital images, 14 with lesions, 16 without, were acquired of the phantom using a Mammomat Novation (Siemens, Erlangen, Germany) at each of three dose levels. These corresponded to 100%, 50% and 30% of the normally used average glandular dose (AGD; 1.3 mGy for a standard breast). Eight observers interpreted the 90 unprocessed images in a free response study, and the data were analysed with the jackknife free response receiver operating characteristic (JAFROC) method. Observer performance was assessed using the JAFROC figure of merit (FOM). The benefit of radiation risk reduction was estimated based on several risk models. There was no statistically significant difference in performance, as described by the FOM, between the 100% and the 50% dose levels. However, the FOMs for both the 100% and the 50% dose were significantly different from the corresponding quantity for the 30% dose level (F-statistic = 4.95, p-value = 0.01). A dose reduction of 50% would result in three to nine fewer breast cancer fatalities per 100,000 women undergoing annual screening from the age of 40 to 49 years. The results of the study indicate a possibility of reducing the dose to the breast to half the dose level currently used. This has to be confirmed in clinical studies, and possible differences depending on lesion type should be examined further.     

Membrane-localized activation of glucuronide prodrugs by beta-glucuronidase enzymes

Gene-mediated enzyme prodrug therapy (GDEPT) seeks to increase the therapeutic index of anti-neoplastic agents by promoting selective activation of relatively nontoxic drug derivatives at sites of specific enzyme expression. Glucuronide prodrugs are attractive for GDEPT due to their low toxicity, bystander effect in the interstitial tumor space and the large range of possible glucuronide drug targets. In this study, we expressed human, murine and Esherichia coli beta-glucuronidase on tumor cells and examined their in vitro and in vivo efficacy for the activation of glucuronide prodrugs of 9-aminocamptothecin and p-hydroxy aniline mustard. We show that (1) fusion of beta-glucuronidase to the Ig-like C(2)-type and Ig-hinge-like domains of the B7-1 antigen followed by the B7-1 transmembrane domain anchored high levels of active murine and human beta-glucuronidase on cells, (2) strong bystander killing of tumor cells was achieved in vitro by murine beta-glucuronidase activation of prodrug, (3) potent in vivo anti-tumor activity was achieved by prodrug treatment of tumors that expressed murine beta-glucuronidase and (4) the p-hydroxy aniline prodrug was more effective in vivo than the 9-aminocamptothecin prodrug. Our results demonstrate that surface expression of murine beta-glucuronidase for activation of a glucuronide prodrug of p-hydroxy aniline mustard may be useful for more selective therapy of cancer.     

Smoking is a strong risk factor for rheumatoid nodules in early rheumatoid arthritis

OBJECTIVE: To examine whether smoking is a risk factor for rheumatoid nodules in early rheumatoid arthritis, and if so to determine the quantitative effect of smoking. METHODS: From a cohort (n = 1589) in a structured programme for follow up of newly diagnosed cases of rheumatoid arthritis (symptoms of swollen joints < or =12 months), 112 individuals with rheumatoid nodules at inclusion were identified. Nodular patients were each compared with two age and sex matched controls without nodules from the same cohort. A detailed self administered tobacco use questionnaire was answered by 210 patients (63%). RESULTS: Seventy patients were current smokers, 71 former smokers, and 69 had never smoked. Current smoking and former smoking were more common in patients with rheumatoid nodules compared with controls (86% v 59%) in both sexes. Positive rheumatoid factor (RF) was found more often among cases with nodules than controls (78% v 64%). Using detailed information from the questionnaires with conditional logistic regression analyses, ever having smoked was associated with an increased risk of the presence of rheumatoid nodules (odds ratio (OR) = 7.3 (95% confidence interval, 2.3 to 23.6); p = 0.001). The risk of having nodules was not obviously dose dependent when smoking duration as well as smoking amount were examined. A stratified analysis showed that only RF positive smokers had an increased risk of rheumatoid nodules. Smoking was associated with rheumatoid nodules among both men (p = 0.006) and women (p = 0.001). Tobacco use other than smoking (n = 31) was not associated with an increased risk of nodules (OR = 0.8 (0.2 to 3.4); p = 0.813). CONCLUSIONS: There is a strong association between smoking and rheumatoid nodules in early seropositive rheumatoid arthritis.     

Topographic organization in the auditory brainstem of juvenile mice is disrupted in congenital deafness

There is an orderly topographic arrangement of neurones within auditory brainstem nuclei based on sound frequency. Previous immunolabelling studies in the medial nucleus of the trapezoid body (MNTB) have suggested that there may be gradients of voltage-gated currents underlying this tonotopic arrangement. Here, our electrophysiological and immunolabelling results demonstrate that underlying the tonotopic organization of the MNTB is a combination of medio-lateral gradients of low-and high-threshold potassium currents and hyperpolarization-activated cation currents. Our results also show that the intrinsic membrane properties of MNTB neurones produce a topographic gradient of time delays, which may be relevant to sound localization, following previous demonstrations of the importance of the timing of inhibitory input from the MNTB to the medial superior olive (MSO). Most importantly, we demonstrate that, in the MNTB of congenitally deaf mice, which exhibit no spontaneous auditory nerve activity, the normal tonotopic gradients of neuronal properties are absent. Our results suggest an underlying mechanism for the observed topographic gradient of neuronal firing properties in the MNTB, show that an intrinsic neuronal mechanism is responsible for generating a topographic gradient of time-delays, and provide direct evidence that these gradients rely on spontaneous auditory nerve activity during development.     

Physical therapy and imaging outcome measures in a haemophilia population treated with factor prophylaxis: current status and future directions

Summary.  Routine infusions of factor VIII to prevent bleeding, known as prophylaxis, and other intensive therapies are being more broadly applied to patients with haemophilia. These therapies differ widely in replacement product usage, cost, frequency of venous access and parental effort. In order to address residual issues relating to recommendations, implementation, and evaluations of prophylaxis therapy in persons with haemophila, a multinational working group was formed and called the International Prophylaxis Study Group (IPSG). The group was comprised of haemophilia treaters actively involved in studies of prophylaxis from North America and Europe. Two expert committees, the Physical Therapy (PT) Working Group and the Magnetic Resonance Imaging (MRI) Working Group were organized to critically assess existing tools for assessment of joint outcome. These two committees independently concluded that the WFH Physical Examination Scale (WFH PE Scale) and the WFH X-ray Scale (WFH XR Scale) were inadequately sensitive to detect early changes in joints. New scales were developed based on suggested modifications of the existing scales and called the Haemophilia Joint Health Score (HJHS) and the International MRI Scales. The new scales were piloted. Concordance was measured by the intra-class correlation coefficient of variation. Reliability of the HJHS was excellent with an inter-observer co-efficient of 0.83 and a test-retest value of 0.89. The MRI study was conducted using both Denver and European scoring approaches; inter-reader reliability using the two approaches was 0.88 and 0.87; test-retest reliability was 0.92 and 0.93. These new PT and MRI scales promise to improve outcome assessment in children on early preventive treatment regimens.     

Home care during the pancytopenic phase after allogeneic hematopoietic stem cell transplantation is advantageous compared with hospital care

After myeloablative treatment and allogeneic stem cell transplantation (SCT), patients are kept in isolation rooms in the hospital to prevent neutropenic infections. During a 3-year period, patients were given the option of treatment at home after SCT. Daily visits by an experienced nurse and daily phone calls from a physician from the unit were included in the protocol. We compared 36 patients who wished to be treated at home with 18 patients who chose hospital care (control group 1). A matched control group of 36 patients treated in the hospital served as control group 2. All home care patients had hematologic malignancies and 19 were in first remission or first chronic phase. Of the donors, 25 were unrelated. The patients spent a median of 16 days at home (range, 0-26 days). Before discharge to the outpatient clinic after SCT, patients spent a median of 4 days (range, 0-39 days) in the hospital. In the multivariate analysis, the home care patients were discharged earlier (relative risk [RR] 0.33, P =.03), had fewer days on total parenteral nutrition (RR 0.24, P <.01), less acute graft-versus-host disease (GVHD) grades II-IV (RR 0.25, P =.01), lower transplantation-related mortality rates (RR 0.22, P =.04), and lower costs (RR 0.37, P <.05), compared with the controls treated in the hospital. The 2-year survival rates were 70% in the home care group versus 51% and 57% (not significant) in the 2 control groups, respectively (P <.03). To conclude, home care after SCT is a novel and safe approach. This study found it to be advantageous, compared with hospital care.     

Long-term follow-up of patients treated at home during the pancytopenic phase after allogeneic haematopoietic stem cell transplantation

To prevent neutropenic infections, patients are kept in isolation rooms after allogeneic haematopoietic stem cell transplantation (ASCT). Patients living within one hours' driving distance from our unit were given the opportunity of treatment at home after ASCT during the pancytopenic phase. We compared 36 patients treated at home during March 1998 until December 2000, with 54 controls treated in the hospital during September 1995 and September 2001. The incidence of grades II-IV acute graft-versus-host disease (GVHD) was lower in the home care group compared to the controls, that is, 17 vs 44% (P < 0.01). The cumulative incidence of chronic GVHD was 52% in the home care group, compared to 57% in the controls. Transplant-related mortality (TRM) was 13% in the home care patients vs 44% in the controls (P = 0.002). The probability of relapse was similar in the two groups. The 4-year survival was 63% in the home care patients compared to 44% in the controls (P = 0.04). Home care after ASCT is a novel approach that resulted in less TRM, similar incidence of chronic GVHD and relapse, and improved long-term survival compared to controls treated in the hospital.     

Homozygosis for (12) CA repeats in the first intron of the human IFN-gamma gene is significantly associated with the risk of aplastic anaemia in Caucasian population

Interferon-gamma (IFN-gamma) mediates the final damage of the stem cell compartment in Aplastic Anaemia (AA). Normal subjects homozygous for 12 (CA) repeats of polymorphism variable number of dinucleotide (CA) repeat (VNDR) in position 1349 of the IFN-gamma gene (IFNG) were shown to overproduce IFN-gammain vitro. We studied the distribution of polymorphism VNDR 1349 of IFNG in 67 Caucasian AA patients and in normal controls. Genotype (CA)12-12, (homozygosis for allele 2) and the single allele 12 were significantly more frequent (P = 0.005 and 0.004 respectively) in patients versus controls. The polymorphism was equally distributed in AA patients regardless of their response to immunosuppression. Homozygosity for 12 (CA) repeats of polymorphism VNDR 1349 of IFNG is strongly associated with the risk of AA in Caucasian subjects.     

Increased costs after allogeneic haematopoietic SCT are associated with major complications and re-transplantation

We wanted to evaluate factors associated with high costs after allogeneic haematopoietic SCT (HSCT). We collected all in-patient and outpatient costs during the first year after HSCT over 5 years, from 2003 to 2007. Mean 1-year costs per patient were \[euro]141,493 (95% confidence interval (95% CI)=125,019-157,967). Patients treated with non-myeloablative conditioning (NMC) had reduced costs, but patients treated with reduced-intensity or myeloablative conditioning had similar 1-year costs. Multivariate analysis showed that increased 1-year costs were seen in post-transplant complications: rejection (relative hazard (RH) 1.24, P<0.001), acute GVHD of grades III-IV (1.31, P<0.001) and invasive fungal infection (1.15, P=0.02). In addition, increased costs were associated with re-transplantation (1.21, P=0.001), mesenchymal stem-cell therapy (1.26, P<0.001), unrelated donor transplants (1.20, P=0.002) and the need for G-CSF treatment due to poor engraftment (1.12, P=0.047). In patients without any of these risk factors, mean 1-year costs were \[euro]84,773 (95% CI=71,145-98,400) (n=51). With three risk factors, the cost increased to \[euro]249,775 (95% CI=166,824-332,727) (n=14). To conclude, major complications increased the costs of HSCT. Unrelated donor transplants were more expensive than HLA-identical sibling transplants. Costs were reduced in patients treated with NMC.