Ductal lavage for detection of cellular atypia in women at high risk for breast cancer.

BACKGROUND: Breast cancer originates in breast epithelium and is associated with progressive molecular and morphologic changes. Women with atypical breast ductal epithelial cells have an increased relative risk of breast cancer. In this study, ductal lavage, a new procedure for collecting ductal cells with a microcatheter, was compared with nipple aspiration with regard to safety, tolerability, and the ability to detect abnormal breast epithelial cells. METHODS: Women at high risk for breast cancer who had nonsuspicious mammograms and clinical breast examinations underwent nipple aspiration followed by lavage of fluid-yielding ducts. All statistical tests were two-sided. RESULTS: The 507 women enrolled included 291 (57%) with a history of breast cancer and 199 (39%) with a 5-year Gail risk for breast cancer of 1.7% or more. Nipple aspirate fluid (NAF) samples were evaluated cytologically for 417 women, and ductal lavage samples were evaluated for 383 women. Adequate samples for diagnosis were collected from 111 (27%) and 299 (78%) women, respectively. A median of 13,500 epithelial cells per duct (range, 43-492,000 cells) was collected by ductal lavage compared with a median of 120 epithelial cells per breast (range, 10-74,300) collected by nipple aspiration. For ductal lavage, 92 (24%) subjects had abnormal cells that were mildly (17%) or markedly (6%) atypical or malignant (<1%). For NAF, corresponding percentages were 6%, 3%, and fewer than 1%. Ductal lavage detected abnormal intraductal breast cells 3.2 times more often than nipple aspiration (79 versus 25 breasts; McNemar's test, P<.001). No serious procedure-related adverse events were reported. CONCLUSIONS: Large numbers of ductal cells can be collected by ductal lavage to detect atypical cellular changes within the breast. Ductal lavage is a safe and well-tolerated procedure and is a more sensitive method of detecting cellular atypia than nipple aspiration.

Human breast cancer progression can be regulated by dominant trans-acting factors in somatic cell hybridization studies.

Human breast cancer is often characterized by a progression to an ER (estrogen receptor)-negative, estrogen-independent, antiestrogen-resistant, EGFR (epidermal growth factor receptor)-positive, and highly metastatic phenotype. The molecular and biochemical mechanisms behind this progression are not well defined. Most studies of breast cancer have focused on one or another aspect or this progression but have not found a common pathway. By constructing stable and complete human-human somatic cell fusions between a highly metastatic, undifferentiated, ER-negative line of melanoma lineage and the estrogen-dependent, ER-positive MCF-7 line, this study produced hybrids that were ER negative, highly expressive of EGFR, estrogen independent, estrogen unresponsive, fully tumorigenic, and highly metastatic. ER negativity was on the basis of complete suppression of ER transcription as evidenced by Northern blot analysis and nuclear run-on assay, not on the basis of gene rearrangement. EGFR positivity was not due to gene amplification or rearrangement but rather to increased EGFR transcription. Mechanisms, including ras activation, fibroblast growth factor 4 expression, and human DNA methyltransferase activation causing ER promoter methylation, which are respectively known to induce estrogen-independent growth, induce spontaneous metastasis, and decrease ER levels in breast carcinoma experimentally, were not mechanisms operating in the hybrids. This model demonstrates that many of the common denominators of human breast carcinoma progression can be regulated by dominant trans-acting factors.

Ionic effects on the structure of nucleoprotein cores from adenovirus.

Nucleoprotein cores, prepared from adenovirus type 5 with a deoxycholate/heat treatment, consist of the viral DNA and two major internal proteins. The core particles exhibit structural characteristics that are highly reproducible and dependent on their ionic environment. In low-ionic-strength buffer, the cores had a sedimentation coefficient of 180 S and appeared in the electron microscope as homogeneous particles with distinct centers from which numerous arms and loops radiated. Condensation of the cores was induced by Mg2+ or Ca2+ over the range 0 to 1 mM. The sedimentation coefficient increased monotonically with divalent cation concentration, reaching a maximum of 405 S in 1 mM Mg2+. A corresponding condensation in the core structure was observed by electron microscopy. Increasing concentrations of NaCl also produced a conformational change in the cores, with an almost linear increase in sedimentation velocity up to 274 S in 0.04 M NaCl. Between 0.05 and 1.0 M NaCl, the cores were insoluble. In 2.0 M NaCl, the cores were again soluble with an s20,w of 228 S. Under all ionic strength conditions in which the cores were soluble, both core proteins remained bound to the DNA.

Regional nodal failure after conservative surgery and radiotherapy for early-stage breast carcinoma.

We retrospectively analyzed the likelihood of regional nodal failure (RNF) for 1,624 patients with stage I or II invasive breast carcinoma treated with conservative surgery and radiotherapy (RT) at the Joint Center for Radiation Therapy (JCRT) between 1968 and 1985. The median follow-up time was 77 months. RNF was the first site of failure for 38 of the 1,624 patients (2.3%). The incidence of axillary failure for patients undergoing axillary dissection (AXD) who were irradiated to the breast only was 2.1% (nine of 420) for patients with negative nodes and 2.1% (one of 47) for patients with one to three positive nodes. The incidence of supraclavicular failure in these two groups was 1.9% (eight of 420) and 0% (zero of 47), respectively. The incidences of axillary and supraclavicular failure in patients without clinically suspicious axillary involvement who did not have AXD but were treated with RT were 0.8% (three of 355) and 0.3% (one of 364), respectively. Despite various combinations of salvage surgery, RT, and systemic therapy, only 47% of patients (18 of 38) achieved complete regional control after nodal relapse. We conclude that RNF is uncommon in patients treated to the breast alone following an adequate AXD when the axillary nodes are negative or when one to three nodes are positive. RNF is also uncommon in patients with a clinically uninvolved axilla treated with nodal RT without AXD. Symptoms of RNF can be controlled in most but not all patients. Further study is needed to determine if the benefits of RT in preventing a small number of symptomatic RNF outweigh the potential toxicity for any subgroup of patients.

Level I and II axillary dissection in the treatment of early-stage breast cancer. An analysis of 259 consecutive patients.

Level I and II axillary dissection involves anatomic dissection of levels I and II of the axilla without clearance of the axillary vein or placement of drains. The results of level I and II axillary dissection with breast conservation in a consecutive series of 259 patients treated from 1981 through 1988, with a mean follow-up of 22.5 months (median, 27.1 months) were reviewed. The number of nodes removed ranged from two to 24, with a mean of nine. Axillary seroma was the most frequent complication (11 patients [4.2%]). Lymphedema was observed in seven patients (2.7%). Axillary recurrences occurred in two patients. These results indicate that a level I and II axillary dissection defined anatomically allows prognostic evaluation while limiting morbidity and recurrence. In addition, this procedure can be done safely without drains on an outpatient basis, with further psychological and economic benefits.

Use of risk factors in counseling patients.

Topics included in this article are a definition and interpretations of relative risk, including which risk factors are most important, the contribution of family history, and prior benign breast disease.

Development of vascularization in the chondroepiphysis of the rabbit.

Although numerous studies have addressed the presence of cartilage canals within developing epiphyses, the chronology of their appearance and their vascular contribution to the developing chondroepiphysis remain to be studied. We have selected a model, similar to the developing human skeletal system, in which extensive cartilage canal development precedes the subsequent secondary ossification process. In the rabbit proximal tibia, both chondroepiphyseal and vascular (cartilage canals) development were quantified from the first evidence of vessels until the formation of the secondary center of ossification. The volume of hyaline cartilage increased 25 times after intraepiphyseal vessels were initially observed. The blood supply, measured in cartilage canal volume, increased 400-fold over the same period. Three distinct cartilage canal morphologies were identifiable before the formation of the secondary center of ossification: (a) an early phase, in which the canals appeared as infoldings derived from the perichondrium; (b) a reactive phase, occurring simultaneously with chondrocyte hypertrophy and characterized by a very large increase in mesenchymal cells within the cartilage canal; and (c) a vascular phase, coincident with mineralization of the matrix, in which the familiar, unitary canal morphology was replaced by that of a vascular plexus. While matrix mineralization and the formation of bone seem dependent on critical cellular events, notably chondrocyte hypertrophy, the role that the vascular supply plays in developing sufficient biological inertia for the ossifying transition must not be underestimated.

Chondro-osseous growth abnormalities after meningococcemia. A clinical and histopathological study.

The cases of nine children who survived the acute stage of meningococcal septicemia and secondary disseminated intravascular coagulation were reviewed. All of the children had major orthopaedic problems as a result of the acute disease. Detailed histological studies were performed on specimens of bone and cartilage, obtained when these patients had either acute amputation for gangrene or subsequent revision for a chondro-osseous deformity. In the specimens that were obtained from the children who had acute gangrene, the histological changes included small-vessel thrombi, osteonecrosis, subperiosteal new-bone formation, cortical disruption, cellular disorganization in the physis, and medullary inflammation. These findings were compatible with a combination of inflammation (acute osteomyelitis) and ischemia. In the specimens that were obtained during revision of the amputation, three years or more after the initial infectious or ischemic process, the clinically relevant findings involved the epiphyses and physes. The growth plates showed variable permanent ischemic damage. Bone bridges connecting the epiphysis and metaphysis were observed in various stages of formation, including several early bridges with involvement of only the physis and metaphysis. Endosteal and cortical bone, in contrast, showed complete recovery with no evidence of permanent ischemic damage. We concluded that children who survive meningococcal septicemia are at high risk for complex orthopaedic problems, both acute and chronic. The disseminated intravascular coagulation and focal infections of the acute phase are primarily responsible for the vascular injuries to the growing chondro-osseous tissues. Ischemic changes also selectively involve the physeal circulation, but may take several years to adversely affect longitudinal and transverse growth of bone.

Reconstruction of the radiated partial mastectomy defect with autogenous tissues.

As conservative surgery and radiation therapy have become accepted treatments for early-stage breast cancer, increasing attention has focused on the cosmetic results of this technique. When partial mastectomy--a term which encompasses a diversity of excisional techniques--is followed by radiation therapy, breast defects characterized by parenchymal loss, nipple-areola complex distortion, and cutaneous abnormalities can occur. From 1981 to 1990, eight patients sought reconstructive correction of a radiated partial mastectomy deformity. Patients were from 42 to 70 years of age (mean 49 years). All had breast cancer, except for one patient with diffuse and chronic breast abscesses. Six patients were reconstructed with latissimus dorsi flaps and two with rectus flaps. No patient underwent reconstruction sooner than 1 year after completion of radiation therapy; for the entire group, a mean of 2.6 years elapsed from completion of radiation therapy to flap reconstruction of the breast. Mammograms were obtained on all the breast cancer patients before and after the myocutaneous flap procedure. Follow-up extended from 1 to 9 years after reconstruction (mean 3.6 years) and included both physical examination and serial mammographic evaluations. Myocutaneous flap reconstruction with either latissimus or rectus flaps achieved an aesthetic improvement of the partial mastectomy deformity in all eight patients. Complications consisted only of seroma formation in two patients following latissimus flap reconstruction. Mammographic evaluation revealed fibrofatty degeneration of the soft tissues of both types of flaps, a change that occurs as early as 6 months after operation and appears as a radiolucent area. The feasibility of mammography as a screening adjunct for recurrent cancer in this group of patients is demonstrated. Advantages of this technique of autogenous tissue reconstruction are improvement of contour deformities associated with conservative surgery and radiation therapy, preservation of normal, sensate breast skin, enhancement of symmetry with the contralateral breast, and avoidance of a prosthesis.

Congenital malformations of the lower extremities.

An understanding of the normal and pathologic development of the lower limb allows the physician a fuller appreciation of the clinical and functional disabilities that each congenital malformation may present. Treatment to allow achievement of each child's fullest potential may then be better attained.

Recurrent breast cancer following immediate reconstruction with myocutaneous flaps.

As immediate breast reconstruction with rectus abdominis and latissimus dorsi myocutaneous flaps has become a recognized technique for patients requiring mastectomy, concerns have arisen regarding the detection and treatment of locoregional recurrence of breast cancer. Because most recurrences develop in the residual native skin of the chest wall following a mastectomy, breast reconstruction procedures involving the placement of a subpectoral prosthesis are unlikely to interfere with postoperative cancer surveillance. Myocutaneous flaps, however, transpose blocs of soft tissues into the mastectomy site. This study was done to evaluate the influence of a myocutaneous flap on the subsequent diagnosis and treatment of locoregional recurrence of breast cancer. Data were obtained from 161 patients with breast cancer who had immediate reconstruction with a myocutaneous flap between 1982 and 1990. Of the 161 patients reviewed, 120 had primary mastectomy with immediate reconstruction; 41 patients had salvage mastectomy and immediate reconstruction after failed conservative surgery and radiation therapy. Modified radical mastectomy was performed on all patients. Either a rectus abdominis (n = 65) or latissimus dorsi (n = 97) myocutaneous flap breast reconstruction was performed. Recurrent tumor was observed in 17 of the 161 patients reviewed (10.6 percent). Fourteen of the 17 recurrences occurred in 120 patients having primary mastectomy and immediate reconstruction for a rate of 11.7 percent; 3 of 41 patients (7.3 percent) who had salvage mastectomy and flap reconstruction developed recurrences. Of the 17 recurrences, 6 patients were stage II, 10 were stage III, and 1 was stage IV. All 17 patients who developed a recurrence had invasive breast cancer, with infiltrating and inflammatory tumors predominating. All locoregional recurrences of breast cancer developed within the native skin and subcutaneous tissues adjacent to the mastectomy and flap reconstruction site. Recurrences were seen as rapidly as 2 weeks or as long as 3.8 years (mean 1.4) after the mastectomy and flap reconstruction. Overall mean follow-up for the entire group of 161 patients was 5.4 years. Thirteen of the 17 patients (76.5 percent) developed distant metastases either concomitantly with the locoregional recurrence or within 4.3 years (mean 1.7). From an oncologic viewpoint, the technique of myocutaneous flap breast reconstruction with rectus abdominis or latissimus dorsi flaps appears to be a safe one. An analysis of locoregional recurrence of breast cancer in patients undergoing primary mastectomy or salvage mastectomy with myocutaneous flap breast reconstruction did not show concealment by the flap of any recurrent tumor.(ABSTRACT TRUNCATED AT 400 WORDS)

Lawn-mower injuries in children.

The power lawn mower is capable of inflicting serious injury, particularly to the pediatric population. A total of 27 patients who had sustained lawn-mower injuries were reviewed to identify those factors responsible for power-mower accidents and to determine an effective treatment regimen for these patients. The injuries included amputations in 19, major lacerations in 34, and fractures in 23 extremities. Aggressive treatment of both the soft tissue and bony injuries was necessary. Fractures were treated with either open reduction and internal fixation or external fixation, as appropriate, and early soft tissue coverage. The results were satisfactory in the majority of patients, but often required multiple surgical procedures over a number of years. The incidence of these injuries can be reduced by educating the public about the potential dangers of these machines, and by encouraging the use of proper safety procedures.

Surgical techniques in breast conservation.

The surgical treatment of breast cancer has changed dramatically in the last 30 years. The era of the Halsted radical mastectomy has passed, and less deforming surgeries have come into use. Partial mastectomy in association with axillary lymph node dissection has become a viable alternative for stage 1 and 2 carcinomas; more advanced tumors may be treated with breast conservative surgery when neoadjuvant chemotherapy is utilized. Further, the use of mammography in screening for breast cancer has led to an increase in the diagnosis of ductal carcinoma in situ (DCIS), another lesion for which breast conservation is often indicated.

The in situ carcinomas of the breast.

In situ carcinoma of the breast is being diagnosed with greater frequency on breast biopsies. Of the two types of CIS, lobular carcinoma in situ is considered a marker for increased risk of developing breast cancer in either breast, and treatment options are based on different philosophies of careful follow-up vs preventive surgery. Ductal carcinoma in situ is a direct precursor to invasive carcinoma and the variety of treatments available reflect the need to completely excise this lesion. Several trials are now in progress to define the roles of surgery, radiation, and hormonal manipulation in the treatment of both types of CIS.

Breast-duct endoscopy to study stages of cancerous breast disease.

BACKGROUND: In breast-cancer research, we lack reproducible non-invasive access to breast tissue. Breast cancer is thought to start in the lining of the milk duct or lobule. We have had no direct access to this area other than in tissue removed surgically or by fine-needle aspiration. Our objective was to explore an intraductal approach to studying breast cancer and precancerous changes by duct cannulation and endoscopy. METHODS: In this pilot study, women in a university hospital were asked to participate. Nine patients with previously diagnosed ductal carcinoma-in-situ (DCIS) or invasive breast cancer who were about to undergo mastectomy under general anaesthesia agreed. After the patient was asleep but before the operation, we spent 15 minutes cannulating their ducts, obtaining washings, and attempting endoscopy. The ducts that had been cannulated were marked by instillation of dye or other materials, the nipple was sutured shut, and the mastectomy proceeded as planned. The mastectomy specimen underwent extensive histopathological examination. FINDINGS: We were successful in intraductal cannulation and endoscopy in seven of the nine patients. In five of the nine, we obtained epithelial cells in the washings. In one the cells were consistent with proliferative disease, in three there was atypical epithelium, and in one there was frank DCIS. With several different contrast materials injected into separate duct orifices, DCIS was confined to a single duct system. INTERPRETATION: We found that the intraductal approach is feasible for the study of the early changes of breast cancer Technical difficulties include identification of the breast duct orifices, determining the distensibility of the duct, and developing a reliable technique to obtain washings.

Lipomatous pseudomass of the breast: diagnosis suggested by discordant palpatory and mammographic findings.

Focal fat collections or lipomas in the breast occasionally present as dominant palpable masses. A retrospective review was done of tissue obtained from 14 breast biopsies performed on the basis of palpatory findings; the specimens consisted almost entirely of fat. Preoperative mammograms were available in nine of these women and all showed the breasts to be composed largely of fat. In three patients there was virtually complete replacement of breast tissue by fat. In selected patients with fatty replacement of breast parenchyma, discordant palpatory and mammographic findings should suggest the diagnosis of a fatty mass or pseudomass and possibly obviate biopsy for purposes of tissue diagnosis.

Postnatal epiphyseal development: the distal tibia and fibula.

At birth, the distal tibial physis is a transverse structure. However, as the tibia enlarges diametrically and the epiphyseal ossification center matures, the physis becomes increasingly undulated, with peripheral lappet formation. The anteromedial area is the first to develop undulation (Poland's hump). This should not be misinterpreted as an injury or premature epiphyseodesis subsequent to trauma. The tibial secondary ossification center forms within the central epiphysis. The medial margin is irregular and may have peripheral foci of ossification. Between the ages of 7 and 8 years, this secondary center extends into the medial malleolus, reaching the distal tip during adolescence. The malleolar tip may develop accessory ossification. Physiologic epiphyseodesis begins over the medial malleolus and then extends laterally, a pattern of closure that affects fracture patterns (e.g., the fracture of Tillaux). The distal fibular physis also begins as a transverse structure that becomes undulated and has extensive peripheral lappet formation. This physis usually becomes level with the articular surface of the distal tibia after the first year. Enchondromalike extensions of the physis into the metaphysis are common. Accessory ossification may develop at the distal end.

Operative treatment of congenital pseudarthrosis of the clavicle.

Eight children were treated operatively with resection of fibrous pseudarthrosis and sclerotic bone ends, careful dissection and preservation of the periosteal sleeve to maintain continuity, and approximation of bone ends. None had additional bone grafts or internal fixation. All had bridging ossification 6-8 weeks postoperatively, and all were solidly healed by 14 weeks after surgery. Follow-up has ranged from 2 to 14 years, with no evidence of recurrence. Remodeling of the prominence occurred slowly in 2-5 years, with the distal clavicle variably underdeveloped in all patients. Early resection of fibrous pseudarthrosis probably does not require the extensive grafting and internal fixation that has been recommended for older children.