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Biomedical subjects

D N Danforth

Publications and source records attributed to D N Danforth.

At least 19 recordsLinked to original sources
PubMed1992

Low-grade angiosarcoma of the skin of the breast: a complication of lumpectomy and radiation therapy for breast carcinoma.

A case of low-grade angiosarcoma arising in the skin of a breast previously irradiated for breast carcinoma is reported. Initially, an asymptomatic breast mass was detected. Excisional biopsy and axillary lymph node dissection revealed a 1.5-cm infiltrating ductal carcinoma with 21 negative lymph nodes. The neoplasm was staged as T1, N0, M0. The patient was entered in a research protocol and was treated with high-dose external beam (4,860 rad) and iridium implant (1,860 rad) irradiation. Seven years later the patient developed low-grade angiosarcoma of the breast skin. The lesion recurred following excision and eventually was treated by simple mastectomy. The patient never had evidence of lymphedema. Cutaneous angiosarcomas occurring as a complication of lumpectomy and radiation therapy for breast carcinoma are rare. In some reported cases the patients have had lymphedema, a known factor predisposing to angiosarcoma. Furthermore, almost all cases previously reported have been high grade. This case suggests that radiation therapy for breast carcinoma may also be complicated by low-grade angiosarcoma.

Breast↗
PubMed1992

Mastectomy versus breast-conserving therapy in the treatment of stage I and II carcinoma of the breast: a randomized trial at the National Cancer Institute.

PURPOSE: Mastectomy versus excisional biopsy (lumpectomy) plus radiation for the treatment of stage I and II breast cancer was compared in a prospective randomized study. PATIENTS AND METHODS: From 1979 to 1987, 247 women were randomized and 237 were treated on this study. All patients received a full axillary dissection and all node-positive patients received adjuvant chemotherapy with cyclophosphamide and doxorubicin. Radiation consisted of external-beam therapy to the whole breast with or without supraclavicular nodal irradiation followed by a boost to the tumor bed. RESULTS: The minimum time on the study was 18 months and the median time on the study was 68 months. No differences in overall survival or disease-free survival were observed. Actuarial estimates at 5 years showed that 85% of mastectomy-treated patients were alive compared with 89% of the lumpectomy/radiation patients (P2 = .49; 95% two-sided confidence interval [CI] about this difference, 0% to 9% favoring lumpectomy plus radiation). The probability of failure in the irradiated breast was 12% by 5 years and 20% by 8 years according to actuarial estimates. Of 15 local breast failures, 14 were treated with and 12 were controlled by mastectomy; the ultimate local-regional control was similar in both arms of the trial. CONCLUSION: These data add further weight to the conclusion that breast conservation using lumpectomy and breast irradiation is equivalent to mastectomy in terms of survival and ultimate local control for stage I and II breast cancer patients.

Adult↗
PubMed1991

Interleukin 1 alpha blocks estradiol-stimulated growth and down-regulates the estrogen receptor in MCF-7 breast cancer cells in vitro.

We studied the effect of interleukin 1 alpha (IL-1 alpha) on estradiol stimulation of cell growth and estrogen receptor (ER) content in MCF-7 human breast cancer cells in vitro to determine if IL-1 alpha altered cellular estradiol responsiveness. We found that IL-1 alpha blocked estradiol-stimulated growth of these cells in a dose-dependent manner (complete antagonism at 1000 units/ml: day 7 mean growth = vehicle, 47.7 micrograms DNA; estradiol 10(-10) M, 95.1; IL-1 alpha/estradiol, 44.6) and at all concentrations of estradiol from 10(-8) to 10(-11) M. IL-1 alpha in combination with trans-hydroxytamoxifen further inhibited estradiol-stimulated growth (vehicle = 44.8 micrograms DNA, estradiol = 108.3, estradiol/trans-hydroxytamoxifen = 47.8, IL-1 alpha/estradiol/trans-hydroxytamoxifen = 3.0, P less than 0.01). Inhibition with trans-hydroxytamoxifen was IL-1 alpha dose dependent (maximum = 97% at 1000 units/ml, P less than 0.01) and estradiol dose dependent (reversible with 10(-8) M estradiol, maximum inhibition at 10(-10) M estradiol). Concomitantly, IL-1 alpha down-regulated ER concentration by 38.0-43.7% (P less than 0.01) as measured by immunoreactivity or Scatchard analysis, respectively. This occurred as early as 3 h without a change in the Kd (vehicle = 0.23 nM, IL-1 alpha = 0.24 nM), persisted for at least 48 h, was dose dependent (maximum, 43.7% at 1000 units/ml, P less than 0.01), and was blocked by cycloheximide. IL-1 alpha, however, did not block estradiol stimulation of progesterone receptor content (vehicle = 221.9, IL-1 alpha = 238.9 fmol/mg protein) and did not block estradiol down-regulation of ER content. Furthermore, IL-1 alpha alone did not alter levels of ER mRNA and did not alter estradiol down-regulation of ER mRNA. These findings indicate that while IL-1 alpha antagonizes estradiol stimulation of growth and reduces ER content, its mechanism may involve other non-estrogen-regulated pathways.

Breast Neoplasms↗
PubMed1991

Level of axillary involvement by lymph node metastases from breast cancer is not an independent predictor of survival.

We examined the relationship of axillary level of lymph node metastases from clinical stage I and II breast cancer to overall survival and disease-free survival rates in 135 patients who underwent complete axillary lymph node dissection to determine if anatomic level of axillary involvement (I vs II vs III) is an independent prognostic factor. All patients underwent either modified radical mastectomy or lumpectomy with axillary dissection and whole breast radiotherapy for breast cancer. Median follow-up was 6.9 years. We found no difference in overall survival or disease-free survival between patients whose highest or only level of axillary involvement was level I compared with patients whose highest or only level was II. Although patients whose highest level of nodal involvement was III had significantly worse overall survival and disease-free survival rates than patients whose highest nodal involvement was I or II, when patients were stratified by the total number of positive nodes (one to three vs four or more), there was no difference in overall survival or disease-free survival rates between levels I, II, and III. These findings indicate that the level of axillary involvement for stage II breast cancer is not of independent prognostic significance.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Interleukin-1 alpha and tumor necrosis factor-alpha (TNF alpha) inhibit growth and induce TNF messenger RNA in MCF-7 human breast cancer cells.

We studied the effects of interleukin-1 alpha (IL-1) and tumor necrosis factor-alpha (TNF), alone and in combination, on MCF-7 breast cancer cells to determine whether these cytokines alter cell growth, TNF gene expression, and TNF secretion. We found that IL-1 alone and TNF alone inhibited cell growth in a dose-dependent manner. Each cytokine arrested growth in the G0/G1 phase of the cell cycle, with maximum growth inhibition at 1000 U/ml (P less than 0.05) and 100 U/ml (P less than 0.01), respectively. However, the combination of these two cytokines did not result in greater growth inhibition or a greater percentage of cells arrested in the G0/G1 phase of the cell cycle compared with each cytokine alone. We examined the effect of exogenous IL-1 and TNF on TNF gene expression by Northern blot analysis. In the absence of any cytokine, these cells do not express TNF mRNA. Exposure to IL-1 (1000 U/ml) induced TNF mRNA at 3 h; however, mRNA levels diminished thereafter to barely detectable levels by 24 h. Exposure to TNF (1000 U/ml) also induced TNF mRNA at 3 h, but in contrast to IL-1, the level of enhanced expression persisted at these levels through 72 h of exposure. Secretion of TNF by these cells is induced by exogenous TNF, but not by IL-1. IL-1 and TNF in combination do not produce greater inhibition of growth, greater amounts of TNF mRNA at 3 h, or greater secretion of TNF than that produced by TNF alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Blotting, Northern↗
PubMed1991

How subsequent pregnancy affects outcome in women with a prior breast cancer.

Of all women who develop breast cancer, approximately 25% will do so in their premenopausal years and may still wish to bear children. The effect of a subsequent pregnancy, with its profound hormonal changes, on the outcome of the breast cancer (which itself may be hormonally responsive) is an important question. The prognosis of the original tumor also may influence the decision regarding pregnancy. Many studies have addressed these issues and have concluded that a pregnancy after a successfully treated breast cancer does not alter the outcome of that tumor, whether analyzed according to overall survival for all breast cancer patients or according to stage or axillary lymph node status. Nevertheless, it is recommended that pregnancy be delayed until 2 to 3 years after completion of treatment, especially if axillary nodes were positive for tumor--not because of any influence of the pregnancy on the malignancy, but rather to defer childbearing until after the period of greatest risk of recurrence of the tumor.

Breast Neoplasms↗
PubMed1991

Splenectomy for the massively enlarged spleen.

The experience at the National Cancer Institute from 1955 to 1988 with 46 cases of splenectomy for massive splenomegaly (greater than or equal to 1,500 grams) was reviewed to assess the indications, pathology, operative, and postoperative course for this procedure. The median age was 51 years. Thirty-one splenectomies (67.4%) were performed for malignancy (chronic lymphocytic leukemia, 11; chronic myelogenous leukemia, 10; lymphoma, 9; hairy cell leukemia, 1), 11 for myeloid metaplasia, and four for other nonmalignant conditions. Indications for splenectomy included hypersplenism (32 patients), symptoms (6), diagnosis (3), and splenic rupture (3). A midline incision (30 patients) was most commonly used. Median operative time was 2 hours, 50 minutes. Median operative blood loss was 1,300 ml (range, 100 ml-60 units). The splenic artery was ligated initially in 16 patients (34.8%) but did not correlate with blood loss or operating time. The median splenic weight was 2,030 grams (range, 1500-5320 gm). The postoperative complication rate was 39.1 per cent (21 complications in 18 patients). This included infection in 10 patients, bleeding in six patients. Six patients required reoperation (bleeding, 4; abscess, 1; small bowel obstruction, 1 patient). The 30-day operative mortality was 19.6 per cent (9 patients). Excluding operative deaths, 35 patients were available for follow-up evaluation. Twenty-nine patients had improvement in parameters for which splenectomy was indicated. Six patients had no change in their course after splenectomy. These findings indicate that many patients with massive splenomegaly benefit from splenectomy, however, the procedure is associated with a high risk for postoperative morbidity and mortality.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Immediate postexcision mammography for occult noncalcified breast lesions.

To evaluate completeness of surgical excision, we studied the use of film screen mammography done immediately after excision of occult noncalcified breast lesions in 11 patients. The postoperative mammograms were well tolerated, and allowed high quality films to be obtained. Complete excision was documented in ten patients, and one patient had small artifacts that resolved on follow-up studies. Roentgenograms of the surgical specimen from ten patients showed a discrete lesion in only three. Histologic analysis revealed malignancy in two patients and benign changes in nine. These findings indicate that mammography done immediately after excision of occult noncalcified lesions is more reliable than roentgenograms of the specimen and may be a useful method for confirming extent of excision. This method may also eliminate the present delay of four to six weeks before adequate postoperative follow-up films can be obtained to evaluate excision.

Adult↗
PubMed1990

Effect of preoperative chemotherapy on mastectomy for locally advanced breast cancer.

Mastectomy is frequently performed after intensive chemotherapy for locally advanced breast cancer. The effects of preoperative chemotherapy on the postoperative course and the timing of subsequent adjuvant therapy, however, have not been defined. We therefore reviewed the perioperative course of 54 patients undergoing mastectomy after combination (CAMFPT) chemotherapy for stage IIIA,B (IIIA - 25 pts; IIIB noninflammatory - 5 pts; IIIB inflammatory-24 patients) breast cancer. A median of 7 cycles (6 months) of chemotherapy was administered preoperatively. Mastectomy was performed a median of 20 days after last chemotherapy; white blood cell count (WBC) and platelet counts returned to normal limits preoperatively. Total mastectomy with or without axillary node dissection was performed in 53 patients, and a Halsted radical mastectomy in 1 patient. Negative margins on breast and/or axillary tissue were achieved in 47 patients (87.0%). Postoperative complications included skin flap necrosis in 8 patients (14.8%), seroma formation in 5 patients (9.3%), and wound infection in 1 patient (1.9%). Median operative blood loss (550 cc), hospital stay (8 days), and duration of wound catheter drainage (6 days) were comparable to published reports for modified radical mastectomy without preoperative chemotherapy. Systemic chemotherapy was resumed a median of 16 days after mastectomy, and radiotherapy started a median of 33 days after mastectomy. These findings indicate that intensive preoperative chemotherapy does not increase the hospital course or the postoperative complications of mastectomy for locally advanced breast cancer. In view of the current interest in treatment of stage I and II breast cancer with preoperative chemotherapy, this information may be useful in their management as well.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Electrophoretic analysis of large molecular weight forms of the estrogen receptor in MCF-7 human breast cancer cells.

The denatured and nondenatured forms of the estrogen receptor (ER) in MCF-7 human breast cancer cells have been characterized by gel electrophoresis using the covalently attaching ligand [3H]tamoxifen aziridine ([3H]TA). A comparison of the ER binding properties of the recently introduced commercial preparation (Amersham) of [3H]TA with the prototype showed no quantitative or qualitative differences, with both preparations binding efficiently and selectively at either 4 degrees C or 37 degrees C. The nuclear and cytosolic labeled ER, when analyzed by denaturing SDS-PAGE, migrate as 67,000 dalton proteins. [3H]TA labeled ER from cytosol prepared in low salt buffer without protease inhibitors migrates on 5%, 6%, or 7% nondenaturing PAGE as two discrete forms. The molecular weights of these two species, determined by Ferguson plot analysis with multiple standard protein markers, are 260,000 and 67,000 daltons, respectively. The 260 kDa form is dissociated by 0.4 M KCl into the 67 kDa form, suggesting that the larger form is composed of one or more noncovalently attached subunit proteins. When enzyme inhibitors leupeptin and molybdate are included in cytosol prepared in low salt, two high molecular weight [3H]TA labeled peaks are identified, the first 600,000 and the second 430,000 daltons. These two forms migrate together on 4%, 5%, and 6% non-SDS, non-denaturing gels, and are not dissociated when cytosol is made 0.4 M in KCl. These findings indicate that the ER of these human breast cancer cells exists in one or more large discrete forms of mol. wt 430,000-600,000 daltons. These forms are not dissociated by high salt but may be digested by proteases to the subunit 67,000 dalton form. These findings support the proposal that the ER is present as a large molecular weight "holoreceptor", and may be important for our understanding the metabolism and function of the ER in estrogen target tissues and human breast cancer.

Breast Neoplasms↗
PubMed1988

Adjuvant chemotherapy for patients with high-grade soft-tissue sarcomas of the extremity.

We have previously reported the results of a randomized trial that demonstrated the survival benefit of adjuvant chemotherapy in the treatment of patients with high-grade extremity sarcomas compared with no chemotherapy. This regimen included doxorubicin, cyclophosphamide, and methotrexate. This report updates and extends our experience. The median follow-up of this trial is now 7.1 years and reveals a 5-year disease-free survival of 75% and 54% for chemotherapy and no chemotherapy groups, respectively (two-sided P [P2] = .037). The 5-year overall survival for patients in this trial was 83% and 60% for the chemotherapy and no chemotherapy groups, respectively, with a trend towards improved survival in the chemotherapy arm (P2 = .124). Because of doxorubicin-induced cardiomyopathy we performed a subsequent randomized trial comparing this high-dose regimen to reduced cumulative doses of doxorubicin and cyclophosphamide without methotrexate. Eighty-eight patients were entered into this trial which has a median follow-up of 4.4 years. The 5-year disease-free and overall survival for patients treated with the reduced doses of chemotherapy was 72% and 75%, respectively, and was not significantly different from the high-dose regimen. No patients developed congestive heart failure on this study. We conclude that adjuvant chemotherapy improves disease-free survival in patients with extremity soft-tissue sarcomas. The overall survival advantage in patients receiving adjuvant chemotherapy in our initial randomized high-dose chemotherapy trial has diminished though it continues to favor the chemotherapy group. A reduced-dose chemotherapy regimen was found to be comparable to the high-dose regimen.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Neoadjuvant chemotherapy in the combined modality approach of locally advanced nonmetastatic breast cancer.

We have treated 76 patients with locally advanced breast cancer, 31 with stage IIIA, 41 with stage IIIB, and 4 with stage IV disease, with primary induction chemotherapy including an attempted hormonal synchronization in 70 patients. All were treated to maximum objective clinical response before proceeding to any local therapy. Patients achieving a complete response with a negative repeat biopsy generally received radiation therapy while patients with residual disease, partial response (PR) or no change (NC) status received debulking surgery prior to radiation therapy. Regardless of response to induction chemotherapy, patients received at least 6 additional months of chemotherapy following local therapy. Initial doses of combination chemotherapy were escalated to targeted myelosuppression. The objective response rate to induction chemotherapy was 93% with 49% complete response (CR), 44% PR, and 7% NC. The median numbers of cycles of chemotherapy to achieve a CR, PR, or NC were 5, 3, and 5, respectively. Three patients who currently have PRs are still on chemotherapy with continued tumor regression. Of 37 patients achieving a CR to chemotherapy, 35 were assessed by biopsies to determine pathological evidence of response. Twenty-three of the 37 patients (62%) were proven to be complete responders with negative biopsies. Twenty-four patients have relapsed, 6 with stage IIIA, 16 with stage IIIB, and 2 with stage IV. Five patients have had locoregional relapses alone, 4 locoregional and distant, and 15 distant alone. Median time to progression is 35.9 months for stage IIIA and 34.2 months for stage IIIB. Median survival is 35.3 months for stage IIIB and is indeterminate for stage IIIA. This aggressive primary chemotherapy regimen with hormonal synchronization followed by local therapy appears to provide excellent local control and encouraging early results on systemic disease control.

Adult↗
PubMed1986

Complete axillary lymph node dissection for stage I-II carcinoma of the breast.

We reviewed the complete axillary dissection specimens of 136 patients with stage I-II breast cancer to clarify the distribution of axillary lymph node metastases in this disease. Our series included 71 patients undergoing axillary dissection as part of a modified radical mastectomy (MRM) and 65 patients undergoing axillary dissection in conjunction with conservative surgery of the breast and definitive postoperative breast radiotherapy (CAD). These two groups of patients were comparable according to age, menopausal status, tumor size, and clinical stage. In all patients the pectoralis minor muscle was excised and all axillary tissue removed. Each specimen contained a median of 23 lymph nodes. The axillary levels (I, II, III) were determined according to the relationship of axillary tissue to the pectoralis minor muscle (lateral, inferior, medial). Thirty-nine percent of the lymph nodes were contained in level I, 41% in level II, and 20% in level III. There were no significant differences noted in the number of lymph nodes or in the distribution of lymph nodes according to axillary level between dissections performed as part of the MRM or those done as a single procedure (CAD). Sixty-five patients (47.8%) had one or more positive lymph nodes in their axillary specimen. The clinical and pathologic stage was determined and compared for all patients. Among patients judged to have a clinically negative axilla, 37.6% had histologically positive lymph nodes (clinical false-negative rate). For patients with a clinically positive axilla, 11.1% had, histologically, no evidence of metastatic disease (clinical false-positive rate). When the distribution of lymph node metastases according to axillary level was studied, it was found that 29.2% of lymph node-positive patients (or 14.0% of all patients) had metastases only to level II and/or III of the axilla, with level I being negative (skip metastases). This incidence of skip metastases was greater among clinically node-negative than among clinically node-positive patients, but was not related to the size or location of the primary tumor in the breast. In addition, it was found that 20.0% of lymph node-positive patients (or 9.6% of all patients) were converted from three or fewer to four or more positive nodes by analysis of lymph nodes contained in levels II and III. This conversion from three or fewer to four or more positive nodes was due primarily to information contained in level II, with level III contributing to a smaller degree.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1985

Cesarean section.

Although the cesarean section rate has increased steadily for the past 12 years, further increase seems unlikely since the indications for performing the operation are already broadly defined. Most of the earlier indications will remain unchanged (eg, the presence of placenta previa and cephalopelvic disproportion). The trend toward vaginal delivery in perhaps 30% to 40% of breech births will probably have no material effect on the number of cesarean sections performed, and the present use of cesarean section for multiple pregnancy will probably continue. The two conditions under which cesarean section rates might become significantly lower are (1) automatic repeat cesarean section (which now accounts for more than 25% of all cesarean sections), a procedure which will probably decline as increasing numbers of such women have vaginal deliveries, and (2) a redefinition of the present midforceps classification, which will permit some of the easy midforceps deliveries from a low level to be performed without the legally abhorrent stigma of mid-forceps delivery. The value of prophylactic antibiotics for women predisposed to infection has now been proved, and further placebo studies to demonstrate this are not warranted. In the past, "type and match 2 units" was a routine prelude to cesarean section, and for every unit of blood transfused to cesarean section patients, some 25 units were cross-matched and held in (unnecessary) readiness. This formula is gradually giving way to type and screen, eliminating countless crossmatches. Because of possible harmful fetal effects, preoperative fluid loading, a necessary part of conduction anesthesia, is changing from the customary 5% glucose to the use of fluids containing no glucose. It has been suggested that conduction anesthesia may not offer unlimited time for cesarean section, as used to be thought. Apgar scores are lower if the time from uterine incision to delivery is longer than three minutes, a diminution that may be a function of the anesthesia or may reflect difficulty in delivery. Cesarean section mortality is much lower than it was in former years, but one may expect from one to two deaths per 1,000 operations. Overall, the maternal mortality from cesarean section per se is probably from three to five times higher than that of vaginal delivery (in one series, 11.5 times higher than vaginal delivery). The incidence of mild, transient respiratory signs in the newborn is higher after cesarean than after vaginal delivery, and the incidence of respiratory distress syndrome is also slightly higher.(ABSTRACT TRUNCATED AT 400 WORDS)

Anesthesia, Obstetrical↗
PubMed1985

Melatonin and malignant disease.

A possible role for the pineal and melatonin in malignant disease is suggested by the studies of hormone-dependent tumours presented here. The most dramatic observation of the effect of the pineal and melatonin in malignancy is that melatonin protects against, while pinealectomy enhances, 7,12-dimethylbenz[a]anthracene-induced mammary tumours in rats. Melatonin may protect against tumours through a suppressive effect on prolactin secretion or an action on oestrogen receptors. Melatonin can change the concentration of oestrogen receptors in hamsters, both juvenile and adults, and in a human breast cancer cell line. The long-term effect of melatonin in the ovariectomized adult hamster and in human breast cancer cells is to inhibit oestrogen-stimulated growth. A possible relationship between melatonin and oestrogen receptors was examined in women with breast cancer. An inverse correlation was observed between the oestrogen receptor concentration in each patient's tumour and her peak plasma melatonin level, suggesting that the more hormone dependent the breast cancer the more blunted the daily melatonin rhythm. Thus, the more robust the daily melatonin rhythm the greater the protective effect on hormone-dependent breast cancer. Unfortunately, this hypothesis is not easily tested as shown in a study of women at high risk for developing breast cancer. These women had daily melatonin profiles that did not differ from those of a normal population. Thus, the use of plasma melatonin as a screening tool for breast cancer risk is not reasonable; however the basic and clinical data argue that the role of melatonin in endocrine-related cancers requires more extensive clinical investigation.

9,10-Dimethyl-1,2-benzanthracene↗