Radiotherapy planning: direct tumor location on simulation and port films using CT. Part I. Principles

Although there have been great advances in cancer diagnosis in recent years, it remains difficult to transfer tumor location information from cross-sectional computed tomographic (CT) scans or magnetic resonance images to the simulation and verification films used in planning radiotherapy. A newly developed system uses radioopaque markers attached to the patient as reference points. These markers are identified on both CT scans and simulation films and their locations entered into the treatment planning computer. The tumor and any desired normal structures are then outlined manually on each CT section. Transparent overlays produced by the computer show the position of the reference markers and tumor outlines for any combination of gantry angles and source-film distance. Because the overlays are scaled to the simulation films, the reference points enable precise alignment of overlay and film. The tumor outline thus appears on the simulation or verification films exactly as it is "seen" by the therapy beam, making field verification straightforward and accurate, even on oblique films.     

The impact of the changing pneumococcal national immunisation program among older Australians

Australia has a universal infant pneumococcal conjugate vaccination program and until recently a universal pneumococcal polysaccharide vaccine program for non-Indigenous adults aged ≥65 years and Indigenous adults aged ≥50 years. We documented the impacts of infant and adult vaccination programs on the epidemiology of invasive pneumococcal disease (IPD) in Indigenous and non-Indigenous adults.IPD notifications from the National Notifiable Disease Surveillance System were analysed from 2002 to 2017, grouped by age, vaccine serotype group and Indigenous status. Since the universal funding of infant and elderly pneumococcal vaccination programs in January 2005, total IPD decreased by 19% in non-Indigenous adults aged ≥65 years but doubled in Indigenous adults aged ≥50 years. Vaccine uptake was suboptimal in both groups but lower in Indigenous adults. IPD due to the serotypes contained in the pneumococcal conjugate vaccines (PCV) except for serotype 3 declined markedly over the study period but were replaced by non-PCV serotypes. Serotype 3 is currently the most common in older adults. In the populations eligible for the adult 23-valent pneumococcal polysaccharide vaccine (23vPPV) program, IPD rates due to its exclusive serotypes increased to a lower extent than non-vaccine types. In 2017, non-vaccine serotypes accounted for most IPD in the older population eligible for the 23vPPV program, while it's eleven exclusive serotypes accounted for the majority of IPD in younger adults.Infant and adult pneumococcal vaccination programs in Australia have shaped the serotype-specific epidemiology of IPD in older adults. IPD remains a significant health burden for the Indigenous population. Herd immunity impact is clear for PCV serotypes excluding serotype 3 and serotype replacement is evident for non-PCV serotypes. The adult 23vPPV immunisation program appears to have partially curbed replacement with IPD due to its eleven exclusive serotypes, highlighting a potential benefit of increasing adult 23vPPV coverage in Australia.     

Dummies and the sudden infant death syndrome

The association between dummy use and sudden infant death syndrome (SIDS) was investigated in 485 deaths due to SIDS in the postneonatal age group and compared with 1800 control infants. Parental interviews were completed in 87% of subjects. The prevalence of dummy use in New Zealand is low and varies within New Zealand. Dummy use in the two week period before death was less in cases of SIDS than in the last two weeks for controls (odds ratio (OR) 0.76, 95% confidence interval (CI) 0.57 to 1.02). Use of a dummy in the last sleep for cases of SIDS or in the nominated sleep for controls was significantly less in cases than controls (OR 0.44, 95% CI 0.26 to 0.73). The OR changed very little after controlling for a wide range of potential confounders. It is concluded that dummy use may protect against SIDS, but this observation needs to be repeated before dummies can be recommended for this purpose. If dummy sucking is protective then it is one of several factors that may explain the higher mortality from SIDS in New Zealand than in other countries, and may also explain in part the regional variation within New Zealand.     

Structurally diverse molecular deletions in the beta-globin gene cluster exhibit an identical phenotype on interaction with the beta S- gene

We have characterized a new deletion that increases hemoglobin F synthesis in an American black woman who is doubly heterozygous for this mutation and the beta S-gene. The 5' endpoint is 2.4 +/- 0.1 kilobases (kb) upstream from the delta-globin gene, and the 3' endpoint is 0.2 +/- 0.1 kb downstream from the beta-globin gene; the deletion is 12 kb long. Both members of the Alu moderately repetitive DNA sequence family, normally present upstream from the delta-globin gene, are preserved. The patient is asymptomatic with a mild anemia and 24.8% HbF. The patient's husband and daughter have a similar clinical syndrome, with HbF levels of 22.4% and 25.4%, respectively. Both husband and daughter are doubly heterozygous for the beta S-gene and the Ghana type of hereditary persistence of fetal hemoglobin (HPFH) deletion (HPFH-2). The 5' end of this deletion is in the psi beta-gene, and its total length is more than 70 kb. All three members of the family have normocytic red cells, of which 95% or more are F cells as detected by immunofluorescence. Previous studies have shown that culture of the erythroid progenitors (BFU-E) from both types of these compound heterozygotes in the presence of fetal sheep serum, rich in "switching factor," resulted in complete suppression of HbF synthesis. Although the newly described deletion resembles the Sicilian type of delta beta-thalassemia by its size and preservation of the Alu sequences, the clinical and biological phenotype produced by its interaction with the beta S-gene is very similar to that of the HPFH- type deletion.     

COMBINATION ANTI-PARATUBERCULOSIS THERAPY WITH CLARITHROMYCIN, RIFABUTIN and CLOFAZIMINE IN THE TREATMENT OF CROHN'S DISEASE. A PRELIMINARY REPORT ON THE AUSTRALIAN MULTICENTRE TRIAL

Mycobacterium paratuberculosis has been proposed as the cause of Crohn's disease, although this remains controversial. Observational studies of antibiotics with activity against this organism have led to the establishment of an Australian multicentre placebo-controlled trial of clarithromycin, rifabutin and clofazimine in patients with active Crohn's disease. All subjects receive treatment with a tapering regimen of prednisolone for the initial 16 weeks, combined with either antibiotics or matching placebos. If remission is achieved at the end of this period and prednisolone has been ceased they continue the trial medications for 2 years. The primary outcomes – remission rates at 1, 2 and 3 years – aim to determine whether these antibiotics are of long-term benefit in Crohn's disease. Secondary outcomes include rate of remission at 4 months, safety and quality of life.
As of May 2001, 171 of the required 212 subjects have been enrolled. Eighty-seven of 146 potential subjects have reached 16 weeks in remission (60%). Eighty of these are ongoing (92%). Only five withdrawals from the trial have occurred for adverse events thought probably related to trial medications – four subjects with raised LFTs and one who developed a rash. Other withdrawals have been mainly due to lack of response or worsening of Crohn's disease (37), hypomania from steroids (one patient) and pregnancy (one patient on placebo). There have been 11 withdrawals for protocol violations. An Independent Data Monitoring Committee has analysed progress of the trial and unanimously recommended that it continue.
This study is the largest and longest suitably powered randomised controlled trial of antibiotics undertaken in Crohn's disease. It will determine whether this antibiotic combination alters the natural history of this disorder.
This study is being supported by Pharmacia Australia Pty Limited.     

Erythropoietin production by the fetal liver in an adult environment

To gain insight into the mammalian liver to kidney erythropoietin (Ep) switch, we heterotopically transplanted livers from preswitch, switched, and postswitch fetal and newborn lambs into normal adult sheep. Recipients' serum Ep and circulating reticulocyte levels were serially determined until rejection of the graft and compared with identical samples from sham-operated control adult ewes. Transplantation of preswitch and switched fetal livers caused an impressive rise in recipients' serum Ep activity and provoked a corresponding increase in reticulocytosis. In contrast, Ep activity and reticulocyte counts did not change from preoperative levels in adult ewes transplanted with postswitch livers or in the sham-operated controls. The production of Ep by the preswitch fetal liver in the adult environment was not dependent on the presence or absence of host kidneys and was stimulated by anemic hypoxia. These results suggest that the fetal liver is capable of producing relatively large amounts of Ep activity, and the production of Ep can be maintained in the adult environment in the presence of functional adult kidneys. This argues against suppression of liver Ep production by renal Ep, or some other factor in the postnatal environment, and suggests that the liver to kidney switch of Ep production during ontogeny may represent a genetically determined event.     

Fluorouracil selectively spares acute myeloid leukemia cells with long- term growth abilities in immunodeficient mice and in culture

A subset of leukemic cells is assumed to maintain long-term growth of acute myeloid leukemia (AML) in vivo. Characterization of these AML progenitor cells may further define growth properties of human leukemia. In vitro incubations with 5-fluorouracil (5-FU) have been used for enrichment of normal primitive hematopoietic stem cells. By analogy to normal hematopoiesis, it was hypothesized that primitive leukemic stem cells might be kinetically more inactive than colony- forming cells (colony-forming units-AML [CFU-AML]). To examine this hypothesis, conditions were established for incubation with 5-FU that eliminated all CFU-AML. These conditions selected a 5-FU-resistant AML fraction that was evaluated for its capacity for long-term growth by transplantation into mice with severe combined immunodeficiency (SCID) and long-term culture in the quantitative cobblestone area-forming cell (CAFC) assay. Transplantation of the 5-FU-resistant fraction of four cases of AML into SCID mice resulted in growth of AML. Whereas no CFU- AML survived, 31% to 82% of primitive (week-6) CAFC were recovered from the 5-FU-treated cells. Hematopoietic cells proliferating in the CAFC assay were shown to be leukemic by cytologic, cytogenetic, or molecular analysis. The reduction of AML growth as determined by outgrowth of AML in SCID mice was in the same order of magnitude as the primitive (week- 6) CAFC reduction. This indicates that both assays measure closely related cell populations and that the CAFC assay can be used to study long-term growth of AML. These results show a hierarchy of AML cells that includes 5-FU-resistant progenitors. These cells are characterized as primitive (week-6) CAFC and as leukemia-initiating cells in SCID mice.     

Efficient retrovirus transduction of mouse pluripotent hematopoietic stem cells mobilized into the peripheral blood by treatment with granulocyte colony-stimulating factor and stem cell factor

Cytokine-mobilized peripheral blood cells have been shown to participate in hematopoietic recovery after bone marrow (BM) transplantation, and are proposed to be useful targets for retrovirus- mediated gene transfer protocols. We treated mice with granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) to mobilize hematopoietic progenitor cells into the peripheral blood. These cells were analyzed for the number and frequency of pluripotent hematopoietic stem cells (PHSC). We found that splenectomized animals treated for 5 days with G-CSF and SCF showed a threefold increase in the absolute number of PHSC over normal mice. The number of peripheral- blood PHSC increased 250-fold from 29 per untreated mouse to 7,200 in peripheral-blood PHSC in splenectomized animals treated for 5 days with G-CSF and SCF. Peripheral blood PHSC mobilized by treatment with G-CSF and SCF were analyzed for their ability to be transduced by retroviral vectors. Peripheral-blood PHSC from splenectomized animals G-CSF and SCF were transduced with a recombinant retrovirus containing the human MDR-1 gene. The frequency of gene transfer into peripheral blood PHSC from animals treated for 5 and 7 days was two-fold and threefold higher than gene transfer into PHSC from the BM of 5-fluorouracil-treated mice (P < .01). We conclude that peripheral blood stem cells mobilized by treatment with G-CSF and SCF are excellent targets for retrovirus- mediated gene transfer.     

Allogeneic bone marrow transplantation with a fixed low number of T cells in the marrow graft [see comments]

Despite prophylaxis with immunosuppressive drugs, severe acute graft- versus-host disease (GVHD) remains a major cause of morbidity and mortality in patients transplanted with unmodified bone marrow (BM) grafts from HLA-identical siblings. Although T-cell depletion of the BM graft has evolved as the most effective method to prevent severe acute GVHD, this beneficial effect is counterbalanced by an increased rate of graft failure and relapse of the disease. To find an approach to T-cell depletion that may avoid these extreme risks, we gave BM recipients a fixed low number of 1 x 10(5) donor T cells per kilogram of recipient's body weight in the graft. This corresponds with 99% T-cell depletion and is achieved by the addition of T cells to the graft that was previously depleted of T cells. A total of 70 patients with hematologic malignancies or aplastic anemia, including 40 patients with standard- risk leukemias, received BM grafts, depleted of T cells according to this approach, from HLA-identical siblings. The preparative regimen consisted of cyclophosphamide and total body irradiation. The patients also received a short course of cyclosporine posttransplant. Graft failure did not occur. Acute GVHD, only grade I or II, was seen in 70% of the patients and was limited to the skin in all patients. Chronic GVHD occurred in 31% of the patients and, with the exception of 1 patient, was limited to the skin as well. Relapse occurred in 3 of 40 (8%) patients with standard-risk leukemias, resulting in a projected survival at 5 years of 80%. Patients with standard-risk diseases had a procedure-related mortality of 11%. Quality of life, determined 1 year after BM transplant, was good in almost all patients with standard-risk diseases. Thus, this approach of T-cell depletion may be an approach that avoids the development of severe acute and chronic GVHD without damaging the function or antileukemic effect of the graft and that has a low transplant-related morbidity and mortality.