Robert W. Miller

Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome

Rothmund-Thomson syndrome (RTS; also known as poikiloderma congenitale) is a rare, autosomal recessive genetic disorder characterized by abnormalities in skin and skeleton, juvenile cataracts, premature ageing and a predisposition to neoplasia. Cytogenetic studies indicate that cells from affected patients show genomic instability often associated with chromosomal rearrangements causing an acquired somatic mosaicism. The gene(s) responsible for RTS remains unknown. The genes responsible for Werner and Bloom syndromes (WRN and BLM, respectively) have been identified as homologues of Escherichia coli RecQ, which encodes a DNA helicase that unwinds double-stranded DNA into single-stranded DNAs. Other eukaryotic homologues thus far identified are human RECQL (Refs 13, 14), Saccharomyces cerevisiae SGS1 (Refs 15,16) and Schizosaccharomyces pombe rqh1+ (ref. 17). We recently cloned two new human helicase genes, RECQL4 at 8q24.3 and RECQL5 at 17q25, which encode members of the RecQ helicase family. Here, we report that three RTS patients carried two types of compound heterozygous mutations in RECQL4. The fact that the mutated alleles were inherited from the parents in one affected family and were not found in ethnically matched controls suggests that mutation of RECQL4 at human chromosome 8q24.3 is responsible for at least some cases of RTS.

Association of Wilms's Tumor with Aniridia, Hemihypertrophy and Other Congenital Malformations

WHEN, through epidemiologic study of persons or families, diseases are found to be associated, the opportunities for determining their etiology may be very much increased. The association of leukem...

Cancer incidence, survival, and mortality for children younger than age 15 years.

Incidence and survival data from the National Cancer Institutes Surveillance, Epidemiology, and End Results (SEER) Program for the 10‐year period 1973–1982 are presented. Childhood cancer incidence rates have remained relatively stable over the last decade. The overall incidence rate increased slightly from 124 to 127 per million children from 1973–1977 to 1978–1982 while rates for leukemias remained unchanged over this same time period at 38 per million for all races combined. Leukemias and lymphomas accounted for 44% of all cancers among white children and 33% among blacks. For all forms of cancer combined, the 5‐year relative survival rate was 57% for both whites and blacks. The 5‐year relative survival rate exceeded 80% for fibrosarcomas, retinoblastomas, Hodgkins disease, and gonadal and germ cell tumors. Survival rates for children have shown improvement during the last decade, the most dramatic improvements occurring among patients with leukemia (15% 5‐year relative survival in 1967–1973 versus 51% in 1973–1981), non‐Hodgkins lymphoma (24% versus 51%), and bone tumors (28% versus 48%). Cancer 58:598‐602, 1986.

Merkel cell carcinoma and HIV infection.

Merkel cell carcinoma (MCC) is a rare skin cancer that occurs more frequently after organ transplantation or B-cell malignancy, conditions of suppressed or disordered immunity. To assess further whether immune suppression increases MCC risk, we studied its occurrence in a cohort of 309365 individuals with acquired immunodeficiency syndrome (AIDS) by using linked AIDS and cancer registries. We identified six cases of MCC, corresponding to a relative risk of 13.4 (95% CI 4.9-29.1) compared with the general population. These results suggest that immune suppression induced by the human immunodeficiency virus increases MCC risk.

Neurofibromatosis and childhood leukemia

Twelve new cases of childhood leukemia and neurofibromatosis were ascertained and evaluated in conjunction with 17 previously well-documented cases. The ratio of ALL: nonlymphocytic leukemia was 9:20, markedly different from the 4:1 ratio in children without NF. Rarer subtypes predominated: 8 CML and 8 AMML. The peculiar distribution of leukemia by cell type and the number of cases observed in the United States indicate that the risk of childhood leukemia in NF is increased. Two possible variants were noted: NF with “transient leukemia,” and multiple skin xanthomas with nonlymphocytic leukemia.

Retinoblastoma: epidemiologic characteristics.

Abstract Nationwide study of 269 death certificates for United States children with retinoblastoma, 1960–67, revealed a peak in mortality at two to three years of age that was 2 1/2 times greater in Negroes than in whites. Nationally, an estimated 81 per cent of children with the neoplasm survived. Study of 1623 hospital records of children with retinoblastoma revealed an excess of mental retardation: 21 cases observed vs. 4.7 expected. Associated malformations in several cases suggested D-deletion syndrome, which has been described by others in six children with retinoblastoma. In accord with previous studies, radiotherapy was associated with an excess of osteosarcoma, soft-tissue neoplasms or carcinoma of the skin. In addition, 11 children had second primary cancers not attributable to radiotherapy, a seeming excess over normal expectation. The cell types were diverse, but three were osteosarcomas, suggesting an innate susceptibility that may add to the risk of radiotherapy.

MUSTARD GAS AS A CAUSE OF RESPIRATORY NEOPLASIA IN MAN

Abstract Factory workers engaged in the manufacture of mustard gas in 1929-45 have since 1952 experienced 33 deaths from neoplasia of the respiratory tract (30 histologically confirmed), compared with 0.9 expected. The neoplasms occurred centrally rather than peripherally, and were of squamous or undifferentiated cell type.

Relation between Cancer and Congenital Defects in Man

WHEN diseases are found to occur together more often than can be attributed to chance, each can be studied in the light of what is known of the other for clues to etiology. Particularly informative...

Advances in 4D Medical Imaging and 4D Radiation Therapy

This paper reviews recent advances in 4D medical imaging (4DMI) and 4D radiation therapy (4DRT), which study, characterize, and minimize patient motion during the processes of imaging and radiotherapy. Patient motion is inevitably present in these processes, producing artifacts and uncertainties in target (lesion) identification, delineation, and localization. 4DMI includes time-resolved volumetric CT, MRI, PET, PET/CT, SPECT, and US imaging. To enhance the performance of these volumetric imaging techniques, parallel multi-detector array has been employed for acquiring image projections and the volumetric image reconstruction has been advanced from the 2D to the 3D tomography paradigm. The time information required for motion characterization in 4D imaging can be obtained either prospectively or retrospectively using respiratory gating or motion tracking techniques. The former acquires snapshot projections for reconstructing a motion-free image. The latter acquires image projections continuously with an associated timestamp indicating respiratory phases using external surrogates and sorts these projections into bins that represent different respiratory phases prior to reconstructing the cyclical series of 3D images. These methodologies generally work for all imaging modalities with variations in detailed implementation. In 4D CT imaging, both multi-slice CT (MSCT) and cone-beam CT (CBCT) are applicable in 4D imaging. In 4D MR imaging, parallel imaging with multi-coil-detectors has made 4D volumetric MRI possible. In 4D PET and SPECT, rigid and non-rigid motions can be corrected with aid of rigid and deformable registration, respectively, without suffering from low statistics due to signal binning. In 4D PET/CT and SPECT/CT, a single set of 4D images can be utilized for motion-free image creation, intrinsic registration, and attenuation correction. In 4D US, volumetric ultrasonography can be employed to monitor fetal heart beating with relatively high temporal resolution. 4DRT aims to track and compensate for target motion during radiation treatment, minimizing normal tissue injury, especially critical structures adjacent to the target, and/or maximizing radiation dose to the target. 4DRT requires 4DMI, 4D radiation treatment planning (4D RTP), and 4D radiation treatment delivery (4D RTD). Many concepts in 4DRT are borrowed, adapted and extended from existing image-guided radiation therapy (IGRT) and adaptive radiation therapy (ART). The advantage of 4DRT is its promise of sparing additional normal tissue by synchronizing the radiation beam with the moving target in real-time. 4DRT can be implemented differently depending upon how the time information is incorporated and utilized. In an ideal situation, the motion adaptive approach guided by 4D imaging should be applied to both RTP and RTD. However, until new automatic planning and motion feedback tools are developed for 4DRT, clinical implementation of ideal 4DRT will meet with limited success. However, simplified forms of 4DRT have been implemented with minor modifications of existing planning and delivery systems. The most common approach is the use of gating techniques in both imaging and treatment, so that the planned and treated target localizations are identical. In 4D planning, the use of a single planning CT image, which is representative of the statistical respiratory mean, seems preferable. In 4D delivery, on-site CBCT imaging or 3D US localization imaging for patient setup and internal fiducial markersfor target motion tracking can significantly reduce the uncertainty in treatment delivery, providing improved normal tissue sparing. Most of the work on 4DRT can be regarded as a proof-of-principle and 4DRT is still in its early stage of development.

Ultraviolet light: A hazard to children

BACKGROUND Sunlight is subdivided into visible light, ranging from 400 nm (violet) to 700 nm (red); longer infrared, “above red” or .700 nm, also called heat; and shorter ultraviolet radiation (UVR), “below violet” or ,400 nm. UVR is further subdivided into UV-A (320–400 nm), also called black (invisible) light; UV-B (290–320 nm), which is more skin-penetrating; and UV-C (,290 nm). UV-B constitutes ,0.5% of sunlight reaching the earth’s surface, but is responsible for most of the acute and chronic sunrelated damage to normal skin.1 Most UVR is absorbed by stratospheric ozone. UV-B has greater intensity in summer than in winter, at midday than in morning or late afternoon, in places closer to the equator, and at high altitudes. Sand, snow, concrete, and water can reflect up to 85% of sunlight, thus intensifying exposure.1