Breast conservation in locally advanced breast cancer: lessons to be learned.
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
L J Pierce
Publications and source records attributed to L J Pierce.
Insulin-like growth factor and epidermal growth factor independence in human mammary carcinoma cells with c-erbB-2 gene amplification and progressively elevated levels of tyrosine-phosphorylated p185erbB-2.
Growth factor-independent proliferation is an essential aspect of the transformation process. To study the influence of c-erbB-2 overexpression on the autonomous growth of human mammary cancer cells, we used a series of non-neoplastic and neoplastic human mammary epithelial cell lines isolated from a patient with intraductal and invasive ductal carcinoma of the breast. The non-neoplastic cell line, H16N-2, which expresses a normal level (single gene copy) of c-erbB-2, was used for comparison with the neoplastic cell lines. Both the metastatic tumor cell lines, 21MT-1 and 21 MT-2, showed equivalent amplification of the c-erbB-2 gene; however, 21MT-1 cells showed a higher level of c-erbB-2 overexpression. Therefore, the H16N-2, 21MT-2, and 21MT-1 cell series forms a distinct gradient of progressively increasing c-erbB-2 gene expression. Furthermore, the overexpression of c-erbB-2 in the 21MT cell lines was concordant with increases in the constitutive tyrosine kinase activity of p185erb-2 measured in the absence of exogenous growth factors in culture. Normal mammary epithelial cells require both insulin-like growth factor (IGF)-l (or supraphysiological concentrations of insulin) and epidermal growth factor (EGF) to proliferate under serum-free conditions in culture. By contrast, 21MT-2 cells showed a reduced requirement for IGF but still required EGF to proliferate. 21MT-1 cells did not require either insulin or EGF to proliferate. Therefore, the progressive increases in constitutive p185erbB-2, tyrosine kinase activity in the 21MT-2 and 21MT-1 cell lines was directly correlated with IGF independence and combined IGF and EGF independence under defined conditions in culture. Experiments using conditioned media and anti-IGF-1 receptor and anti-EGF receptor neutralizing antibodies showed that the growth-factor independence of the tumor cells did not involve detectable IGF- or EGF-like autocrine activity expressed by the 21MT cells. Furthermore, neu differentiation factor/heregulin, a ligand that indirectly activates p185erbB-2 by direct binding to erbB-3 receptors, potently stimulated the proliferation of the growth factor-dependent H16N-2 cells (which expressed c-erbB-2 and c-erbB-3 but not c-erbB-4) in the absence of both IGF and EGF. Thus, HRG-induced mitogenesis mimicked the autonomous growth seen in the 21MT cells that have the highest level of constitutive p185erbB-2 activation. These data support the hypothesis that the constitutive activation of p185erbB-2 in human mammary carcinoma cells causes growth-factor independence by directly activating multiple signal-transduction pathways that substitute for both IGF and EGF during proliferation.
Base Sequence↗
Locally advanced breast carcinoma: accuracy of mammography versus clinical examination in the prediction of residual disease after chemotherapy.
PURPOSE: To determine the mammographic features of locally advanced breast carcinoma treated with neoadjuvant chemotherapy and to evaluate the accuracy of mammography in the prediction of residual carcinoma. MATERIALS AND METHODS: Of 90 women treated with hormonally synchronized cytotoxic therapy before mastectomy or lumpectomy for advanced breast carcinoma, 56 were selected because they had undergone mammography before and after neo-adjuvant therapy. Mammographic and clinical opinion on the presence of residual disease was compared with histologic results. RESULTS: Fifty-four (96%) of 56 women had a complete (n = 34 [61%]) or partial (n = 20 [36%]) clinical response. Thirteen (23%) of 56 women had no residual tumor. Sensitivity of mammography in the prediction of residual carcinoma was greater than that of clinical examination (79% vs 49%), but specificity was lower (77% vs 92%). In 24 women with inflammatory carcinoma, sensitivity of mammography was 78% while that of clinical examination was 39%; specificity was equal (83%). CONCLUSION: Mammography was more sensitive than clinical examination in the prediction of residual carcinoma; it was not accurate enough to obviate surgical biopsy.
Antineoplastic Agents↗
Defining the role of post-mastectomy radiotherapy: the new evidence.
In an early meta-analysis of the post-mastectomy radiotherapy trials, the use of obsolete radiotherapy techniques resulted in increased cardiac mortality. With maturation of these data and inclusion of more recent trials, however, a survival advantage is now emerging. This, in concert with the improvement in disease-free and overall survival evident in the larger studies of post-mastectomy radiotherapy with adjuvant chemotherapy, generates a new enthusiasm in support of post-mastectomy radiotherapy. The lessons we have learned from the earlier trials emphasize the importance of precise radiation planning and delivery so that long-term morbidity can be minimized and survival improved by the reduction in breast cancer deaths.
Antineoplastic Combined Chemotherapy Protocols↗
Microscopic extracapsular extension in the axilla: is this an indication for axillary radiotherapy?
PURPOSE: Although the axilla is often treated with radiotherapy (RT) postoperatively when microscopic extracapsular extension (ECE) of lymph nodal metastases is present, little data are available to assess axillary failure in the absence of such treatment. As it has been the practice at this institution to withhold axillary irradiation in the presence of microscopic extracapsular spread, we retrospectively analyzed our results for axillary recurrence, disease-free survival (DFS), and overall survival (OS). METHODS AND MATERIALS: Clinical records were reviewed of 82 women with Stage II node positive breast cancer treated with lumpectomy, axillary dissection, and RT in addition to systemic chemo/hormonal therapy. Axillary surgery consisted of a level I, II, +/- III dissection, with a median of 16.5 nodes removed. Tangential radiotherapy fields were used to treat the breast. All patients were also treated with an abbreviated supraclavicular field with the lateral border medial to the humeral head. Pathological sections were available for review in 72 of the 82 women. RESULTS: Twenty-seven of 72 (37.5%) had evidence of ECE; 45 of 72 (62.5%) had metastatic carcinoma confined within the nodal capsule. Clinical characteristics were comparable between the patients with and without ECE with the exception of (a) pathologic subtype, with a greater percentage of infiltrating ductal tumors associated with ECE (p = 0.044), and (b) number of positive lymph nodes, with 93% of patients without ECE having one to three positive nodes vs. only 56% among patients with ECE (p < 0.001). With a median follow-up of 40 months, 1 of 27 patients (4%) with ECE experienced an axillary failure as a component of first failure compared to 0 of 45 patients without ECE (p = 0.4). There were no isolated axillary failures. Five-year disease-free survival (72% without ECE vs. 57% with ECE, p = 0.12) and overall survival (83% vs. 53%, respectively, p = 0.068) suggested a less favorable outcome for patients with ECE. CONCLUSIONS: Microscopic ECE appears to be associated with increased axillary involvement and decreased survival rather than subsequent axillary failure. Our data suggest that radiotherapy to a dissected axilla may be omitted for the sole indication of microscopic extracapsular disease.
Axilla↗
Postmastectomy radiotherapy in the management of operable breast cancer.
There is a long and detailed history of radiation therapy as an adjuvant to surgery in operable breast cancer. The results of a large number of randomized clinical trials will be reviewed. They can be summarized by saying that although the trials show a reduction in local-regional failure with the use of postoperative radiotherapy, a survival advantage has not been clearly identified. Many of the older trials used techniques and radiation doses inadequate by current standards, which may have affected the results. Recent trials that used therapeutic doses of radiation, however, did demonstrate a survival advantage among patients who received postoperative radiotherapy. These trials generally have included chemotherapy and required careful integration of radiotherapy and systemic therapy. Although all trials have not demonstrated a survival benefit by the addition of radiotherapy, the ability to maintain local-regional control after mastectomy is an important goal. Administration of prophylactic chest wall and nodal radiotherapy to patients at high risk for local-regional recurrence significantly reduces the chance of a local treatment failure. Because a chest wall recurrence is a distressing event that dramatically affects quality of life, improved local-regional control with postoperative radiotherapy is a highly significant end point.
Breast Neoplasms↗
Mastectomy versus conservative surgery and radiation therapy. Psychosocial consequences.
BACKGROUND: Clinical trials comparing mastectomy to conservative surgery plus radiation therapy in the treatment of breast cancer have provided an opportunity to increase understanding of the biology of this disease and the psychological adaptation of the breast cancer patient. Because these local treatments appear to be equal in terms of survival, the question remains as to whether conservative surgery plus radiation therapy confers a measure of psychological comfort superior to that of mastectomy for women diagnosed with early-stage breast cancer. METHODS: One hundred forty-two women participating in a clinical trial randomizing patients to mastectomy or lumpectomy and radiation therapy were prospectively evaluated for psychological response to their respective local therapy. A baseline assessment before randomization and subsequent questionnaires at 6, 12, and 24 months after treatment were completed by patients entered in the clinical trial. RESULTS: At 6 months, mastectomy patients reported significantly less control over events in their lives (P = 0.003) and more problems with sexual relations (P = 0.021) than did their conservatively treated counterparts. In addition, there were marked differences between mastectomy patients and lumpectomy and radiation therapy patients in the degree of distress over their nude bodies, with P = 0.001 at 6 months, P = 0.019 at 12 months, and P = 0.057 at 24 months. CONCLUSIONS: From our findings, it appears that breast conservation therapy protects women's perception of their body but does not, over time, contribute to a more positive sexual adjustment.
Adaptation, Psychological↗
Is c-erb B-2 a predictor for recurrent disease in early stage breast cancer?
PURPOSE: To assess the prognostic importance of c-erb B-2 expression in early stage breast cancer. METHODS AND MATERIALS: Immunohistochemical analysis for c-erb B-2 over-expression was retrospectively performed on 107 paraffin-embedded specimens of women with Stage I or II breast cancer entered in a randomized trial. Results were correlated with known prognostic factors such as pathologic axillary involvement, T-size, estrogen and progesterone receptor status, and nuclear grade. Immunohistochemical staining for c-erb B-2 protein expression was also correlated with breast/chest wall failure as well as survival without evidence of disease (NED) and overall survival. RESULTS: C-erb B-2 overexpression was positive in 21% of the biopsy specimens. A significant association was found between c-erb-2 positivity and lesions containing an intraductal component, with 62% of lesions staining positively for c-erb B-2 having an intraductal component compared to only 36% of lesions with an intraductal component staining negatively for the c-erb B-2 protein (p2 = .031). A significant correlation between c-erb B-2 protein over-expression and axillary nodal status, primary tumor size, nuclear grade, and estrogen and progesterone receptor status was not identified. Cox proportional hazards model did not show a significant effect of c-erb B-2 expression for NED or overall survival. CONCLUSION: Our study did not find over-expression of c-erb B-2 to reliably predict for recurrent disease in early stage breast cancer. This data can be added to other series comparing erb B-2 expression and disease outcome among node-positive and node-negative women with carcinoma of the breast.
Adult↗
A dose intensity study of FLAC (5-fluorouracil, leucovorin, doxorubicin, cyclophosphamide) chemotherapy and Escherichia coli-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) in advanced breast cancer patients.
BACKGROUND: It has been demonstrated that granulocyte-macrophage colony-stimulating factor (GM-CSF) can ameliorate chemotherapy-induced neutropenia. The extent to which GM-CSF can increase the actual delivered dose intensity of combination chemotherapy over multiple cycles of therapy to patients with advanced breast cancer has not been well defined. We conducted a phase I/II study of dose-intensive FLAC chemotherapy (5-fluorouracil, leucovorin, doxorubicin, cyclophosphamide) in combination with GM-CSF in patients with locally advanced and metastatic breast cancer to study the acute and cumulative toxicities, anti-tumor activity and dose-intensity achievable with this regimen. METHODS: Eighty-one patients with newly diagnosed stages IIB, III and IV breast cancer who were previously untreated with chemotherapy and who had measurable disease received multiple cycles of FLAC chemotherapy plus E. coli-derived GM-CSF administered every three weeks. RESULTS: FLAC plus GM-CSF as associated with significant cumulative hematologic toxicity. Ninety-eight percent of patients developed grade 4 neutropenia; 29% of all cycles administered required hospitalization for fever and neutropenia; 41% and 22% of cycles required red blood cell and platelet transfusions, respectively. Other significant toxicities with E. coli-derived GM-CSF included mild to moderate first dose effects (hypotension, dyspnea, abdominal cramping) in 30% of patients; late occurring anaphylactoid reactions in 11% of patients; and vascular thromboses. The average delivered dose intensities over all cycles were cyclophosphamide, 210 mg/m2/week; doxorubicin, 14.8 mg/m2/week and 5-fluorouracil, 342 mg/m2/week. The overall clinical response rates were 100% and 83% for LABC and metastatic patients, respectively. There were 23% (6/26) pathologic CR's in the LABC patients given neoadjuvant FLAC and 22% (12/54) clinical CR's in the stage IV patients. The median survival of the LABC patients has not been reached (> 26 months) and is 30 months for the stage IV patients. CONCLUSIONS: The administration of multiple cycles of FLAC plus E. coli-derived GM-CSF therapy is associated with cumulative, dose-limiting myelosuppression, especially thrombocytopenia, as well as significant clinical toxicity. A modest increase in FLAC dose intensity over the starting doses was achievable with the addition of GM-CSF. FLAC chemotherapy has substantial antitumor activity in the treatment of advanced breast cancer. The potential usefulness of FLAC plus GM-CSF must be balanced by its considerable cost and alteration in patients' quality of life due to toxicity. Combination hematopoietic growth factor strategies may be able to reduce the toxicity of FLAC and to allow further increase dose intensity.
Adult↗
Postmastectomy radiotherapy: more than locoregional control.
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Breast Neoplasms↗
Primary soft tissue sarcomas of the breast: local-regional control with post-operative radiotherapy.
PURPOSE: A retrospective analysis was undertaken to determine the efficacy of postoperative radiotherapy in patients with primary sarcoma of the breast. METHODS AND MATERIALS: Ten patients with high-grade nonmetastatic primary sarcoma of the breast were treated at the National Cancer Institute, NIH, between 1979 and 1989 with mastectomy and adjuvant radiotherapy. Chemotherapy was given to three patients as part of a randomized trial. RESULTS: With a median potential followup of 99 months postoperatively, seven patients remain alive and without evidence of disease 142, 119, 82, 48, 45, 28, and 19 months postoperatively. Three patients died of metastatic disease 7, 25, and 29 months, postoperatively. There were no local or regional failures. Actuarial 5-year disease free and overall survival were 68% and 66%, respectively. CONCLUSION: Sarcomas of the breast have a prognosis similar to that of extremity sarcomas. When adjuvant radiotherapy is used, excellent local control may be achieved.
Adolescent↗
Cancer in the contralateral breast after radiotherapy for breast cancer.
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Adult↗
The effect of systemic therapy on local-regional control in locally advanced breast cancer.
One hundred and seven patients with locally advanced breast cancer were prospectively referred for multimodality treatment on protocol using chemohormonal therapy to maximal response followed by local treatment and maintenance therapy. Forty-eight patients (45%) were diagnosed with Stage IIIA disease, 46 (43%) with Stage IIIB inflammatory cancer, and 13 (12%) with Stage IIIB non-inflammatory disease. Induction therapy consisted of cyclophosphamide, doxorubicin, methotrexate, and 5-fluorouracil with hormonal synchronization using tamoxifen and conjugated estrogens. Local treatment was determined by response to chemotherapy. Patients with a clinical parital response underwent mastectomy followed by local-regional radiotherapy while patients with a clinical complete response were biopsied for pathologic correlation. Those with residual disease received mastectomy followed by radiotherapy while those with a pathologic complete response received radiation only to the intact breast and regional nodes. With a median follow-up of 64 months, patients with IIIA disease had a significantly lower local-regional failure rate compared to IIIB inflammatory patients, with the 5-year actuarial local-regional failure rate as only site of first failure 3% for IIIA disease versus 21% for IIIB inflammatory cancer (p = .02), and local-regional failure as any component of first failure 12% versus 36% (p = .01), respectively. When local-regional failure was analyzed by repeat biopsy, 5/31 (16%) patients with a pathologic complete response treated with radiation only developed a local-regional failure versus 2/53 (4%) with residual disease treated with mastectomy and postoperative radiotherapy. The 5-year actuarial local-regional failure rate as first site of failure was 23% for radiation only versus 5% for mastectomy and post-operative radiotherapy (p = .07). The response to chemotherapy did not reliably predict local-regional control. Both relapse-free survival and overall survival were significantly better for IIIA versus IIIB patients; stratification by repeat biopsy did not however, significantly affect either relapse-free or overall survival.
Adult↗
Pharmacologic erection with intracavernosal injection for men with sexual dysfunction following irradiation: a preliminary report.
Impotence is a possible consequence of treatment of pituitary adenomas and prostatic carcinomas. Following pituitary irradiation, the effect has been attributed to decreased gonadotrophins, while a variety of mechanisms, primarily vascular and neurogenic, have been proposed to explain the impotence following irradiation of prostatic carcinomas. Men with impotence of any etiology have been entered on a program to evaluate prospectively the efficacy of intracavernosal injection of vasoactive compounds in producing a satisfactory erection with pharmacologic means. Ten of these men had developed impotence following therapy for pituitary adenomas (2) or prostatic carcinomas (8). Test doses of 0.1 to 0.5 ml of a phentolamine (1 mg/ml) and papaverine (30 mg/ml) mixture were used; the dose was titrated to produce an erection deemed sufficient for vaginal penetration. All patients achieved a satisfactory response (i.e., tumescence and rigidity) lasting 10 minutes to 3 hours. Seven patients have continued in the pharmacologic erection program, with six patients functioning normally, and the remaining patient noting decreased tumescence after 18 months of treatment, but adequate erections are maintained with supplemental penile ring. Two patients have discontinued intracavernosal injections due to inconvenience, and one patient was lost to follow-up. Recent substitution of prostaglandin E1 (PGE1) has produced similar results and has replaced the phentolamine-papaverine combination. These preliminary results indicate that pharmacologic erection can be achieved in patients with impotence related to the treatment of pituitary and prostatic neoplasms and represents a reasonable alternative to implanted penile prostheses.
Adenoma↗
The case of Ohio v. Robinson. An 1870 bite mark case.
In 1870, Ansil L. Robinson was charged with the murder of his mistress, Mary Lunsford, in Mansfield, Ohio, U.S.A. Evidence against Robinson included an attempt to match his teeth to bite marks on the victim's arm. Robinson was acquitted after a 3-week trial despite the evidence linking his teeth to the wounds. This trial represents an early and perhaps the first attempt to admit bite-mark evidence in a court of law in the United States. The acquittal resulted in the obscurity that prevented this case from coming to the awareness of the forensic dental and legal communities sooner.
Bites and Stings↗
"Stalactite" calculus formation.
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Alveolar Process↗
Evaluation and treatment of patients with human bite marks.
Physicians and other health care workers who care for patients who have sustained human bite marks need a working protocol to ensure that these patients receive proper care. This protocol involves taking a thorough history and performing a physical examination, approximately determining the bite mark age, and administering proper therapy. The history will help to determine whether a criminal act has been committed and which agencies need to be notified. The American Board of Forensic Odontology published criteria for bite mark analysis in 1984 that included a description of the bite mark including its size, shape, and color, along with techniques for collection of evidence from both the victim and suspect. To determine bite mark age, tissue response to injury (inflammation, granulation tissue formation, and matrix formation and remodeling) is reviewed. Finally, the bacteria that are found in these wounds and the proper use of antimicrobial agents are expanded upon.
Anti-Bacterial Agents↗
Human bite marks. Differential diagnosis.
Human bite marks are common findings in cases of fights among children, child abuse, sexual abuse, among institutionalized persons, and in a number of homicide cases. Human bites can mimic annular or arciform dermatoses. These are reviewed from both a clinical and histologic viewpoint. An example is presented of a 2 year-old girl with several annular lesions that were clinically mistaken for a dermatophyte infection. Antifungal medications were ineffective. After several days, a dermatologist identified the lesions as human bites. Physicians and other health care workers must be able to differentiate the clinical appearance of bite marks from other dermatologic diseases at an early stage so as to initiate proper therapy and counseling and, if indicated, a search for the perpetrator.
Bites and Stings↗