Effects of radiation and lifestyle factors on risks of urothelial carcinoma in the Life Span Study of atomic bomb survivors.

Among the Life Span Study (LSS) of Atomic-bomb survivors, recent estimates showed that unspecified bladder cancer had high radiation sensitivity with a notably high female-to-male excess relative risk (ERR) per radiation dose ratio and were the only sites for which the ERR did not decrease with attained age. These findings, however, did not consider lifestyle factors, which could potentially confound or modify the risk estimates. This study estimated the radiation risks of the most prevalent subtype of urinary tract cancer, urothelial carcinoma, while accounting for smoking, consumption of fruit, vegetables, alcohol and level of education (a surrogate for socioeconomic status). Eligible study subjects included 105,402 (males = 42,890) LSS members who were cancer-free in 1958 and had estimated radiation doses. Members were censored due to loss of follow-up, incident cancer of another type, death, or the end of calendar year 2001. Surveys (by mail or clinical interview) gathered lifestyle data periodically for 1963-1991. There were 63,827 participants in one or more survey. Five hundred seventy-three incident urothelial carcinoma cases occurred, of which 364 occurred after lifestyle information was available. Analyses were performed using Poisson regression methods. The excess relative risk per weighted gray unit (the gamma component plus 10 times the neutron component, Gy(w)) was 1.00 (95% CI: 0.43-1.78) but the risks were not dependent upon age at exposure or attained age. Lifestyle factors other than smoking were not associated with urothelial carcinoma risk. Neither the magnitude of the radiation ERR estimate (1.00 compared to 0.96), nor the female-to-male (F:M) ERR/Gy(w) ratio (3.2 compared to 3.4) were greatly changed after accounting for all lifestyle factors. A multiplicative model of gender-specific radiation and smoking effects was the most revealing though there was no evidence of significant departures from either the additive or multiplicative joint effect models. Among the LSS cohort members with doses greater than 0.005 Gy(w) (average dose 0.21 Gy(w)), the attributable fraction of urothelial carcinoma due to radiation was 7.1% in males and 19.7% in females. Among current smokers, the attributable fraction of urothelial carcinoma due to smoking was 61% in males and 52% in females. Relative risk estimates of smoking risk were approximately two for smokers compared to nonsmokers. After adjustment for lifestyle factors, gender-specific radiation risks and the F:M ERR/Gy(w), the ratios of excess urothelial carcinoma risk were similar to the estimates without adjusting for lifestyle factors. Smoking was the primary factor responsible for excess urothelial carcinoma in this cohort. These findings led us to conclude that the radiation risk estimates of urothelial carcinoma do not appear to be strongly confounded or modified by smoking, consumption of alcohol, fruits, or vegetables, or level of education.

Molecular alterations of the IDH1 gene in AML: a Children's Oncology Group and Southwest Oncology Group study.

Recent whole-genome sequencing efforts led to the identification of IDH1(R132) mutations in acute myeloid leukemia (AML) patients. We studied the prevalence and clinical implications of IDH1 genomic alterations in pediatric and adult AML. Diagnostic DNA from 531 AML patients treated on Children's Oncology Group trial COG-AAML03P1 (N=257), and Southwest Oncology Group trials SWOG-9031, SWOG-9333 and SWOG-9500 (N=274), were tested for IDH1 mutations. Codon R132 mutations were absent in the pediatric cohort, but were found in 12 of 274 adult patients (4.4%, 95% CI 2.3-7.5). IDH1(R132) mutations occurred most commonly in patients with normal karyotype, and those with FLT3/ITD and NPMc mutations. Patients with IDH1(R132) mutations trended toward higher median diagnostic white blood cell counts (59.2 x 10(9) vs 29.1 x 10(9) per liter, P=0.19) than those without mutations, but the two groups did not differ significantly in age, bone marrow blast percentage, overall survival or relapse-free survival. Eleven patients (2.1%) harbored a novel V71I sequence alteration, which was found to be a germ-line polymorphism. IDH1 mutations were not detected in pediatric AML, and are uncommon in adult AML.

Benefits of routine use of coronal and sagittal reformations in multi-slice CT examination of the abdomen and pelvis.

AIM: To evaluate the usefulness of coronal and sagittal reformations from isotropic abdomino-pelvic computed tomography (CT) examinations. METHODS: Fifty consecutive abdomino-pelvic CT examinations were reconstructed into two sets of axial source images: 0.9 mm section width with 0.45 mm reconstruction interval (isotropic) and 4 mm section width with 3 mm reconstruction interval. The isotropic dataset was reformatted into coronal and sagittal stacks with 4 mm section widths. Three readers independently reviewed the three image sets with 4 mm section widths. The coronal and sagittal reformations were compared with the axial images, in the same sitting, for depiction of lesions in various abdominal organs. RESULTS: There was better visualization of lesions in the liver, kidneys, mesentery, lumbar spine, major abdominal vessels, urinary bladder, diaphragm and hips on the coronal reformations compared with source axial images (p<0.05). Sagittal reformations scored better than axial source images for showing lesions in the liver, thoracic spine, abdominal vessels, uterus, urinary bladder, diaphragm and hips (p<0.05). The coronal and sagittal series showed significant additional information in 23 and 17% of patients, respectively. CONCLUSION: Radiologists should consider the routine review of at least one additional plane to the axial series in the interpretation of abdomino-pelvic CT studies.

Routine isotropic computed tomography scanning of the abdomen and pelvis.

For 30 years, abdominal CT has been imaged and reviewed in the axial plane. It is now possible to carry out isotropic imaging of the whole abdomen and pelvis using a 40-channel scanner. This allows creation of coronal and sagittal reformats with the same image quality as the axial images. In this study, we present our experience of reviewing routinely coronal and, occasionally, sagittal reformats. We discuss situations where these nonaxial reformats are most beneficial.

Childhood leukaemia in Belarus, Russia, and Ukraine following the Chernobyl power station accident: results from an international collaborative population-based case-control study.

BACKGROUND: There is little evidence regarding the risk of leukaemia in children following exposure to radionuclides from the Chernobyl Nuclear Power Plant explosion on April 26, 1986. METHODS: This population-based case-control study investigated whether acute leukaemia is increased among children who were in utero or <6 years of age at the time of the Chernobyl accident. Confirmed cases of leukaemia diagnosed from April 26, 1986 through December 31, 2000 in contaminated regions of Belarus, Russia, and Ukraine were included. Two controls were matched to each case on sex, birth year, and residence. Accumulated absorbed radiation dose to the bone marrow was estimated for each subject. RESULTS: Median estimated radiation doses of participants were <10 mGy. A significant increase in leukaemia risk with increasing radiation dose to the bone marrow was found. This association was most evident in Ukraine, apparent (but not statistically significant) in Belarus, and not found in Russia. CONCLUSION: Taken at face value, these findings suggest that prolonged exposure to very low radiation doses may increase leukaemia risk as much as or even more than acute exposure. However the large and statistically significant dose-response might be accounted for, at least in part, by an overestimate of risk in Ukraine. Therefore, we conclude this study provides no convincing evidence of an increased risk of childhood leukaemia as a result of exposure to Chernobyl radiation, since it is unclear whether the results are due to a true radiation-related excess, a sampling-derived bias in Ukraine, or some combination thereof. However, the lack of significant dose-responses in Belarus and Russia also cannot convincingly rule out the possibility of an increase in leukaemia risk at low dose levels.

Proximal small bowel intussusceptions in adults: CT appearance and clinical significance.

BACKGROUND: According to the clinical literature, intestinal intussusception in adults is rare, is associated with a pathologic lead point, and is usually treated surgically. Nonobstructing small bowel intussusception has been reported as a transient finding on computed tomographic (CT) studies. METHODS: We evaluated the radiographic and clinical findings in 24 patients who were found to have 26 proximal small bowel intussusceptions on abdominal CT scans performed for a variety of indications. RESULTS: Twenty patients with intussusceptions had no evidence of small bowel obstruction. The transient and clinically insignificant nature of 22 intussusceptions in these 20 patients was proven radiologically (n = 14), surgically (n = 1), or by clinical follow-up (n = 7). These patients demonstrated a bowel-within-bowel pattern on multiple contiguous images and absence of strangulation or intestinal dilatation. No lead points were demonstrated in these patients. Three other patients had symptoms of low-grade small bowel obstruction and were treated conservatively. Extensive follow-up investigations showed no recurrence of intussusception or a lead point. One patient had high-grade obstructive intussusception with intestinal ischemia and required surgical resection of necrotic bowel. CONCLUSIONS: Proximal small bowel intussusceptions are likely to be transient and nonobstructive and unlikely to have a significant lead point.

Iodine deficiency, radiation dose, and the risk of thyroid cancer among children and adolescents in the Bryansk region of Russia following the Chernobyl power station accident.

BACKGROUND: Little is known about the joint effect of iodine deficiency and radiation exposure on the risk of thyroid cancer. No epidemiological studies have been published assessing the modifying effect of iodine deficiency on radiation-induced thyroid cancer following the Chernobyl accident. METHODS: A population sample of 3070 individuals (2590 ages 6-18, and 480 adults) from 75 settlements in the most highly contaminated regions of the Bryansk Oblast of Russia was identified and sampled for urinary iodine measurements in 1996, and iodine deficiency in each geopolitical unit (raion) was estimated. All cases of thyroid cancer were identified in those born 1968-1986 who were resident in the study area in May-June 1986 (34 histologically confirmed cases). The risk of thyroid cancer was examined in relation to population estimates of thyroid radiation dose and urinary iodine excretion level. RESULTS: The excess relative risk (ERR) of thyroid cancer was significantly associated with increasing thyroid radiation dose, and was inversely associated with urinary iodine excretion levels. There was a joint effect of radiation exposure and iodine deficiency. At 1 gray (Gy), the ERR in territories with severe iodine deficiency was approximately two times that in areas of normal iodine intake. CONCLUSIONS: These findings suggest that elimination of iodine deficiency in areas affected by Chernobyl may be important in reducing the effects of radiation exposure on the thyroid. If confirmed by studies based on individuals, they may have implications for the use of stable iodine in the case of population exposure to radioactive iodine.

The first technique for non-invasive measurements of volumetric ophthalmic artery blood flow in humans.

AIM: To validate the first non-invasive measurements of volumetric ophthalmic artery blood flow in humans. METHODS: The ophthalmic arteries of healthy normal adults were examined by Advanced Technology Laboratories (ATL, a subsidiary of Phillips Medical Systems Inc) high definition imaging (HDI) 5000 colour Doppler imaging ultrasound with a 5-12 MHZ probe. A group of 14 subjects for experiment 1 and a group of 10 subjects for experiments 2 and 3 were selected, with the examined eye chosen randomly. Peak systolic velocities (PSV) and end diastolic velocities (EDV) of the ophthalmic artery and central retinal artery were measured and recorded. Cineloops (cinegraphic videos) of the ophthalmic arteries were then recorded with the ATL HDI 5000 and values for ophthalmic artery blood flow were produced offline using experimental analysis software. Multiple regression analysis was used to compare blood flow measurements with PSV and EDV measurements in the ophthalmic artery. In two follow up experiments, intraobserver variation in obtaining cineloops and the interanalyser variability in cineloop analysis were studied. RESULTS: Volumetric flow correlated with ophthalmic artery PSV and EDV (p = 0.02, r(2) = 0.5). There was no correlation with the cental retinal artery. The intraobserver coefficient of variation in obtaining cineloops was 29.89% for blood flow, 19.07% for diameter, and 22.27% for velocity. The coefficients of variation of the measurements of the two cineloop analysers were 40.21% for blood flow, 22.71% for diameter, and 26.34% for velocity. CONCLUSION: Cineloop analysis produces ophthalmic artery flow measurements which correlate with PSV and EDV, suggesting validity. The intraobserver variation and cineloop analyser variation were found to be in the acceptable range.

Usefulness of color Doppler ultrasound in the management of a spinal arteriovenous fistula.

BACKGROUND: While color Doppler ultrasonography and microvascular Doppler recordings have been used intraoperatively for spinal cord vascular malformations, they have not been employed for similar spinal cord lesions preoperatively. CASE DESCRIPTION: We report the usefulness of color Doppler ultrasonography through a lumbar laminectomy defect in the management of a spinal arteriovenous fistula. CONCLUSION: Color Doppler ultrasonography should be considered for spinal lesions in which a laminectomy defect is present.

Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest Oncology Group study.

Cyclosporine A (CsA) inhibits P-glycoprotein (Pgp)-mediated cellular export of anthracyclines at clinically achievable concentrations. This randomized controlled trial was performed to test the benefit of CsA addition to treatment with cytarabine and daunorubicin (DNR) in patients with poor-risk acute myeloid leukemia (AML). A total of 226 patients were randomly assigned to sequential treatment with cytarabine and infusional DNR with or without intravenous CsA. Remitting patients received one course of consolidation chemotherapy that included DNR with or without CsA as assigned during induction. Addition of CsA significantly reduced the frequency of resistance to induction chemotherapy (31% versus 47%, P =.0077). Whereas the rate of complete remission was not significantly improved (39% versus 33%, P =.14), relapse-free survival (34% versus 9% at 2 years, P =.031) and overall survival (22% versus 12%, P =.046) were significantly increased with CsA. The effect of CsA on survival was greatest in patients with moderate or bright Pgp expression (median 12 months with CsA versus 4 months for controls) compared to patients with absent or low Pgp expression (median 6 months in both arms). The frequency of induction deaths was 15% with CsA and 18% in controls. Steady-state serum concentrations of DNR (P =.0089) and daunorubicinol (P <.0001) were significantly higher in CsA-treated patients. Survival (P =.0003) and induction response (P =.028) improved with increasing DNR concentration in CsA-treated patients but not in controls, suggesting a targeted interaction by CsA to enhance anthracycline cytotoxicity. These results indicate that addition of CsA to an induction and consolidation regimen containing infusional DNR significantly reduces resistance to DNR, prolongs the duration of remission, and improves overall survival in patients with poor-risk AML.

Evaluation of prospective living renal donors for laparoscopic nephrectomy with multisection CT: the marriage of minimally invasive imaging with minimally invasive surgery.

Laparoscopic technique for excision of a kidney from a living donor has advantages over conventional open surgery, but operative visibility and surgical exposure are limited. Preoperative multisection computed tomography (CT) can provide necessary anatomic information in a minimally invasive procedure. A three-phase examination is suggested: (a) imaging from the top of the kidneys to the pubic symphysis with a section width of 2.5 mm and no contrast medium, (b) scanning of the kidneys and upper pelvis during the arterial phase of enhancement with a section width of 1.0 mm, and (c) scanning of the kidneys and upper retroperitoneum during the nephrographic phase of enhancement with a section width of 1.0 mm. Emphasis in this article is placed on analysis of the venous anatomy because most radiologists are unfamiliar with the anatomic variations. Conventional radiography of the abdomen and pelvis is performed after CT to evaluate the collecting system and ureters and to provide a lower total radiation dose than if CT were used. Of several postprocessing techniques that may be used, the authors prefer maximum intensity projection for arterial evaluation and multiplanar reformatting for venous evaluation.

Stent grafting of abdominal aortic aneurysms: pre-and postoperative evaluation with multislice helical CT.

Endovascular stent grafting of abdominal aortic aneurysms is a new technique that may replace open surgery in selected cases. Pre-and postoperative angiography can be replaced by helical CT. This pictorial essay describes and illustrates the use of multislice helical CT where maximum intensity projection and multiplanar reformats play a central role in the evaluation.

FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia.

The prevalence and significance of genetic abnormalities in older patients with acute myeloid leukemia (AML) are unknown. Polymerase chain reactions and single-stranded conformational polymorphism analyses were used to examine 140 elderly AML patients enrolled in the Southwest Oncology Group study 9031 for FLT3, RAS, and TP53 mutations, which were found in 34%, 19%, and 9% of patients, respectively. All but one of the FLT3 (46 of 47) mutations were internal tandem duplications (ITDs) within exons 11 and 12. In the remaining case, a novel internal tandem triplication was found in exon 11. FLT3 ITDs were associated with higher white blood cell counts, higher peripheral blast percentages, normal cytogenetics, and less disease resistance. All RAS mutations (28 of 28) were missense point mutations in codons 12, 13, or 61. RAS mutations were associated with lower peripheral blast and bone marrow blast percentages. Only 2 of 47 patients with FLT3 ITDs also had a RAS mutation, indicating a significant negative association between FLT3 and RAS mutations (P =.0013). Most TP53 mutations (11 of 12) were missense point mutations in exons 5 to 8 and were associated with abnormal cytogenetics, especially abnormalities in both chromosomes 5 and 7. FLT3 and RAS mutations were not associated with inferior clinical outcomes, but TP53 mutations were associated with a worse overall survival (median 1 versus 8 months, P =.0007). These results indicate that mutations in FLT3, RAS, or TP53 are common in older patients with AML and are associated with specific AML phenotypes as defined by laboratory values, cytogenetics, and clinical outcomes. (Blood. 2001;97:3589-3595)

Methylation profiling in acute myeloid leukemia.

Aberrant methylation of multiple CpG islands has been described in acute myeloid leukemia (AML), but it is not known whether these are independent events or whether they reflect specific methylation defects in a subset of cases. To study this issue, the methylation status of 14 promoter-associated CpG islands was analyzed in 36 cases of AML previously characterized for estrogen-receptor methylation (ERM). Cases with methylation density of 10% or greater were considered positive. Seventeen cases (47%) were ERM(+) while 19 cases were ERM(-). Hypermethylation of any of the following, p15, p16, CACNA1G, MINT1, MINT2, MDR1, THBS1, and PTC1 (2 promoters), was relatively infrequent (6% to 31% of patients). For each of these CpG islands, the methylation density was positively correlated with ERM density (rank order correlation coefficients, 0.32-0.59; 2-tailed P < or = .058 for each gene). Hypermethylation of MYOD1, PITX2, GPR37, and SDC4 was frequently found in AML (47% to 64% of patients). For each of these genes as well, methylation density was positively correlated with ERM density (correlation coefficients 0.43 to 0.69, P < or = .0087 for each gene). MLH1 was unmethylated in all cases. Hypermethylation of p15, MDR1, and SDC4 correlated with reduced levels of expression. There was an inverse correlation between age and the number of genes methylated (P = .0030). It was concluded that CpG-island methylation in AML results from methylation defects in subsets of cases. These results have potential implications for the classification and prognosis of AML and for the identification of patients who may benefit from treatment with methylation inhibitors.

Comparison of the L10M consolidation regimen to an alternative regimen including escalating methotrexate/L-asparaginase for adult acute lymphoblastic leukemia: a Southwest Oncology Group Study.

The effectiveness of intensive post-remission chemotherapy regimens for adult patients with acute lymphoblastic leukemia (ALL) is limited by both a high rate of disease recurrence and a substantial incidence of treatment toxicity. To evaluate a potentially more effective and less toxic approach, we conducted a multicenter phase III trial of consolidation therapies comparing the standard L10M regimen with one combining the brief, intensive L17M regimen and escalating methotrexate (MTX) and L-asparaginase (L-asp). Patients over age 15 with previously untreated ALL were eligible. Induction therapy included vincristine, prednisone, doxorubicin, cyclophosphamide and intrathecal methotrexate administered over 36 days. Patients who achieved complete remission (CR) were randomized to receive consolidation with either the L10M regimen or with DAT (daunomycin, cytosine arabinoside, 6-thioguanine) and escalating MTX and L-asp. The randomization was stratified by age, WBC and Ph chromosome status. Maintenance therapy was the same in both arms. Of 353 eligible patients, 218 (62%) achieved CR and 195 were randomized. The treatment arms did not differ significantly with respect to disease-free survival (DFS; P= 0.46) or overall survival (P= 0.39). Estimated DFS at 5 years was 32% (95% confidence interval (CI) 23-42%) in the L10M arm and 25% (95% CI 16-33%) in the DAT/MTX/L-asp arm. In each arm, 4% of patients died of toxicities (infection in all but one case). Infections and nausea/vomiting were somewhat more common in the L10M arm (occurring in 68% and 53% of patients respectively) than the DAT/MTX/L-asp arm (56% and 33%). The DAT/MTX/L-asp consolidation regimen was associated with some reduction in nonfatal toxicities, but no significant improvement in DFS, overall survival or non-relapse mortality when compared to the standard L10M regimen.

Blasts from elderly acute myeloid leukemia patients are characterized by low levels of culture- and drug-induced apoptosis.

Increasing evidence suggests that the biology of acute myeloid leukemia (AML) may differ between older and younger patients, with a higher incidence of antecedent myelodysplasia, unfavorable cytogenetic abnormalities, and multidrug resistance seen in the elderly. Abrogation of apoptosis in response to cytotoxic medications is associated with drug resistance in AML, as is expression of bcl-2, an important anti-apoptotic protein. We hypothesized that blasts from elderly (> or = 55 years) and young adult AML patients might have different levels of apoptotic and cell cycle responses to chemotherapeutic agents, as well as different levels of proliferation and of bcl-2 protein expression. Therefore, we cultured bone marrow leukemia samples from previously untreated elderly (n=33) and young (n=21) AML patients for 48 h and then measured apoptosis, bcl-2 protein levels, cell cycle distributions, and expression of a proliferation marker, proliferating cellular nuclear antigen (PCNA) in multi-parametric flow cytometry assays. In some experiments, leukemia samples were exposed to cytarabine (Ara-C) or daunomycin (DNR) for the last 16-18 h of the culture period. In comparison to samples from young patients, cultured samples from elderly AML patients had a higher fraction of viable cells, as measured by Trypan blue exclusion, higher PCNA expression, and significantly less culture-induced and drug-induced apoptosis. The mean apoptosis after culture was 13% for elderly AML samples, versus 20% for young AML samples (P=0.009). Similarly, the mean apoptosis after Ara-C was lower in elderly than in young AML samples, 13 versus 28% (P=0.001), as was the mean apoptosis after DNR, 15 versus 26% (P=0.012). Diminished apoptotic responses in elderly AML cells were not consistently associated with high bcl-2 levels at thaw or bcl-2 levels increased by culture. These data suggest that new therapies should be developed to overcome abrogated apoptosis, particularly in elderly AML patients.