Can chemotherapy alter the histologic features of breast cancer?
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Biomedical subjects
Publications and source records attributed to M E Taylor.
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Very small breast cancers are being diagnosed with increased frequency, and, until recently, little information regarding the incidence of axillary lymph node metastases in these most favorable tumors was available. Moreover, scarce data exist regarding axillary failure in this cohort as a function of initial treatment, be it surgery, radiation, or simply observation. In the present study, limited to women with invasive cancers measuring no more than 10 mm, the incidence of pathologically positive axillary nodes was 12.3%. The incidence of nodal metastases was influenced by tumor size (albeit not quite significantly, p = .08); not one patient with a tumor < or = 5 mm had axillary node metastases, compared to 14.7% in those with cancers 6 to 10 mm. The histologic grade and tumor location were also important in predicting nodal positivity. The incidence of positive nodes was 38% in those with poorly differentiated cancers, compared to 8% and 7% in women with well and moderately differentiated cancers, respectively, p = .03. Axillary nodal positivity was seen in 17% of outer quadrant vs 3% of central and inner quadrant primaries, p < .01. The axilla was managed with surgery alone (76%), radiation alone (6%), surgery and radiation (6%), or simply observation (10%). With a median follow-up of 55 months, not one patient has suffered a nodal recurrence, and in our experience, survival free of distant relapse was not adversely affected by the omission of axillary surgery.
PURPOSE: To evaluate the association between age and breast/regional nodal relapse following breast conserving surgery and irradiation. METHODS AND MATERIALS: The results of treatment in 511 patients with 519 Stage I and II breast cancers treated at Mallinkrodt Institute of Radiology and affiliated hospitals between 1958 and 1988 were reviewed. RESULTS: Seventy women, of whom 96% had axillary dissections, were 39 years of age or younger. These young patients were more likely to have chemotherapy (p < 0.0001), and tumor bed reexcision (p < 0.01), and less likely to have an undissected axilla (p < 0.01), or estrogen receptor positive tumor (p = 0.02) than the older women (> 40 years). Although breast recurrence tended to appear earlier in the younger patients (12% at 5 years for those < 40 years vs. 6% at 5 years for those older), by 7 years the breast failure rate for the two groups was the same (12%), p = 0.13. In the 37 women 35 years of age or younger, the actuarial rate of breast recurrence was 9% at 7 years. Compared to other series in the literature, in which cancers were grossly excised without regard to the microscopic margins of resection, and reexcision was not routinely performed, young women treated with breast conserving surgery and irradiation at our institution frequently underwent reexcision of the tumor bed (57%), and had negative pathologic margins of resection (75%). Regional nodal relapse was in general uncommon, and not seen with increased frequency in the youngest cohort. CONCLUSION: Our experience suggests that young age is not a contraindication to breast conserving surgery and irradiation. Although breast cancers in this cohort may have certain features rendering them prone to local failure, we believe this risk can be mitigated by appropriate patient selection and optimal surgical resection.
PURPOSE: To determine the incidence, pattern of regional nodal failure, and treatment sequelae as determined by the extent of lymphatic irradiation. METHODS AND MATERIALS: The records of 511 patients with 519 Stage I and II breast cancers treated with breast conserving surgery with or without axillary dissection and irradiation were reviewed. The extent of nodal irradiation was at the discretion of the attending radiation oncologist and varied considerably over the years. Management of the axilla consisted of axillary dissection alone in 351, axillary dissection and supplemental irradiation in 74, irradiation alone in 75, and simply observation in 21 patients. RESULTS: Overall, axillary recurrence was uncommon (1.2%), but was slightly more frequent after irradiation alone (2.7%) than after surgery alone (0.3%), p = 0.14. There was no benefit for supplemental axillary irradiation after an axillary dissection yielding negative or 1 to 3 positive nodes. In the 21 patients in whom the axilla was observed, axillary recurrence was not observed. Supraclavicular failures were rare in women with negative or 1 to 3 positive axillary lymph nodes (0.5%), and not significantly affected by elective irradiation. Internal mammary node recurrence was seen in only one patient, and was not significantly influenced by elective internal mammary irradiation. Both arm and breast edema were significantly more common in women having breast and nodal irradiation than after breast irradiation alone. These sequelae were not influenced significantly by the number of lymph nodes obtained in the axillary dissection specimen. Radiation pneumonitis was seen with increased frequency with more extensive nodal radiotherapy. Pneumonitis was not found to be affected by the administration or sequencing of chemotherapy. CONCLUSION: There is little justification for axillary or supraclavicular irradiation following an axillary dissection which yields negative or minimally involved (1 to 3 positive) lymph nodes. There were too few patients with extensive axillary node metastases (> or = 4 positive) in our series to draw conclusions about the optimal extent of nodal irradiation in this subset. Elective internal mammary lymph node irradiation increases technical complexity, does not appear to be advantageous, and when combined with supraclavicular irradiation places the patient at highest risk for pneumonitis.
The mannose receptor of macrophage and hepatic endothelial cells discriminates between endogenous and exogenous sugar-bearing structures. Previous competition studies have indicated that the receptor binds the monosaccharides mannose, fucose, and N-acetylglucosamine but displays much higher affinity for multivalent oligosaccharides, such as those found on the surface of potentially pathogenic microorganisms. The hydrodynamic properties of the receptor have been examined, revealing that the receptor is a monomer. This result suggests that multiple carbohydrate recognition domains (CRDs) in the extracellular domain of a single receptor polypeptide cooperate to achieve high affinity binding of complex ligands. In order to determine the importance of individual CRDs, properties of receptor segments containing groups of CRDs expressed in insect cells have been examined. The results indicate that two of the CRDs (4 and 5) form a protease-resistant, ligand-binding core but that five CRDs in tandem (4-8) are required to match the affinity of the intact receptor for yeast mannan. A consequence of the organization of the receptor is that both valency and geometry of glycoconjugates are important determinants of binding affinity.
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In a single centre double blind study of 66 patients, the value of cisapride (10 mg twice daily) was compared with placebo in the prevention of duodenal ulcer relapse. Patients who remained ulcer free attended for clinical review every two months and had a mandatory endoscopy at 0, 4, 8, and 12 months or if symptoms suggestive of ulcer recurrence developed. The 12 month crude relapse rates (that underestimate the probability of ulcer recurrence) showed that cisapride was superior to placebo (34% (11/32) relapsed on cisapride v 68% (23/34) on placebo, p = 0.007). This finding was confirmed using lifetable analysis, with a 35% reduction (95% confidence intervals 10-59%, p < 0.05) in the proportion of ulcer relapses in patients who had received cisapride compared with those treated with placebo. These results are similar to those reported in maintenance trials of H2 receptor antagonists analysed by the same method. Drug related adverse clinical events were mainly trivial, but led to three patients on cisapride and one on placebo withdrawing from the trial.
When two stationary, stereoscopically separated targets are viewed in a completely dark surround, and no cues concerning their egocentric distances from the observer are salient, the farther target tends to be seen at the same distance it would have assumed if it were by itself. The nearer target is seen as being closer than it would have been if seen alone. The present studies extend this previous finding (now termed the far-anchor effect) into the domain of targets that move in stereoscopic space. Observers viewed two small illuminated targets, which began at either the same or different stereoscopic distances. One of the targets was moved in depth and the observers identified the target that appeared to move. Conditions varied according to the initial depth location of the moving target. Significantly more correct responses were reported when the nearer target moved than when the farther one moved, consistent with the hypothesis that the perception of motion in depth is affected by the aforementioned perceptual anchoring effect of the farther target.
The reported relapse-free survival for women with invasive breast cancers measuring no more than 10 mm in dimension ranges from 75% to 95%, with axillary status an important prognostic factor in most series. Further study of prognostic variables in this most favorable subset is notably limited. We retrospectively reviewed the records of 168 women with invasive breast cancers < or = 10 mm treated with either breast conserving surgery+axillary dissection (AXD) and radiation therapy, or mastectomy+AXD. The actuarial survival and survival free of distant metastases (DMFS) at 7 years was 95% and 97%, respectively. Location and size of the primary tumor were most important in predicting outcome, although statistical significance was not achieved. The 5-year distant metastases-free survival (DMFS) was 100% for central and inner quadrant tumors, compared to 97% in those with outer quadrant tumors, p = 0.18. The 5-year DMFS was 100%, 95%, and 98% for patients with cancers 2-5 mm, 6-9 mm, and 10 mm, respectively, p = 0.15. Status of the axillary lymph nodes, type of breast surgery, clinical tumor status (palpable vs. nonpalpable), age, menopausal status, histologic grade, systemic therapy, or histologic type were not found to have a significant impact on prognosis.
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The extracellular portion of the macrophage mannose receptor is composed of several cysteine-rich domains, including a fibronectin type II repeat and eight segments related in sequence to Ca(2+)-dependent carbohydrate-recognition domains (CRDs) of animal lectins. Expression of portions of the receptor in vitro, in fibroblasts and in bacteria, has been used to determine which of the extracellular domains are involved in binding and endocytosis of ligand. The NH2-terminal cysteine-rich domain and the fibronectin type II repeat are not necessary for endocytosis of mannose-terminated glycoproteins. CRDs 1-3 have at most very weak affinity for carbohydrate, so the carbohydrate binding activity of the receptor resides in CRDs 4-8. CRD 4 shows the highest affinity binding and has multispecificity for a variety of monosaccharides. However, CRD 4 alone cannot account for the binding of the receptor to glycoproteins. At least 3 CRDs (4, 5, and 7) are required for high affinity binding and endocytosis of multivalent glycoconjugates. In this respect, the mannose receptor is like other carbohydrate-binding proteins, in which several CRDs, each with weak affinity for single sugars, are clustered to achieve high affinity binding to oligosaccharides. In the mannose receptor, these multiple weak interactions are achieved through several active CRDs in a single polypeptide chain rather than by oligomerization of polypeptides each containing a single CRD.
Gene fusion has been used to produce the cytoplasmic domain of an endocytic receptor. DNA sequences coding for the 52 COOH-terminal amino acids of the mannose receptor from human macrophages, including the 41-amino acid cytoplasmic tail, were fused to the codons specifying the carbohydrate-recognition domain (CRD) of rat mannose-binding protein. The fusion protein was expressed in Escherichia coli and purified in one step on mannose-Sepharose, making use of the carbohydrate-binding activity of the CRD. The tail peptide was released from the fusion protein using endoproteinase Arg-C. This method provides an alternative to chemical synthesis for the production of midlength peptides.
Evidence for human T cell lymphotropic viruses (HTLV) was sought in sera and cells collected from adults in 13 isolated South and Central American Indian tribes. Serologic tests identified frequent HTLV-II-like reactivity among the Cayapo and Kraho tribes, who live 330 km apart in Central Brazil. Polymerase chain reaction analyses of viral DNA in cell pellet and plasma fractions confirmed the virus as HTLV-II. Both tribes speak Gé and, at the time of blood collection (1974), subsisted as hunter/gatherers and slash and burn agriculturalists. Further testing of plasma from Cayapo and Kraho of all ages revealed overall HTLV-II prevalence rates of 33.3% and 12.2%, respectively, with increasing prevalence associated with age and female gender. These data reveal for the first time a high prevalence of HTLV-II infection in remote South American Indians with little contact with non-Indians. Thus, HTLV-II is postulated to be an ancient human virus in the New World.
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The structure of the gene encoding a chicken liver receptor, the chicken hepatic lectin, which mediates endocytosis of glycoproteins has been established. The coding sequence is divided into six exons separated by five introns. The first three exons correspond to separate functional domains of the receptor polypeptide (cytoplasmic tail, transmembrane sequence, and extracellular neck region), while the final three exons encode the Ca(2+)-dependent carbohydrate-recognition domain. These results, as well as computer-assisted multiple sequence comparisons, establish this receptor as the evolutionary homolog of the mammalian asialoglycoprotein receptors. It is interesting that the chicken receptor falls into a subfamily of proteins along with the mammalian asialoglycoprotein receptors, since the saccharide-binding specificity of the chicken receptor resembles more closely that of a different set of calcium-dependent animal lectins, which includes the mannose-binding proteins. The portions of the genes encoding the carbohydrate-recognition domains of these proteins lack introns. The results suggest that divergence of intron-containing and intron-lacking carbohydrate-recognition domains preceded shuffling events in which other functional domains were associated with the carbohydrate-recognition domains. This was followed by further divergence, generating a variety of saccharide-binding specificities.