John H. Ward

Genetic testing for a BRCA1 mutation: Prophylactic surgery and screening behavior in women 2 years post testing

Mutations in the BRCA1 gene are associated with an increased risk of breast and ovarian cancer in carrier women. An understanding of behavioral responses to BRCA1 mutation testing by mutation carriers and non‐carriers is important to guide the clinical application of this new technology. This study examined the utilization of genetic testing for a BRCA1 mutation in high‐risk individuals and the response of tested women with respect to interventions for early cancer detection and prevention. This study assessed the utilization of genetic testing for both men and women in a large kindred and the behavioral responses by women with respect to use of health care interventions during the 2 years following testing. Participants were offered BRCA1 mutation testing. Surveillance behaviors related to breast and ovarian cancer were assessed by computer‐assisted telephone interviews at baseline (prior to genetic counseling and testing), 1–2 weeks, 4–6 months, 1 and 2 years after the provision of test results. Mutation carriers, non‐carriers, and individuals of unknown mutation status were compared to determine the impact of test results. Utilization of genetic testing for both men and women are reported and, for women, mammography, breast self‐exam, clinical breast exam, mastectomy, oophorectomy, transvaginal ultrasound, and CA125 screening were assessed. Of those fully informed of the opportunity for testing, 55% of the women and 52% of the men pursued genetic testing. With respect to mammography for women 40 years and older, 82% of mutation carriers obtained a mammogram in each year following testing compared to 72% of non‐carrier women the first year and 67% the second year. This mammography utilization represents a significant increase over baseline for both mutation carriers and non‐carriers. Younger carrier women also significantly increased their mammography utilization from baseline. Overall, 29% of the carrier women did not obtain a single mammogram by 2 years post‐testing. At 2 years, 83% of the carrier women and 74% of the non‐carriers reported adherence to recommendations for breast self‐exam and over 80% of carrier women had obtained a clinical breast examination each year following testing. None of the carrier women had obtained a prophylactic mastectomy by 2 years after testing, although 11% were considering this procedure. Of carrier women 25 years of age and older who had at least one intact ovary at the time of testing, 46% of carriers had obtained an oophorectomy 2 years after testing, including 78% of women 40 years of age and older. The majority of carrier women (73%) had discussed their genetic test results with a medical doctor or health care provider. Our results indicate utilization of genetic testing by a majority of high‐risk individuals who received information about testing. Both carriers and non‐carriers increased their utilization of mammography and breast self‐exam following testing. Oophorectomy was obtained by a large proportion of carrier women in contrast to mastectomy which was not utilized within the first 2 years following testing.

Agreement Between Self-Reported Breast Cancer Treatment and Medical Records in a Population-Based Breast Cancer Family Registry

PURPOSE Although self-report data on treatment for breast cancer are collected in some large epidemiologic studies, their accuracy is unknown. METHODS As part of a population-based Breast Cancer Family Registry, questionnaires on initial breast cancer treatment and subsequent recurrence were mailed to Australian women diagnosed between 1991 and 1998. These self-report data were validated against medical records for 895 women. RESULTS The median recall period was 3.2 years, mean age at diagnosis was 44 years, and 81% of women had early-stage breast cancer. Agreement between the two data sources was very high for general questions about type of treatment (100%, 99%, 99%, and 94% for surgery, radiotherapy, chemotherapy, hormonal therapy, respectively). For more specific questions about details of each treatment received, agreement was: for radiation therapy, 96% and 99% for radiation to the breast and chest wall, respectively; for surgery, 83%, 97%, and 88% for lumpectomy, mastectomy, and lymph node dissection, respectively; for hormonal therapy, 94% for tamoxifen; and for chemotherapy, range between 76% and 93%. There was 97% agreement about whether there had been a recurrence, and agreement about the location of recurrence was at least 90% for all sites. Agreement regarding stage at diagnosis was 62%, with discrepancies mostly due to women with locoregional disease incorrectly reporting distant spread. CONCLUSION This self-report questionnaire can be used to collect accurate data on broad categories of initial breast cancer treatment and recurrence, and even for more detailed information on specifics of treatment and site of recurrence.

A review of the subject of congenital hemihypertrophyand a complete case report

Summary 1. The literature pertaining to hemihypertrophy is reviewed. 2. A more applicable classification is suggested. 3. The etiologic, clinical, and pathologic findings are discussed. 4. A case of congenital total hemihypertrophy with necropsy findings isreported.

Combination chemotherapy using adriamycin, DTIC, cyclophosphamide, and actinomycin D for advanced soft tissue sarcomas: a randomized comparative trial. A phase III, Southwest Oncology Group Study (7613).

The term soft tissue sarcoma refers to a large variety of malignant tumors arising in extraskeletal connective tissues that connect, support, and surround discrete anatomic structures. All visceral organs also contain a connective stroma that can undergo malignant transformation. Because of the histological similarities of this group of tumors and their relative rarity, treatment prescriptions for patients that have disseminated disease are most often uniform. In this study, we asked the question whether adding a third drug (cyclophosphamide or actinomycin D) to Adriamycin (Adr [Adria Laboratories, Columbus, OH])-(3,3-dimethyl-1-triazeno)- imidazole-4-carboxamide (DTIC) would improve the response rate and/or survival. A unique feature of this cooperative group clinical trial was the mandatory pathology review of the histological material. All patients of the Southwest Oncology Group between June 1, 1976, and November 17, 1979, who had a biopsy-confirmed diagnosis of a soft tissue sarcoma with convincing clinical or biopsy-documented evidence of metastatic disease were eligible for the study. Patients were randomized to receive (1) Adr, 60 mg/m2 intravenously, day 1, and DTIC, 250 mg/m2 every 3 weeks (104 patients); (2) Adr and DTIC as in (1) and cyclophosphamide, 500 mg/m2, day 1 (112 patients); or (3) Adr and DTIC as in (1) and actinomycin D, 1.2 mg/m2, day 1, (119 patients). There was no statistically significant difference in response rates (33%, 34%, and 24%) (P = .25). Median durations of response were 31 weeks in the Adr-DTIC arm, 26 weeks in the cyclophosphamide-DTIC-Adr arm, and 23 weeks in the Adr-DTIC-Actinomycin D arm (P = .78). Median durations of survival were 37, 42, and 50 weeks, respectively. Again, no statistically significant differences were observed (P = .59). Toxicities from each of these treatment arms were formidable and were equivalent. Prognostic factor analysis showed a prognosis based on bone marrow reserve, sex, and pathology subtype favorable to patients.

Estimating Historical Exposures to Formaldehyde in a Retrospective Mortality Study

Abstract Dose-response is an important consideration in any epidemiologic study. This paper describes the development of exposure classifications for 30,000 persons exposed to formaldehyde since the early 1930s. The general approach was to make initial estimates of historical exposures from existing data, to monitor current exposures, to have plant industrial hygienists review the ranking of the jobs, and to review all three sources of information to develop final estimates. Job histories were abstracted from personnel files. The job titles from the abstracts were standardized and aggregated, reducing the number from 300,000 to 6700 job titles. Walk-throughs of the plants were made to gather historical and current production, control, and monitoring data. Historical exposure information for each job was coded and computerized. A list of the jobs, ranked by level of formaldehyde exposure, was generated and sent to each workplace for review. While the exposures were being coded, approximately 2000 air samp...

No Increased Risk of Breast Cancer Associated with Alcohol Consumption among Carriers of BRCA1 and BRCA2 Mutations Ages <50 Years

Epidemiologic studies have reported positive associations between alcohol consumption and risk of invasive breast cancer. Combined analyses suggest that breast cancer risk increases ∼9% for every 10-gram increment (less than one drink) in daily alcohol consumption ([1][1]-[3][2]). A recent

Lobular breast cancer: Excess familiality observed in the Utah Population Database

Family history of breast cancer (BC) is a strong predictor for developing female BC. Whether this excess familiality differs within morphological BC subgroups remains unclear. We assessed the risk of lobular breast cancer (LOB) and any BC among relatives of probands with LOB. We used the Utah Population Database (UPDB) to estimate familial relative risks (FRR) as well as average relatedness, using the genealogical index of familiality (GIF) statistic. The UPDB, a population‐based resource, links genealogical data from over 2 million individuals to the Utah Cancer Registry. Consistent with other studies, analysis of all BC cases showed significantly increased risk of BC to relatives (first‐degree relative [FDR]: FRR = 1.83, 95% confidence interval [CI] = 1.75–1.90). Morphology‐specific risks showed that relatives of LOB probands had an increased risk of LOB (FDR: FRR = 4.51, 95% CI = 2.79–6.89) and an increased risk of any BC (FDR: FRR = 2.47, 95% CI = 2.12–2.85); both measures were significantly greater than the all BC FRR estimates, and surpassed even generalized early‐onset BC risk. GIF analyses corroborated the FRR results and indicated that the excess relatedness of LOB cases extended to third‐degree relatives. Our findings suggest that LOB has a heritable component and may represent a genetically homogeneous form of BC. Pedigrees with excess LOB may be useful in isolating additional BC predisposition genes. Relatives of women with LOB are at higher risk for BC than relatives of other BC subtypes; a more rigorous BC screening regime may be warranted for these individuals.

Evolution from heterozygous to homozygous KIT mutation in gastrointestinal stromal tumor correlates with the mechanism of mitotic nondisjunction and significant tumor progression

Activating mutation in KIT or platelet-derived growth factor-α can lead to gastrointestinal stromal tumors (GISTs). Eighty-four cases from two institutes were analyzed. Of them, 62 (74%) harbored KIT mutations, 7 of which are previously unreported. One exhibited duplication from both intron 11 and exon 11, which has not been reported in KIT in human cancer. A homozygous/hemizygous KIT-activating mutation was found in 9 of the 62 cases (15%). We identified three GIST patients with heterozygous KIT-activating mutations at initial presentation, who later recurred with highly aggressive clinical courses. Molecular analysis at recurrence showed total dominance of homozygous (diploid) KIT-activating mutation within a short period of 6–13 months, suggesting an important role of oncogene homozygosity in tumor progression. Topoisomerase II is active in the S- and G2 phases of cell cycle and is a direct and accurate proliferative indicator. Cellular and molecular analysis of serial tumor specimens obtained from consecutive surgeries or biopsy within the same patient revealed that these clones that acquired the homozygous KIT mutation exhibited an increased mitotic count and a striking fourfold increase in topoisomerase II proliferative index (percentage cells show positive topoisomerase II nuclear staining compared to the heterozygous counterpart within the same patient. KIT forms a homodimer as the initial step in signal transduction and this may account for the quadruple increase in proliferation. Using SNPs for allelotyping on the serial tumor specimens, we demonstrate that the mechanism of the second hit resulting in homozygous KIT-activating mutation and loss of heterozygosity is achieved by mitotic nondisjunction, contrary to the commonly reported mechanism of mitotic recombination.

Hypocholesterolemia in patients treated with recombinant interleukin-2: appearance of remnant-like lipoproteins.

Reversible acute hypocholesterolemia was observed during treatment of metastatic cancer with high-dose intravenous recombinant interleukin-2 (IL-2). Further analysis revealed virtual disappearance of high-density lipoproteins (HDLs) and marked reduction in the concentration of low-density lipoproteins (LDL); the remaining LDL and intermediate-density lipoproteins (IDL) were enriched in triglyceride relative to cholesterol and had broad-beta electrophoretic mobility, properties reminiscent of remnant lipoproteins. These changes differ qualitatively and quantitatively from those previously reported for other cytokines such as tumor necrosis factor (TNF) or the interferons (IFNs).

Glucocorticoid toxicity: Single contrasted with divided daily doses of prednisolone

Abstract The present study was designed to investigate whether single daily doses of prednisolone cause less glucocorticoid toxicity than divided daily doses while providing equal relief of the signs and symptoms of rheumatoid arthritis. By the use of placebo tablets, the nature of the dosage regimens was concealed from patients and physicians. The number of tablets taken was estimated by supplying a known number in excess of the amount prescribed and counting the tablets returned at each monthly visit. Large discrepancies were found between the dose of prednisolone advised and that taken by many of the patients. An equivalent degree of relief of the signs and symptoms of rheumatoid arthritis was attained on both dosage regimens. Although the amount of prednisolone taken was 20 per cent larger on the single- than on the divided-dosage regimen, the difference was not statistically significant. No significant difference in glucocorticoid toxicity was found between patients on the single- and on the divided-dose regimens.