Postmastectomy radiotherapy: questions for the twenty-first century.
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Breast Neoplasms↗
Biomedical subjects
J R Harris
Publications and source records attributed to J R Harris.
Hospital service interventions and improving survival of AIDS patients St Mary's Hospital, London, 1982-1991.
The relationship between changes in hospital service interventions at St Mary's Hospital, London, reduced case fatality for patients with their first episode of Pneumocystis carinii pneumonia (PCP) and improved survival from diagnosis of AIDS was investigated for the period 1982-1991. Multivariate logistic regression models identified factors independently associated with episode survival; for those patients who survived their first episode of PCP, survival from time of diagnosis of AIDS was analysed using multivariate Cox's proportional hazards models. The case-fatality rate after 1987 was significantly lower for the 159 subjects. Median survival from diagnosis of AIDS increased significantly from 142 days to 554 days (P=0.01). Improved survival of first episode of PCP was associated with it being the index diagnosis and having a haemoglobin at diagnosis of PCP greater than 12 g/dl. The presence of a concurrent AIDS-defining condition in patients who presented with an A-a gradient equal to or greater than 40 mmHg was associated with reduced episode survival, especially before 1987. For the 126 individuals who survived their first episode of PCP, death rates were lowest in patients treated with primary or secondary PCP prophylaxis and those who received zidovudine since their first episode of PCP. Survival in patients with HIV disease is better in patients who receive appropriate antiretroviral treatment of HIV infection and timely treatment of opportunistic illnesses. Early diagnosis of HIV-1 infection with early diagnosis and treatment of first episode of PCP was associated with improved episode survival. Subsequent medical follow up combined with PCP prophylaxis and zidovudine were significantly associated with long-term survival.
AIDS-Related Opportunistic Infections↗
How heritable is individual susceptibility to death? The results of an analysis of survival data on Danish, Swedish and Finnish twins.
Molecular epidemiological studies confirm a substantial contribution of individual genes to variability in susceptibility to disease and death for humans. To evaluate the contribution of all genes to susceptibility and to estimate individual survival characteristics, survival data on related individuals (eg twins or other relatives) are needed. Correlated gamma-frailty models of bivariate survival are used in a joint analysis of survival data on more than 31,000 pairs of Danish, Swedish and Finnish male and female twins using the maximum likelihood method. Additive decomposition of frailty into genetic and environmental components is used to estimate heritability in frailty. The estimate of the standard deviation of frailty from the pooled data is about 1.5. The hypothesis that variance in frailty and correlations of frailty for twins are similar in the data from all three countries is accepted. The estimate of narrow-sense heritability in frailty is about 0.5. The age trajectories of individual hazards are evaluated for all three populations of twins and both sexes. The results of our analysis confirm the presence of genetic influences on individual frailty and longevity. They also suggest that the mechanism of these genetic influences may be similar for the three Scandinavian countries. Furthermore, results indicate that the increase in individual hazard with age is more rapid than predicted by traditional demographic life tables.
Adult↗
Increased cesarean section rates and emerging patterns of health insurance in Shanghai, China.
OBJECTIVES: This study examined the trend in cesarean section deliveries and the factors associated with it in the Minhang District of Shanghai, China. METHODS: A representative sample of the members of 2716 households in the district were interviewed in the fall of 1993. This study analyzed the data from 1959 married women of reproductive age with at least one live birth. RESULTS: During the past 3 decades, the proportion of infants born by cesarean section increased from 4.7% to 22.5%. Logistic regression analysis revealed that the highest cesarean section rate, which occurred in the most recent period of 1988 through 1993, was associated with form of medical payment, self-reported complications during pregnancy, higher birthweight, and maternal age. Government insurance pays all costs of cesarean sections and accounted for the highest proportion of the cesarean section rate. CONCLUSIONS: The high rates of cesarean sections in China are surprising given the lack of the factors that usually lead to cesarean sections. The increasing cesarean section rates may be an early indication that emerging forms of health insurance and fee-for-service payments to physicians will lead to an excessive emphasis on costly, high-technology medical care in China.
Adolescent↗
Predictors of breast recurrence after conservative surgery and radiation therapy for invasive breast cancer.
The majority of women with breast cancer are adequately treated with breast-conserving surgery and radiation therapy. Although most women need very limited surgery, some require a larger volume of resection to attain a high level of local control, and some might even require a mastectomy. This article summarizes the current state of knowledge concerning the assessment of the adequacy of excision.
Breast Neoplasms↗
Measuring the public's health in an era of accountability: lessons from HEDIS. Health Plan Employer Data and Information Set.
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Health Benefit Plans, Employee↗
Current scientific issues related to clinical radiation oncology.
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Apoptosis↗
Impact of respiratory maneuvers on cardiac volume within left-breast radiation portals.
BACKGROUND: Late cardiac morbidity and mortality have been reported among left-breast cancer survivors treated with radiation therapy. Radiation-induced cardiotoxicity is affected by the volume of myocardium included in the radiation portals. We hypothesize that simple respiratory maneuvers may alter the position of the heart relative to the portals without altering the radiation dose delivered to the breast. METHODS AND RESULTS: Fourteen healthy female adult volunteers underwent cardiac MRI to determine the cardiac volume included in the typical left-breast radiation field during respiratory maneuvers. Cardiac volume within the radiation portals was assessed from a transverse stack of 14 1-cm-thick contiguous slices covering the entire heart, obtained during breath holding at end-tidal volume (baseline), deep inspiration, and forced expiration. Thirteen subjects (92%) had inclusion of a portion of the heart within the radiation portals at end-tidal volume (median, 20.9 cm3; range, 1.3 to 88.4 cm3). In these subjects, inspiration decreased the cardiac volume included within the radiation portals (median change: -10.7 cm3 [-40.2%], P<.001 versus end-tidal volume), whereas expiration increased the cardiac volume included (median change: 4.0 cm3 [21.5%]; P<.001 versus end-tidal volume). CONCLUSIONS: Inclusion of a portion of the heart in the left-breast radiation field is common. The use of simple inspiratory maneuvers significantly decreases cardiac volume within the radiation portals. Such an approach during delivery of radiation therapy may allow for preservation of radiation dosage to the breast while reducing cardiac involvement and subsequent mortality.
Adult↗
Vascular permeability factor (vascular endothelial growth factor) expression and angiogenesis in patients with ductal carcinoma in situ of the breast.
BACKGROUND: Prior studies have indicated that ductal carcinoma in situ (DCIS) lesions are capable of inducing a vascular stroma. However, the mechanisms responsible for angiogenesis in DCIS currently are not defined. The goal of this study was to determine the relationship between the expression of the angiogenic cytokine vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), and angiogenesis in patients with DCIS. METHODS: Forty-six breast biopsies with DCIS were characterized with regard to histologic features on hematoxylin and eosin stained sections, and microvessel density and distribution using sections immunostained for factor VIII-related antigen. In addition, in situ hybridization was performed on formalin fixed, paraffin embedded sections using 35S labeled riboprobes specific for VPF/VEGF. RESULTS: VPF/VEGF expression by tumor cells in DCIS was greater than that observed in adjacent benign ductal or lobular epithelial cells in 96% of the evaluable cases. Moreover, the degree of VPF/VEGF mRNA expression was significantly associated with the degree of angiogenesis in these lesions. Among 22 cases with strong VPF/VEGF mRNA expression, the median microvessel count was 100 +/- 30.6 vessels/field. In contrast, among 24 cases with low level VPF/VEGF mRNA expression, the median microvessel count was 71 +/- 48.6 vessels/field (P = 0.04). In addition, high grade DCIS lesions more commonly were associated with strong VPF/VEGF mRNA expression than low grade lesions, but the results were not statistically significant. CONCLUSIONS: These findings suggest that VPF/VEGF is an important angiogenic factor in patients with DCIS.
Breast Neoplasms↗
Treatment outcome after tangential radiation therapy without axillary dissection in patients with early-stage breast cancer and clinically negative axillary nodes.
PURPOSE: To determine the risk of nodal failure in patients with early-stage invasive breast cancer with clinically negative axillary lymph nodes treated with two-field tangential breast irradiation alone, without axillary lymph node dissection or use of a third nodal field. METHODS AND MATERIALS: Between 1988 and 1993, 986 evaluable women with clinical Stage I or II invasive breast cancer were treated with breast-conserving surgery and radiation therapy. Of these, 92 patients with clinically negative nodes received tangential breast irradiation (median dose, 45 Gy) followed by a boost, without axillary dissection. The median age was 69 years (range, 49-87). Eighty-three percent had T1 tumors. Fifty-three patients received tamoxifen, 1 received chemotherapy, and 2 patients received both. Median follow-up time for the 79 survivors was 50 months (range, 15-96). Three patients (3%) have been lost to follow-up after 20-32 months. RESULTS: No isolated regional nodal failures were identified. Two patients developed recurrence in the breast only (one of whom had a single positive axillary node found pathologically after mastectomy). One patient developed simultaneous local and distant failures, and six patients developed distant failures only. One patient developed a contralateral ductal carcinoma in situ, and two patients developed other cancers. CONCLUSION: Among a group of 92 patients with early-stage breast cancer (typically T1 and also typically elderly) treated with tangential breast irradiation alone without axillary dissection, with or without systemic therapy, there were no isolated axillary or supraclavicular regional failures. These results suggest that it is feasible to treat selected clinically node-negative patients with tangential fields alone. Prospective studies of this approach are warranted.
Aged↗
Mass determination, subunit organization and control of oligomerization states of keyhole limpet hemocyanin (KLH).
Analytical dark-field scanning transmission electron microscopy (STEM) of freeze-dried unstained specimens of keyhole limpet hemocyanin (KLH; from Megathura crenulata, a prosobranch gastropod) gave a molecular mass of 400 kDa for the subunit of KLH1 and of 345 kDa for the subunit of KLH2, which confirms our published values from SDS/PAGE. Within the 400-kDa KLH1 subunit we identified, by limited proteolysis, isolation of fragments and N-terminal sequencing, eight distinct 45-60 kDa functional domains (termed 1a through 1h) and determined their sequential arrangement. The KLH1 domains differ biochemically and immunologically from each other and from the previously characterized seven domains of KLH2 (termed 2a through 2g). Our partial amino acid sequences suggest that a domain, equivalent to the C-terminal domain 1h, is missing in KLH2. This deficiency is believed to be genuine and not an artifact of the subunit preparation procedure, since STEM measurements of the native didecamers yielded a mass difference of about 800 kDa between KLH1 and KLH2 (8.3 MDa versus 7.5 MDa), correlating with 20 copies of a functional 1h domain. It was also shown that the KLH1 didecamer can be rapidly split (minutes) into an almost homogeneous population of stable decamers by increasing the pH of the Tris/saline stabilizing buffer (routinely pH 7.4), which contains 5 mM CaCl2 and 5 mM MgCl2, to pH 8.5. Reformation of the didecamers occurred more slowly (days) upon dialysis against the pH 7.4 stabilizing buffer. Addition of 100 mM calcium and 100 mM magnesium ions to the pH 7.4 stabilizing buffer leads to the more rapid (overnight) formation of didecamers together with a significant number of previously unobserved KLH1 multidecamers, which could be structurally distinguished from the established multidecamers of KLH2.
Amino Acid Sequence↗
Structure of keyhole limpet hemocyanin type 1 (KLH1) at 15 A resolution by electron cryomicroscopy and angular reconstitution.
A three-dimensional reconstruction of keyhole limpet hemocyanin type 1 (KLH1) has been obtained using electron cryomicroscopy at liquid helium temperatures and single particle image processing. The use of a high-contrast embedding medium, 1% (w/v) glucose and 2% (w/v) ammonium molybdate (pH 7.0), enables high-resolution electron micrographs to be recorded close to focus, i.e. with excellent transfer of high-resolution information, while maintaining enough image contrast to localise the individual macromolecules in the images. When low-pass filtered to approximately 45 A resolution, the new 15 A resolution reconstruction is very similar to the earlier reconstructions of gastropodan hemocyanins of specimens embedded in vitreous ice. The map shows much detail and reveals many new symmetry elements in this very large cylindrical molluscan hemocyanin. The full KLH1 didecamer has D5 pointgroup symmetry, yet within the KLH1 decameric half-molecules local 2-fold axes have emerged that make the wall of the KLH1 decamer, in spite of its having an exact C5 symmetry only, resemble the D5-symmetric wall of the decameric cephalopod hemocyanins. In fact, the outside of each tier of this six-tiered gastropodan hemocyanin was found to have an approximate D5 symmetry. Local 2-fold axes also relate the "functional units" within the dimeric "morphological units" of the wall and the collar areas of the 8 MDa KLH1 molecule. Certain local-symmetry-related surface motifs may be present up to 60 times on the outside wall of this highly symmetric cylindrical hemocyanin. Keyhole limpet hemocyanin is used clinically as an immunostimulant. The very strong immune reaction elicited by this hemocyanin may be associated with its intricate hierarchy of local-symmetry components.
Animals↗
The relationship between shaved margin and inked margin status in breast excision specimens.
BACKGROUND: The presence of tumor at the inked margins (IMs) of breast specimens is associated with an increased risk of local recurrence after breast-conserving therapy for invasive breast carcinoma and ductal carcinoma in situ (DCIS). Given the importance of margin status, some have advocated the use of shaved margins (SMs) as a means of conducting a more complete examination of the specimen margins than could be done with sections taken perpendicular to the IMs. However, it is not known whether these two methods of margin assessment provide comparable information. METHODS: To address this issue, the authors studied 22 consecutive breast reexcision specimens (10 DCIS, 6 infiltrating ductal carcinomas, and 6 infiltrating lobular carcinomas) in which the specimen surfaces were inked, the margins were shaved, and tumor was present in at least one of the SM sections. A total of 199 SMs were examined. The SMs were originally embedded in a way that permitted histologic sections to be cut opposite the inked surface. Sections of SM stained with hematoxylin and eosin (H & E) were reviewed and scored for the presence and extent (number of low-power fields) of cancer. The remaining tissue from the SM was then removed from the blocks, cut perpendicular to the IM, and reembedded to permit visualization of tumor in relation to the IM. Sections were then cut from two different levels of each reembedded block and stained with H & E. An SM was considered positive if tumor was present anywhere on the section. An IM was considered positive when tumor extended to the inked surface. RESULTS: Although all 22 excisions had at least 1 positive SM, tumor was present at an IM in only 12 specimens (55%). Among 69 positive SMs, the corresponding IM was positive in only 42 (61%). The likelihood of a positive IM increased with the number of low-power fields of involvement by invasive carcinoma or DCIS on the SM, as follows: 19% with 1 low power-field, 67% with 2 low-power fields, and 97% with > or = 3 low-power fields (all P < 0.02). When the SM was negative, the corresponding IM was negative in 98% of cases. CONCLUSIONS: Many patients with positive SMs do not have positive IMs. A positive SM more reliably predicts a positive IM when tumor involves > or = 3 low-power fields of the SM. The authors conclude that the clinical implications of a positive SM may not be the same as those of a positive IM. Clinical outcome studies are needed to define further the implications of positive SMs. [See editorial counterpoint on pages 1453-8 and reply to counterpoint on pages 1459-60, this issue.]
Breast Neoplasms↗
Breast-conserving therapy for stage I-II synchronous bilateral breast carcinoma.
BACKGROUND: Synchronous bilateral breast carcinoma (SBBC) is an uncommon presentation, and the management of patients with this disease is not well established. METHODS: In order to evaluate whether patients with early-stage SBBC could be safely and effectively treated with bilateral breast-conserving therapy (BCT), the authors retrospectively reviewed the records of 24 patients with clinical Stage I-II SBBC treated during the period 1977-1989 with bilateral BCT. SBBC was defined as bilateral invasive carcinomas diagnosed no more than 1 month apart. The median age at diagnosis was 56 years (range, 32-85 years), and the median follow-up for surviving patients was 95 months (range, 68-157 months). Pathology slides were available for review in 19 cases. Cosmetic results and complications after BCT were scored. Outcome was compared with that of 1314 patients with unilateral Stage I or II breast carcinoma, within the same age range, treated during the same time period. RESULTS: There were no significant differences between the SBBC and unilateral groups in actuarial disease free survival (70% and 74%, respectively, at 5 years), overall survival (88% and 87%, respectively, at 5 years), or crude distribution of sites of first failure. Multivariate analysis of overall survival and disease free survival also did not show bilaterality to be a significant factor. The cosmetic results for the SBBC group were not significantly different from those for the unilateral group. Physician assessment of cosmetic outcome was excellent in 57% and good in 43% of SBBC patients evaluated 25-48 months after BCT. Long term complications were rare in both groups. CONCLUSIONS: Patients with early-stage SBBC can be safely treated with carefully planned, bilateral BCT, with outcome that appears to be comparable to that of patients with early-stage unilateral breast carcinoma.
Adenocarcinoma↗
Frequency of sexual partner change in a Norwegian population. Data distribution and covariates.
The number of new sexual partners per year (partner frequency) is a key factor in the spread of sexually transmitted diseases. Data from two Norwegian population-based surveys conducted in 1987 and 1992 were used to estimate recent (in the previous 3 years) and earlier partner frequency and to examine covariates affecting the distribution of partner frequency. Seventy-two percent of respondents reported having no new partners per year, and 2% reported having more than three new partners per year. Results from a Poisson regression model indicated that a low partner frequency was associated with being married or cohabiting, being female, greater age, and late sexual debut. Partner frequency was lower in 1992 than in 1987 (rate ratio = 0.8, 95% confidence interval 0.7-0.9). In comparison with earlier life, there was a large reduction in partner frequency for married/cohabiting individuals. In contrast, there was either no change or some increase in partner frequency for single persons.
Adolescent↗
Is machine energy (4-8 MV) associated with outcome for stage I-II breast cancer patients?
PURPOSE: To assess the relationship between machine energy (4-8 MV) and treatment outcome in patients treated with conservative surgery and radiation therapy. METHODS AND MATERIALS: Between 1968 and 1985, 1624 patients were treated for clinical Stage I or II invasive breast cancer. The study population was limited to 1380 patients who underwent complete gross excision and received greater than or equal to 60 Gy to the tumor bed. Of these, 1125 were treated on a 4 MV, 153 on a 6 MV, and 102 on an 8 MV linear accelerator. Patients were selected for treatment on the 8 MV machine based on chest wall separations greater than 24 cm. Of patients treated on the 8 MV, netting was used for 42% and bolus was used for 26%. The median dose with bolus was 14 Gy in seven fractions (range: 2-34.2 Gy). Patients treated on the 8 MV accelerator were older, had a higher percentage of clinical T2 tumors, a higher percentage of pathologically positive nodes, and a lower incidence of extensive intraductal component (EIC). Median follow-up times were 130, 153, and 102 months, respectively, for survivors treated on the 4, 6, and 8 MV machines. RESULTS: We analyzed the site and 5-year crude incidence of first failure by machine energy and found the pattern of first failure site (local, nodal, or distant) to be virtually identical for each energy group. Of the local failures, 12 were in the skin of the treated breast, and these failures were evenly distributed by machine energy. We performed a multivariate analysis to adjust for factors known to predict for treatment failure. When adjusted for these other variables, machine energy was not associated with an increased (or decreased) risk of recurrence (RR for 8 MV vs. 4 MV = 0.94, p = 0.7; RR for 6 MV vs. 4 MV = 1.0, p = 0.9). We also analyzed the nature and incidence of treatment complications (rib fracture, radiation pneumonitis, soft tissue necrosis, and brachial plexopathy) and found no significant differences among the three treatment groups when stratified by treatment technique (tangents only vs. three-field). There was also no significant difference in cosmetic outcome at 5 years among the three groups. CONCLUSIONS: We conclude that machine energy over the range of 4 to 8 MV does not significantly affect treatment outcome. Specifically, it was feasible to treat patients with large chest wall separations using an 8 MV machine without an increase in skin recurrences and with the improved dose homogeneity afforded by 8 MV machines as compared with those of lower energies.
Adult↗
Keyhole limpet hemocyanin (KLH), II: Characteristic reassociation properties of purified KLH1 and KLH2.
Subunits of the two types of keyhole limpet hemocyanin (KLH1 and KLH2), purified by gel filtration chromatography and preparative polyacrylamide gel electrophoresis from Immucothel, have been used for macromolecular reassociation studies. In-vitro reassociation has been achieved with a standardized system using a Tris-saline stabilizing buffer at pH 7.4 containing 100 mM calcium and magnesium chloride at 4 degrees C. The relatively slow progress of reassociation has been monitored and the varying oligomeric forms of KLH1 and KLH2 produced have been studied by transmission electron microscopy, using specimens negatively stained with 5% ammonium molybdate containing 1% trehalose. Specimens have also been prepared by platinum-carbon shadowing, following freeze-cleavage. The two hemocyanins reassociate to produce characteristic oligomeric and polymeric forms. Subunits of purified KLH1 reassociate to produce a small number of didecamers, short multidecamers (ca 33 nm diameter) and much larger quantity of a ca 25 nm diameter flexible/undulatory tubular form of varying length. These tubules exhibit characteristic oblique features, indicative of an 'open' helical structure which appears to be a loosly or incompletely annealed twisted ribbon of subunits. After a period of days the tubules aggregate in parallel to produce large paracrystalline bundles, which do not have a tendency to associate end-to-end. Following transfer of this reassociated KLH1 to low calcium magnesium stabilizing buffer, the tubular bundles are unstable; they slowly break down into shorter lengths, fragments, subunit groups and individual subunits, which subsequently regenerate decamers, didecamers, and some multidecamers. Subunits of purified KLH2 reassociate to produce ca 25 nm diameter 'closed' tubules, which do not exhibit the oblique 'open' features shown by the KLH1 tubules; however, the ends of the these 'closed' tubules are often oblique. In addition to the tubular form, KLH2 reassociation also generates a somewhat small proportion of ca 33 nm diameter multidecamers, often containing many decamers and more than one 'nucleating' didecamer. On transfer to low calcium magnesium stabilizing buffer the KLH2 tubules are remarkably stable, but the number of multidecamers slowly increases with time. There is a significant structural difference between the short KLH1 multidecamers (only detected following in-vitro reassociation) and those of KLH2 quite apart from their length. Study of the metal shadowed specimens confirmed the difference between the KLH1 and KLH2 tubular forms, with relatively smooth helical surface ridges and a rougher internal surface, indicating internalization of subunit domains that are not required for the construction of the tubular wall, in accord with current understanding of the subunit organization within the native molecules.
Calcium Chloride↗
Keyhole limpet hemocyanin (KLH), I: Reassociation from Immucothel followed by separation of KLH1 and KLH2.
Studies of keyhole limpet hemocyanin (KLH) normally require purification of functional complexes directly from living animals. An alternative procedure is described wherein a commercial preparation of KLH which is fully dissociated into its subunits (Immucothel, biosyn Arzneimittel GmbH) is reassociated in the presence of a high concentration of calcium and magnesium. The reassociation products, when observed by electron microscopy, consist of didecamers, multidecamers and flexible tubules of varying length. The two forms of KLH described previously and designated KLH1 and KLH2, are present in the reassociated mixture as homo-oligomers/polymers and can be separated by selective dissociation of the KLH2 by treatment with 1% ammonium molybdate-0.2% PEG at pH 5.7, followed by gel filtration chromatography in this solution. In addition to discrete elution peaks containing didecameric KLH1 and dissociated subunits of KLH2, a leading peak contains a tubular/polymeric form of KLH1, not previously described. Under negative staining in conditions designed specifically for the creation of 2-dimensional crystals on mica (the negative staining-carbon film procedure), this tubular form of KLH1 can be transformed into a larger diameter multidecameric form, again not previously described for KLH1. The purified KLH2 peak is indistinguishable from subunit material prepared from living animals. This, Immucothel appears to provide a standardized source of subunits suitable for biochemical and structural studies on the two types of KLH.
Animals↗