Salivary gland progenitor cell biology provides a rationale for therapeutic salivary gland regeneration.

An irreversible loss of salivary gland function often occurs in humans after removal of salivary tumors, after therapeutic radiation of head and neck tumors, as a result of Sjögren's syndrome and in genetic syndromes affecting gland development. The permanent loss of gland function impairs the oral health of these patients and broadly affects their quality of life. The regeneration of functional salivary gland tissue is thus an important therapeutic goal for the field of regenerative medicine and will likely involve stem/progenitor cell biology and/or tissue engineering approaches. Recent reports demonstrate how both innervation of the salivary gland epithelium and certain growth factors influence progenitor cell growth during mouse salivary gland development. These advances in our understanding suggest that developmental mechanisms of mouse salivary gland development may provide a paradigm for postnatal regeneration of both mice and human salivary glands. Herein, we will discuss the developmental mechanisms that influence progenitor cell biology and the implications for salivary gland regeneration.

Effect of quinidine on differing sensitivities of Purkinje fibers and myocardium to inhibition of monovalent cation transport by digitalis in dogs.

Studies have implicated quinidine in increasing serum digoxin levels, resulting in serious arrhythmias. Arrhythmias caused by digitalis intoxication are thought to originate in Purkinje fibers. Thus, the extent of inhibition of monovalent cation-active transport in Purkinje fibers and myocardium may explain the enhanced toxicity of the combined administration of digoxin and quinidine. Monovalent cation transport was assessed by measuring the uptake of the potassium analog rubidium in samples of myocardium and Purkinje fibers after in vitro exposure to ouabain and after long-term administration of digoxin and quinidine or digoxin alone. A group of dogs received chronic digoxin administration and achieved a steady-stage digoxin administration and achieved a steady-stage digoxin level of 2.1 +/- 0.3 ng/ml. Quinidine administered intravenously caused a 134% increase in the serum digoxin level. The transport in myocardium was unchanged, while it was reduced to 40% of control levels in Purkinje fibers. The difference in sensitivity between Purkinje fibers and myocardium may explain the finding that digitalis-toxic arrhythmias arise in Purkinje fibers and that quinidine, when combined with digitalis, increases the incidence of such arrhythmias.

Parasympathetic innervation maintains epithelial progenitor cells during salivary organogenesis.

The maintenance of a progenitor cell population as a reservoir of undifferentiated cells is required for organ development and regeneration. However, the mechanisms by which epithelial progenitor cells are maintained during organogenesis are poorly understood. We report that removal of the parasympathetic ganglion in mouse explant organ culture decreased the number and morphogenesis of keratin 5-positive epithelial progenitor cells. These effects were rescued with an acetylcholine analog. We demonstrate that acetylcholine signaling, via the muscarinic M1 receptor and epidermal growth factor receptor, increased epithelial morphogenesis and proliferation of the keratin 5-positive progenitor cells. Parasympathetic innervation maintained the epithelial progenitor cell population in an undifferentiated state, which was required for organogenesis. This mechanism for epithelial progenitor cell maintenance may be targeted for organ repair or regeneration.

Perlecan: how does one molecule do so many things?

Perlecan is a large multi-domain extracellular matrix proteoglycan that plays a crucial role in tissue development and organogenesis. In vertebrates, perlecan functions in a diverse range of developmental and biological processes, from the establishment of cartilage to the regulation of wound healing. How can a single molecule modulate such a wide variety of processes? We suggest that perlecan employs the same basic mechanism, based on interactions with growth factors, morphogens and matrix proteins, to regulate each of these processes and that the local extracellular environment determines the function of perlecan and consequently its downstream effects on the structure and function of the organ. We discuss this hypothesis in relation to its role in three major vertebrate developmental processes: angiogenesis, chondrogenesis and endochondral ossification.

Tumor hormone receptor status and recurrences in premenopausal patients with node-negative breast carcinoma.

To ascertain the prognostic significance of tumor hormone receptor status in premenopausal patients with node-negative breast cancer, a retrospective review of 199 patients who met these criteria was conducted. Of these 199 patients, estrogen receptor (ER) data were available for 147. One hundred four patients (71%) had ER-negative disease and 22 (21%) exhibited local or distant recurrence with a median follow-up time of 85.4 months. Thirteen patients in this group had died of breast cancer. Of the 43 patients who had ER-positive disease, 5 (12%) had recurrences and 2 died of breast cancer. After observing patients for a longer period of time (median follow-up time, 85.4 months), no statistically significant differences in disease-free survival (DFS) or overall survival (OS) were demonstrated. However, as seen in our first analysis of this group at 45 months, tumor size after a median follow-up time of 85.4 months continues to have significant prognostic implications, regardless of ER status.

The transition to a nursing home: meeting the family's needs. Family members face their own transition when a loved one enters a nursing home.

The lack of preparation for the experience of admission to a nursing home, as represented by these family members, indicates there is a need for nursing interventions targeted to the family before the admission of a loved one to the nursing home. The program could address information and problem solving, as well as provide emotional support. The day of admission is too late to prepare for this experience. Access to families occurs before any admission to LTCFs. Nurses in acute care and home care are in a position to inform, assist, and advocate for families in this decision-making and admission process. The family members we questioned have provided some of the content for an educational preparation program that may be useful to all families. The responses also indicate that each family will have its own concerns and functional relationships that would alter specific content. Maslow's framework could aid the identification of needs and direct the specific interventions to empower the family to cope with this transition. A few guidelines have been suggested in this article to stimulate discussion about the family's transition to the nursing home. Appraisal of a family's perceptions about the use of nursing homes may alert the nurse to potential conflicts and areas of uncertainty. These assessments provide direction for family interventions that may alleviate the extent of uncertainty and conflict before the admission and serve as ongoing family-centered activity in the nursing home. The view of this experience as a family transition also supports the concept of continuity of care through nursing interventions.

Clinical recognition and management of depression in node negative breast cancer patients treated with tamoxifen.

Depression is not an uncommon complaint of women with breast cancer and is usually assumed to be related to the cancer diagnosis itself or its treatment. As part of a prospective clinical trial of adjuvant therapy of node negative breast cancer, 301 patients treated and assessed by one oncologist (SEJ) were serially questioned for symptoms of depression in the first 6-12 months after completing initial treatment (surgery, radiation therapy, and/or chemotherapy). Two hundred and fifty-seven patients were evaluable for assessment of depression; 155 were receiving tamoxifen and 102 were not. Twenty-six patients had symptoms of depression including 23 (15%) treated with tamoxifen compared to 3 (3%) in the group not placed on tamoxifen (p < 0.005). Of the 23 patients with depression in the tamoxifen group, symptoms were temporally related to the initiation of therapy and occurred generally in the first 2 months of treatment. Eight patients had mild symptoms not requiring a dose reduction, 8 had significant depression requiring a dose reduction to relieve symptoms, and 7 required discontinuation of tamoxifen. We conclude that clinical depression as a side effect of tamoxifen therapy may be more common than previously believed and should be further rigorously investigated to confirm or deny our clinical impressions.

Phase I trial of adjuvant chemotherapy with cyclophosphamide, epirubicin and 5-fluorouracil (CEF) for stage II breast cancer.

Epirubicin is a new anthracycline with a potentially more favorable toxicity profile than the parent compound, doxorubicin. Accordingly, the feasibility and toxicity of 6 courses of adjuvant chemotherapy with cyclophosphamide (C), epirubicin (E), and 5-fluorouracil (F) were assessed in 10 patients with Stage 2 (node positive) breast cancer. Doses of C and F were 600 mg/m2 and E was 75 mg/m2. Moderate granulocytopenia (median count = 610/mm3) occurred on day 14 of the first 21 day treatment course and was the main toxicity encountered with treatment, although there were no episodes of granulocytopenic fever. Grade 3 or 4 vomiting occurred in 40% and significant alopecia in 30% of patients. Four patients experienced transient asymptomatic decreases in calculated radionuclide cardiac ejection fraction of greater than or equal to 10% but no signs or symptoms of cardiac failure were observed. If epirubicin proves to be less cardiotoxic than doxorubicin, this combination would merit further evaluation as potential adjuvant therapy for early breast cancer.

Evaluation of neoadjuvant chemotherapeutic response of locally advanced breast cancer by magnetic resonance imaging.

BACKGROUND: The implementation of new treatment protocols for locally advanced breast cancer is currently limited by inaccurate evaluation of response to neoadjuvant chemotherapy. A recently developed dedicated breast magnetic resonance imaging (MRI) method (RODEO MRI) was evaluated as a tool for determining tumor response and extent of residual disease after neoadjuvant chemotherapy. METHODS: Thirty-nine patients with Stage II, III, or IV breast carcinoma were prospectively evaluated prior to and following neoadjuvant chemotherapy by MRI, physical examination, and mammography. Assessment of response determined by the three methods was compared. In addition, detailed pathologic correlation of residual disease was determined by serial sectioning of 31 mastectomy specimens from 30 patients. Nine patients had breast conservation, and were included in the response evaluation only. Estimates of tumor response were made by both surgical and medical oncologists. Independent interpretations of MRI studies without knowledge of clinical response were made by three radiologists. RESULTS: The surgical oncologists assessed complete response (CR), partial response (PR), and no response (NR) in 11, 22, and 7 cases, respectively. The medical oncologists assessed CR, PR, and NR in 12, 21, and 7 cases, respectively. The surgical and medical oncologists' clinical assessment of response agreed with the results of MRI in 52% and 55% of cases, respectively, and with each other in 30 of 40 cases (75%). Mammography correlated with MRI response in only 52% of cases. However, MRI accurately predicted the pathologic determination of residual disease in 30 of 31 cases (97%). There was no disagreement in the assessments of residual disease or response among the three radiologists. CONCLUSIONS: RODEO breast MRI accurately estimates residual disease after induction chemotherapy. It assesses response to neoadjuvant chemotherapy better than traditional methods of physical examination or mammography. The information obtained from this MRI technique may be used as an objective tool during clinical trials, and to select patients better for breast conservation after neoadjuvant chemotherapy for locally advanced disease.

Fat-suppressed three-dimensional MR imaging of the breast.

Rotating delivery of excitation off-resonance (RODEO) is a new magnetic resonance (MR) imaging pulse sequence that uses a jump return sine excitation on fat resonance to produce fat-suppressed, T1-weighted images. New three-dimensional MR imaging techniques were used to examine 57 women with abnormalities suspicious for breast cancer. MR imaging findings were compared with those of mammography in all cases and with those of other imaging techniques when appropriate. Thirty-five specimens obtained at mastectomy were analyzed with rigorous pathologic examination that included imaging of the entire breast at 5-mm incremental sections. Histologic confirmation was obtained in 76 lesions in 47 patients. MR imaging helped detect 100% of malignant lesions, whereas mammography produced 33% false-negative findings. The use of RODEO in breast imaging is in the early investigational phases, but it has potential for supplementing mammography in the diagnosis of breast cancer.