Developing a prognostic index for ductal carcinoma in situ of the breast. Are we there yet?
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Breast Neoplasms↗
Biomedical subjects
J R Harris
Publications and source records attributed to J R Harris.
The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer.
BACKGROUND: Patients with early-stage breast cancer who are at substantial risk for systemic metastases are increasingly treated with breast-conserving therapy and adjuvant chemotherapy. However, the optimal sequencing of chemotherapy and radiation therapy is not clear. METHODS: Two hundred forty-four patients with stage I or II breast cancer who were at substantial risk for distant metastases were randomly assigned to receive a 12-week course of chemotherapy either before or after radiation therapy. All had had breast-conserving surgery. The median length of follow-up in surviving patients was 58 months (range, 10 to 124). RESULTS: The five-year actuarial rates of cancer recurrence at any site and of distant metastases in the radiotherapy-first group and the chemotherapy-first group were 38 percent and 31 percent (P = 0.17) and 36 percent and 25 percent (P = 0.05), respectively. Overall survival was 73 percent and 81 percent (P = 0.11), respectively. The five-year crude rates of first recurrence according to site in the radiotherapy-first and chemotherapy-first groups, respectively, were 5 percent and 14 percent for local recurrence and 32 percent and 20 percent for distant or regional recurrence or both. This difference in the pattern of recurrence was of borderline statistical significance (P = 0.07). CONCLUSIONS: This study suggests that for patients ar substantial risk for systemic metastases, it is preferable to give a 12-week course of chemotherapy followed by radiation therapy, rather than radiation therapy followed by chemotherapy.
Actuarial Analysis↗
Extensive apoptosis in ductal carcinoma in situ of the breast.
BACKGROUND: More than 50% of breast ductal carcinomas in situ (DCIS) contain significant histologic necrosis, an important prognostic factor for determining recurrence and progression to invasive breast cancer. We have examined whether the mechanism of this spontaneous cell death might be apoptosis, a genetically encoded suicide pathway that may be triggered by various events including dysregulated cell proliferation. METHODS: Twenty-five untreated DCIS cases accessioned at our institution were examined for subtype, grade, and presence of apoptosis using two criteria: (1) cellular morphology (shrinkage, nuclear condensation, fragmentation, apoptotic bodies, and lack of inflammatory component); and (2) terminal transferase (TUNEL) staining of DNA fragmentation, a characteristic though less specific feature of apoptosis. Immunohistochemical staining was also carried out to assess whether wild-type p53, a regulator of apoptosis, was associated with this cell death. RESULTS: In all 19 cases with intraductal necrosis, cellular morphology was consistent with apoptotic death, despite its presence within sheets of "geographic necrosis." Additionally, the identical regions were all strongly TUNEL-positive. No evidence of TUNEL staining was seen in 5 Grade I DCIS cases without intraductal necrosis. Immunohistochemical staining suggested that this apoptosis was independent of p53 mutational status. CONCLUSIONS: Extensive intraductal necrosis in DCIS is likely to represent apoptosis. However, it is unlikely that this apoptosis is regulated by p53. The apparently abundant apoptosis identified here, particularly in high grade DCIS, may be important in explaining why spontaneous cell death in DCIS is associated with a worse prognosis.
Apoptosis↗
A prospective study of conservative surgery alone in the treatment of selected patients with stage I breast cancer.
BACKGROUND: Randomized clinical trials have clearly demonstrated that the use of radiation therapy (RT) following breast-conserving surgery (CS) substantially reduces the risk of local recurrence. However, the low rate of local recurrence after CS and RT for patients without known risk factors, and the recent increase in the detection of smaller cancers due to mammographic screening have led to the speculation that a subgroup of patients who have a low risk of local recurrence without RT might be identified. In 1986, we initiated a one-arm, prospective clinical trial of CS alone for treatment of highly selected breast cancer patients without known risk factors for local recurrence. METHODS: The study had a sequential design with a planned accrual of 90 patients. Criteria for entry into the trial were: a unicentric, clinical TI infiltrating ductal, mucinous or tubular carcinoma without an extensive intraductal component or lymphatic vessel invasion; a wide excision with a pathologically-documented negative margin of at least 1 cm; and histologically negative axillary lymph nodes. No adjuvant RT or systemic therapy was administered. Seventy-six per cent of the lesions were detected by mammography alone. The median gross pathologic tumor size was 0.9 cm. The median patient age was 67 years. RESULTS: Eighty-seven patients were enrolled in the trial before it closed prematurely in 1992 because the predefined stopping boundary was crossed (i.e., the sixth local recurrence was observed). At that time, the average annual local recurrence rate was 4.2%. With a median follow-up of 56 months, there are now 14 patients (16%) with local recurrence as their site of first failure (average annual local recurrence rate: 3.6%). Four patients without local recurrence developed distant metastases. Three patients have died, one of metastatic breast cancer and two of unrelated causes. CONCLUSIONS: Even in a highly selected group of patients with early-stage breast cancer, there is a substantial risk of early local recurrence for those treated with wide excision alone.
Adenocarcinoma, Mucinous↗
bcl-2 expression in the spectrum of preinvasive breast lesions.
BACKGROUND: The bcl-2 gene encodes for a protein that blocks apoptosis. Although the bcl-2 protein has been identified in some invasive breast cancers, its expression in preinvasive breast lesions has not been well characterized. METHODS: We studied bcl-2 expression using immunohistochemistry in cases of normal breast tissue (n = 10), ductal hyperplasia (n = 18), atypical ductal hyperplasia (ADH) (n = 10), atypical lobular hyperplasia/lobular carcinoma in situ (lobular neoplasia, LN) (n = 10), and ductal carcinoma in situ (DCIS) (n = 42). We also related bcl-2 expression to p53 expression in these lesions because the p53 gene is altered in many invasive breast cancers and is also involved in the regulation of apoptosis. RESULTS: bcl-2 was consistently expressed in the epithelial cells in all normal breast tissue, ductal hyperplasia, ADH, and LN lesions. In contrast, bcl-2 expression was present in 76% of the DCIS cases and was related to the histologic grade of DCIS. Staining for bcl-2 was observed in 100% of the well differentiated DCIS cases, 90% of intermediately differentiated cases, and 33% of poorly differentiated cases (P < 0.001). No immunoreactivity for the p53 protein was seen in any of the cases of normal breast tissue, ductal hyperplasia, ADH, or LN lesions. However, 24% of the DCIS cases were p53 positive. The bcl-2+/p53- phenotype, as seen in all cases of normal breast tissue, ductal hyperplasia, ADH, and LN was also observed in 67% of the DCIS cases. In contrast, the remaining 33% of DCIS cases showed combinations of bcl-2 and p53 expression that differed from that of normal breast epithelium and the other pathologic lesions studied. Most lesions with altered bcl-2/p53 phenotypes, including all bcl-2-/p53+ cases, represented examples of poorly differentiated DCIS. CONCLUSIONS: The bcl-2 protein is consistently expressed in normal breast epithelium, ductal hyperplasia, ADH, and LN. bcl-2 expression is variable in DCIS. Among DCIS cases, bcl-2 is most common in well differentiated and intermediately differentiated lesions. Most DCIS lesions are bcl-2+ and p53-, similar to normal epithelium, benign proliferative lesions, and LN. However, a minority of DCIS lesions show combinations of bcl-2 and p53 expression that differ from normal breast epithelium and from the other pathologic lesions studied. It is possible that such lesions may represent a subset of DCIS in which the regulation of apoptosis is no longer under normal control mechanisms, resulting in enhanced tumor cell survival and tumor growth.
Adult↗
Otitis media: relationship to tonsillitis, sinusitis and atopic diseases.
In order to estimate the co-morbidity between ear infections and related childhood diseases, data about the occurrence of recurrent ear infections, tonsillitis, sinusitis and atopic diseases from a population based sample of 7992 Norwegian twins were analysed. Correlational results revealed two general clusters, one consisting of upper respiratory tract infections (URI), the other defined by the atopic diseases. Overall, associations between the diseases were greater in males. The sizes of the correlations within each subgroup of infections were moderate, but significant, ranging from 0.191 to 0.363. Similar results were found for the relationship within the subgroup of atopies, with correlations ranging from 0.134 to 0.466. The correlations between the infectious and atopic diseases were weak. Both ear infections and tonsillitis seemed to be predisposing factors for sinusitis. The relative risk of sinusitis among individuals with a history of ear infections was 3.4 (1.9-6.2) and 1.9 (1.2-3.0) for males and females, respectively. Ear infections conferred an increase in tonsillitis, estimated at 2.3 (1.6-3.0) and 2.0 (1.2-3.6) for males and females, respectively. In conclusion, the present study finds evidence for a common predisposition of upper respiratory infections as well as for atopic diseases, but only moderate correlation between the subgroups. Specifically, between ear infections and hay fever there was no covariation.
Adolescent↗
The relationship between otitis media and intrauterine growth: a co-twin control study.
The association between intrauterine growth, as measured by weight and gestational age, and the occurrence of recurrent ear infections was studied using data from a population-based sample of 7992 Norwegian twins. Perinatal measures were collected from the Medical Birth Registry, and reports of recurrent ear infections were based on questionnaires completed when the twins were aged 18-25 years. First, the individual effects of birth weight and gestational age on the occurrence of otitis media (OM) were estimated Birth weight among individuals who reported OM was significantly lower than for controls, with a mean weight difference of 86 g. The average difference in gestational age was 3 days shorter among individuals with a positive history of OM. Next, the effect of birth weight was estimated using the co-twin control method. Among MZ twins, within-pair differences in birth weight reflect environmental differences experienced in utero. Among DZ pairs, birth weight differences may be due to genetic and environmental differences. Among OM-discordant pairs, the co-twin without a history of OM is a matched control for comparisons of intra-pair differences in birth weight. When within-pair birth weight differences were compared, the co-twin without a history of OM was used as the matched control. Results indicated that lower birth weight may be a risk factor for OM. The average birth weight difference among OM-discordant pairs was 48 g, with the control twin weighing significantly more than the twin with a history of OM.
Adolescent↗
The use and cost of hospital services by London AIDS patients with different AIDS defining conditions.
BACKGROUND: Contracting for HIV service provision is now an established part of the National Health Service commissioning process. AIDS is a heterogeneous condition, comprising various opportunistic illnesses which require different services and which have different resource implications. This study describes the use of hospital services and associated costs for the management of different AIDS defining conditions. METHOD: A retrospective case-notes analysis was performed, of 335 AIDS patients treated at St Mary's Hospital, London, between 1 January 1983 and 30 September 1989, as well as a costing exercise of 37 clinical departments to calculate HIV-related costs. RESULTS: Mean age at time of AIDS diagnosis for these predominantly homosexual men was 38 years. Use of services varied, as did associated costs-from 8163 pounds per patient-year for patients with Constitutional Disease to 42,124 pounds for those with Cytomegalovirus Disease Most diagnostic categories showed a shift over the study period from an in-patient- to an out-patient-based service. Patients diagnosed after 1987 had overall lower costs per patient-year compared with those diagnosed before 1987: whereas out-patient costs for most groups had increased, in-patient expenditure decreased. For most categories, in-patient care costs and out-patient drugs prescribed provided the greatest proportion of total costs. Average costs per in-patient day ranged from 334 pounds to 433 pounds, and average costs per out-patient visit ranged from 99 pounds to 411 pounds for different AIDS defining conditions. CONCLUSIONS: Different opportunistic illnesses of symptomatic HIV disease have different treatment and resource implications. Casemix will need to be taken into consideration when contracting for HIV services, including extra-contractual referrals.
AIDS-Related Opportunistic Infections↗
Financial implications of an erectile dysfunction clinic in a Trust hospital.
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Community Health Centers↗
Options in the local management of invasive breast cancer.
Newly diagnosed, early-stage breast cancer confronts the patient and her clinician with multiple treatment decisions. This review examines some of these local treatment options including the choice between breast-conserving treatment (BCT) and mastectomy, how best to treat the axilla, and the optimal sequencing of local and systemic therapy. Key elements in the selection of patients for BCT or mastectomy include preoperative mammography, careful pathological evaluation, and an assessment of patient desires in order to balance the risk of local recurrence against preservation of a cosmetically acceptable breast. Although some absolute contraindications to BCT exist, most patients are candidates for BCT. The role of axillary dissection is currently being redefined, and in the future, more limited procedures may be able to identify patients who can avoid axillary dissection. The relationship between timing of breast surgery with regard to the menstrual cycle and outcome is intriguing but not yet established. As well, the appropriate sequencing of chemotherapy and radiotherapy (RT) after conservative surgery (CS) is uncertain, although randomized trials are beginning to shed some light on this issue. Whether all patients treated with CS require treatment with RT is another question that is currently under investigation. This article addresses these issues, focusing on the specifics of treatment implementation.
Axilla↗
Local control following breast-conserving surgery for invasive cancer: results of clinical trials.
Prospective, randomized clinical trials have demonstrated that the alternatives of mastectomy or conservative surgery plus radiation therapy provide equivalent survival for patients with invasive breast cancer. The identification of a subset of women who could undergo conservative surgery without radiotherapy would avoid the costs, inconvenience, and complications of radiotherapy and is an important research goal. Four randomized trials comparing conservative surgery alone with conservative surgery plus radiotherapy have demonstrated an average reduction in the risk of disease recurrence in the breast of 84% with the use of radiotherapy. No significant differences in survival have been observed, although the available studies lack sufficient numbers of patients to demonstrate a potential small, but clinically important, survival advantage for patients treated with radiotherapy. Subset analysis in the randomized trials and prospective studies of highly selected patients have failed to consistently identify a group of patients who do not benefit from radiation therapy. Any recurrence of breast cancer is psychologically devastating, and fewer than one half of the patients who have had disease recurrence after conservative surgery alone have undergone further breast-conserving treatment. At present, a group of patients who do not require radiotherapy has not been reproducibly identified, and radiotherapy should remain a part of breast-conserving therapy for invasive carcinoma.
Breast Neoplasms↗
Cigarette smoking in China. Prevalence, characteristics, and attitudes in Minhang District.
OBJECTIVE: To determine the prevalence, pattern, and financial implications of cigarette smoking and the attitudes toward and knowledge of the health effects of tobacco use in a population in China. DESIGN: A two-stage, stratified cluster survey using door-to-door interviews. SETTING: Minhang District, China (near Shanghai), with a population of 506,000. PARTICIPANTS: A total of 3423 males and 3593 females aged 15 years and older. MAIN OUTCOME MEASURES: Smoking prevalence, age of initiation of smoking, reasons for smoking, knowledge of tobacco hazards, and costs of smoking. RESULTS: A total of 2279 males (67%) but only 72 females (2%) smoke. Many males initiate smoking in adulthood. A total of 1156 males (50.7%) began smoking between 20 and 24 years of age, and 666 (29.2%) began between 25 and 39 years of age. Among all respondents, 6202 (88.4%) believe smoking is harmful for both the smoker and those exposed passively to the smoke. Only 332 (14.1%) of all male smokers reported a desire to quit smoking. Current smokers spent an average of 3.65 yuan daily on cigarettes or 1332 yuan yearly (8.5 yuan per US dollar), which represents 60% of personal income and 17% of household income. CONCLUSIONS: The survey reveals a dangerous health situation that in all likelihood will worsen. More than two thirds of men smoke, and people in successive age cohorts start smoking at earlier ages. Smokers spend a substantial proportion of their income on cigarettes. There is a low rate of quitting and a low desire to quit despite high awareness of the health hazards. Tobacco control measures need to be implemented urgently in China.
Adolescent↗
Long-term outcome following breast-conserving surgery and radiation therapy.
PURPOSE: To examine the long-term pattern and frequency of recurrences after breast-conserving therapy and whether the outcome was influenced by the era of treatment. METHODS AND MATERIALS: From 1968 to 1986, 1870 patients with unilateral Stage I or II breast cancer were treated at the Joint Center for Radiation Therapy. Of these, 1628 underwent gross tumor excision and received a dose of > 60 Gy to the tumor bed and constituted the study population. Patients were classified as without evidence of disease, dead from other causes (DOC), or by their first site of recurrence. First sites of recurrent disease were categorized as distant/regional (DF/RNF) or local (LR). Local recurrence was defined as the detection of any invasive or in situ carcinoma occurring in the ipsilateral breast and was further categorized as: true recurrence (TR), marginal miss (MM), skin recurrence (S), or elsewhere in the breast (E). Median follow-up in survivors was 116 months. Eighty patients (4.9%) were lost to follow-up at 3-175 months. The population was divided into two time cohorts: 1968-1982 (n = 810), with a median follow-up time of 143 months, and 1983-1986 (n = 792), with a median follow-up time of 95 months. RESULTS: The overall crude rates of ipsilateral breast recurrence were 7.4 and 13.3% at 5 and 10 years, respectively. Crude rates at 5 and 10 years were 5.7 and 9.3% for TR/MM and were 0.9 and 2.8% for E recurrences, respectively. The annual incidence rates for all LR ranged from 0.5-2.4% and was relatively constant after the first year. The annual incidence rates for TR/MM ranged from 0.4 to 1.9%, whereas for E recurrences the range was 0.1-0.7%. The crude rates of DF/RNF were 16.6 and 23.1% at 5 and 10 years, respectively. The annual incidence rates for DF/RNF ranged from 1-5% over all years. Although the magnitude of the incidence was different, DF/RNF recurrence predominated in years 1-3 for both node-positive and node-negative patients. For the 1968-1982 and 1983-1986 cohorts, the 5-year crude rates of ipsilateral breast recurrence were 8.8 and 5.9%, respectively. CONCLUSIONS: Distant and regional nodal failures were the predominant form of recurrence. The annual incidence rate of LR was relatively constant over the first decade. True recurrence/marginal miss was the most frequent type of ipsilateral breast recurrence and was highest during years 2 through 7. The risk of a recurrence elsewhere in the breast increased with longer follow-up and was highest during years 8 through 10. The 5-year crude rate of ipsilateral breast recurrence appeared lower in the 1983-1986 patient cohort compared to the 1968-1982 patient cohort (8.8% vs. 5.9%), but the distributions of site of first failure did not differ significantly (p = 0.13). Any decrease in ipsilateral breast recurrence likely reflects improvements in mammographic and pathologic evaluation, patient selection, and the increased use of reexcision.
Adult↗
Understanding the distribution of cancer within the breast is important for optimizing breast-conserving treatment.
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Breast↗
Sex-specific effects for body mass index in the new Norwegian twin panel.
Sex-specific effects for body mass index (BMI) were explored in a newly established, population-based Norwegian twin panel. The sample includes 5,864 individuals, aged 18-25 years, who responded to a questionnaire containing items for zygosity classification, height, weight, health, health-related behaviors, well-being, and demographic information. Among the 2,570 intact pairs who returned the questionnaire there were 416 identical (MZ) male pairs, 387 fraternal (DZ) male pairs, 528 MZ female pairs, 443 DZ female pairs, and 796 unlike-sexed pairs. Alternate sets of models testing for either sex-specific genetic or environmental parameters were evaluated using structural equation analysis. Results from the most parsimonious model indicated that the genes contributing to variation in BMI are not identical for men and women; rather, some genetic effects were shared by the sexes and some were unique to each sex. Total variation in BMI could be explained by sex-specific additive genetic effects, as well as genetic and non-shared environmental effects common to men and women. Estimates of heritability were .708 for men and .789 for women, and the male-female genetic correlation was 0.622. The series of models specifying sex-specific shared environment also fit the data and suggests that shared environmental factors may be important for males but not for females. The findings raise questions concerning the relationship between sex-specific effects for BMI and sex differences in health outcomes.
Adolescent↗
Sex-specific causal factors and effects of common environment for symptoms of anxiety and depression in twins.
Two thousand five hundred seventy intact pairs and 724 single responders from Norwegian twins aged 18-25 years completed questionnaires with information about anxiety and depression and perceived cotwin closeness. The aim of the study was the univariate estimation of sex-specific genetic and environmental effects on an index tapping symptoms of anxiety and depression. An index of social closeness between cotwins was significantly related to the cotwin correlation for anxiety/depression scores. MZ pairs were reported to be closer than DZ pairs, and like-sexed DZ pairs were closer than unlike-sexed pairs. The symptom data were adjusted for this apparent violation of the "equal-environment" assumption in twin studies, but the adjustment did not dramatically affect the parameter estimates of genetic and environmental effects on anxiety/depression. A model specifying male (aM) and female (aF) genetic additive effects, shared environment for males (cM), and individual environmental effects (eM and eF) fitted the adjusted data very well. An alternative model, specifying aM = aF, cM = cF, and eM = eF, and no correlation between those environmental factors shared by brothers and those shared by sisters, fitted equally well. Estimated proportions of total variance from the first model were aM2 = .30, aF2 = .52, and cM2 = .21. The estimates from the second model were aM2 = aF2 = .43 and cM2 = cF2 = .11.
Adolescent↗
Evolution of pulmonary HIV-1 infection in a patient with Pneumocystis carinii pneumonia.
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Acquired Immunodeficiency Syndrome↗
HIV media campaigns and HIV-1 testing trends at London genitourinary medicine clinic, 1985-1993.
OBJECTIVE: To describe HIV-related media events in the context of first-time HIV-1-antibody testing trends at a London genitourinary medicine clinic. DESIGN: Demographic and behavioural data were collected prospectively for individuals tested for HIV-1 antibodies between September 1985 and September 1993, at the genitourinary medicine clinic of St Mary's Hospital, London. RESULTS: A total of 19,242 individuals were tested of whom 37% were women. Of the men tested 60% were heterosexual. The women at first time of testing were significantly younger [29.3 years; 95% confidence interval (CI), 28.8-29.7] than the men (32.5 years; 95% CI, 29.2-35.8); mean ages for both sexes did not change significantly over time. Overall, 199 women and 1539 men tested HIV-antibody-positive. The proportions of women testing positive increased significantly over time (chi 2 = 21.7, degrees of freedom = 1; P < 0.001), whereas the proportion of HIV-positive men remained constant for all sexual orientation groups. The proportion of heterosexual women testing positive (2.8%) was similar to the proportion of HIV-positive heterosexual men (2.9%). HIV-positive individuals were significantly older for both sexes. Throughout the study period numerous education campaigns were run using a variety of media complemented by a number of other HIV-related media events. CONCLUSIONS: Peak periods of attendance for HIV testing generally corresponded with increased HIV-related media activity and the greatest testing rates were observed when various HIV media events occurred concurrently. The increase in the number of heterosexuals tested suggests that the risk of heterosexual transmission of HIV has been recognized, at least among older individuals. The exact role of HIV-related media events, including celebrities disclosing their HIV-positive status, remains to be elucidated. Whether the relative under-representation of younger people is due to a lack of awareness, increased use of safer sex practices or reluctance to use the service also remains to be addressed. Given the increasing number of HIV-positive women and the relatively constant rate of HIV-positive tests in the male attendees an urgent need exists to assess the impact and effectiveness of specific HIV media campaigns.
Adult↗