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C Reynolds

Publications and source records attributed to C Reynolds.

At least 37 records · Page 2Linked to original sources
PubMed2001

Influence of hepatic impairment on everolimus pharmacokinetics: implications for dose adjustment.

OBJECTIVE: We assessed the influence of hepatic impairment on the pharmacokinetics of the immunosuppressant everolimus to provide dose recommendations for clinical use. METHODS: In this open-label, single-dose, case-control study, 8 subjects with liver cirrhosis classed as moderate hepatic impairment (Child-Pugh score, 7-9) and 8 demographically matched healthy control subjects received a single oral 2-mg dose of everolimus. Routine safety assessments were made, and blood samples were taken for determination of everolimus concentrations and protein binding. RESULTS: The apparent clearance of everolimus was significantly reduced by 53% in subjects with moderate hepatic impairment compared with healthy subjects (9.1 +/- 3.1 versus 19.4 +/- 5.8 L/h). This was manifested by a 115% higher area under the blood concentration-time curve (AUC) (245 +/- 91 versus 114 +/- 45 ng. h/ml) and 84% prolonged half-life (79 +/- 42 versus 43 +/- 18 hours) in subjects with hepatic impairment. The rate of absorption of everolimus was not altered by hepatic impairment on the basis of the maximum blood concentration (C(max)) and time to reach C(max) (t(max)). Protein binding was similar in the two groups (73.8% +/- 3.6% versus 73.5% +/- 2.4%). A significant positive correlation of the everolimus AUC with bilirubin level (r = 0.86) and a significant negative correlation with albumin concentration (r = 0.72) was observed. CONCLUSIONS: The dose of everolimus should initially be reduced by half in patients with mild and moderate hepatic impairment on the basis of the Child-Pugh classification. Therapeutic monitoring would be a helpful adjunct to subsequent titration of everolimus exposure in this subpopulation. Everolimus has not been assessed in patients with severe hepatic impairment.

Adult↗
PubMed2000

The caM kinase, Pnck, is spatially and temporally regulated during murine mammary gland development and may identify an epithelial cell subtype involved in breast cancer.

While screening for protein kinases expressed in the murine mammary gland, we identified previously a Ca2+/calmodulin-dependent kinase, Pnck, that is most closely related to CaMKI. In this report, we show that Pnck is temporally regulated during murine mammary development with highest levels of expression observed late in pregnancy, concomitant with the decreased cellular proliferation and terminal differentiation of the mammary epithelium. Consistent with this finding, Pnck is up-regulated in confluent mammary epithelial cells and is down-regulated as serum-starved cells are stimulated to reenter the cell cycle. In the mammary gland, Pnck is expressed in an epithelial-specific and markedly heterogeneous manner, suggesting that the expression of this kinase may be restricted to a particular mammary epithelial cell type. Potentially related to its heterogeneous in vivo expression pattern, Pnck expression is oncogene-associated in murine epithelial cell lines derived from mammary tumors arising in different transgenic mouse models of breast cancer; cell lines derived from mammary tumors initiated by c-myc or int-2/Fgf3 express Pnck, whereas cell lines initiated by neu or H-ras do not. In an analogous manner, expression of the human homologue of Pnck is restricted to a subset of human breast cancer cell lines. Moreover, PNCK was found to be highly overexpressed in a subset of human primary human breast cancers compared with benign mammary tissue. Together, our data suggest that Pnck may play a role in mammary development, and that expression of this kinase may be restricted to a mammary epithelial cell type that is transformed in a subset of human breast cancers.

Animals↗
PubMed2000

Anti-CD20 chimeric monoclonal antibody treatment of refractory immune-mediated thrombocytopenia in a patient with chronic graft-versus-host disease.

BACKGROUND: Autoimmune thrombocytopenia in chronic graft-versus-host disease may represent an instance of B-cell dysregulation leading to clinical disease. OBJECTIVE: To attempt to treat refractory immune-mediated thrombocytopenia in a patient with chronic graft-versus-host disease by using anti-CD20 chimeric monoclonal antibody. DESIGN: Case report. SETTING: Academic medical center. PATIENT: A patient with chronic graft-versus-host disease after allogeneic peripheral blood stem-cell transplantation who had severe refractory immune-mediated thrombocytopenia. INTERVENTION: Weekly infusion of rituximab, 375 mg/m2, for 4 weeks. MEASUREMENTS: Platelet count, CD3+ cell count, and CD19+ cell count. RESULTS: Rituximab therapy resulted in marked depletion of B cells in the peripheral blood and decreased levels of platelet-associated antibody. The increase in platelet count persisted despite tapering and discontinuation of immunosuppressive therapy for chronic graft-versus-host disease. CONCLUSION: The efficacy of rituximab for the treatment of immune-mediated thrombocytopenia suggests that this drug may have activity in other autoimmune diseases or chronic graft-versus-host disease.

Adult↗
PubMed2000

Accuracy of sentinel lymph node biopsy in patients with large primary breast tumors.

BACKGROUND: Patients with large breast tumors are increasingly undergoing neoadjuvant treatment to downstage local disease; however, accurate staging of the axilla before the initiation of chemotherapy remains problematic. In the current study, the authors report on the accuracy of sentinel lymph node (SLN) biopsy in such patients to determine the feasibility of applying this technique before induction chemotherapy. METHODS: One hundred three patients with 104 tumors classified as American Joint Committee on Cancer (AJCC) T2 (tumor >/= 2 cm but </= 5 cm) or larger were recruited at the University of Pennsylvania and the Mayo Clinic. In the majority of cases, combined blue dye and radiotracer was used for SLN identification. After SLN identification, a completion axillary lymph node dissection was performed in 87 cases. The SLN was evaluated with hematoxylin and eosin and immunohistochemistry. RESULTS: The SLN was identified in 99% of cases. The overall rate of lymph node metastasis was 59% (95% exact confidence interval [95% CI], 49-68%) (61 of 104 cases). The SLN false-negative rate was 2% (95% exact CI, < 1-11.5%) (2 patients). In 56 tumors >/= 3 cm, 1 false-negative result (2% [95% exact CI, < 1-15%]) was identified, and the rate of lymph node metastasis was 62.5% (95% exact CI, 48. 5-75%) (35 of 56 tumors). Within 30 SLN positive patients with tumors >/= 3 cm and complete axillary lymph node dissection, 3 of 8 patients (37.5% [95% exact CI, 8.5-75.5%]) with micrometastasis (</= 2 mm) to the SLN had positive non-SLN compared with 21 of 22 patients (95.5% [95% exact CI, 77-100%]) with macrometastasis (> 2 mm) to the SLN (P = 0.002). CONCLUSIONS: SLN biopsy for patients with large breast tumors is technically feasible and highly accurate. SLN biopsy should be considered for the staging of clinically negative axilla in patients scheduled to receive neoadjuvant chemotherapy.

Adult↗
PubMed2000

Losses of the tumor suppressor BIN1 in breast carcinoma are frequent and reflect deficits in programmed cell death capacity.

Oncogenic activation of MYC occurs often in breast carcinoma and is associated with poor prognosis. Loss or inactivation of mechanisms that restrain MYC may therefore be involved in tumor progression. In this study, we show that the MYC-interacting adaptor protein BIN1 is frequently missing in malignant breast cells and that this loss is functionally significant. BIN1 was expressed in normal and benign cells and tissues but was undetectable in 6/6 estrogen receptor-positive or estrogen receptor-negative carcinoma cell lines examined. Similarly, complete or partial losses of BIN1 were documented in 30/50 (60%) cases of malignant breast tissue analyzed by immuno-histochemistry or RT-PCR. Abnormalities in the organization of the BIN1 gene were apparent in only a minority of these cases, suggesting that most losses were due to epigenetic causes. Nevertheless, they were functionally significant because ectopic BIN1 induced programmed cell death in malignant cells lacking endogenous BIN1 but had no effect on the viability of benign cells. We propose that loss of BIN1 may contribute to breast cancer progression by eliminating a mechanism that restrains the ability of activated MYC to drive cell division inappropriately.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Intercellular adhesion molecule expression in ductal carcinoma of the breast: correlation of immunohistochemical staining with cytologic smear pattern.

Recent studies suggest that altered expression of intercellular adhesion molecules (ICAM) in ductal carcinoma of the breast is associated with a higher incidence of metastases and decreased patient survival. In addition, the presence of significant cellular dyscohesion in cytologic smear preparations has been found to correlate with the presence of regional and distant metastases in a subset of patients. In this study, we correlate the smear pattern in preparations taken directly from surgically excised breast tumors with their immunohistochemical staining pattern, using antibodies directed against a panel of ICAM. We found excellent correlation, as all three tumors with an extremely high degree of tumor cell cohesion showed strong staining with all ICAM antibodies in the vast majority (>/=90%) of tumor cells in corresponding tissue sections. In contrast, five tumors displaying a largely dyscohesive smear pattern demonstrated decreased staining (</=70% of tumor cells) with at least one of the ICAM antibodies used. Tumors with intermediate degrees of cellular cohesion in smear preparations showed varied patterns of ICAM staining. These findings support the theory that loss of ICAM expression represents the physiologic basis for patterns observed in cytologic smears of ductal carcinoma of the breast.

Adult↗
PubMed2000

Active macromolecule uptake by lymph node antigen-presenting cells: a novel mechanism in determining sentinel lymph node status.

BACKGROUND: Although sentinel lymph node (SLN) biopsy is a powerful staging tool for patients with melanoma and breast cancer, controversy remains regarding specific aspects of technique. We examined particle uptake by antigen-presenting cells (APCs) to determine if this mechanism is responsible for the differential retention of radioactivity in SLNs relative to nonsentinel lymph nodes (NSLNs). METHODS: Mapping was conducted in pigs injected with vital blue dye, fluoroscein isothiocyanate-labeled human serum albumin (FITC-HSA), and one of two 99mtechnetium-labeled tracers, i.e., human serum albumin, a small macromolecule, or unfiltered sulfur colloid, a mixture of small and large particles. Macromolecule uptake by APCs was studied in vitro by using FITC-HSA and measured by fluorescence-activated cell sorting (FACS). SLNs and NSLNs were analyzed by fluorescence microscopy or FACS, with counterstaining for leukocyte cell surface markers. RESULTS: Both radiotracers were effective. Cultured APCs rapidly took up FITC-HSA. Microscopy showed FITC-HSA in the subcapsular sinus of SLNs shortly after injection and subsequent distribution to interfollicular areas. FACS revealed increasing amounts of FITC-HSA in SLNs over time. Cells responsible for uptake were APCs, expressing major histocompatibility (locus) class II. CONCLUSIONS: This report establishes active macromolecule uptake as a mechanism that determines SLN status. This mechanism has important implications for performing SLN biopsy.

Animals↗
PubMed2000

MR imaging in patients with nipple discharge: initial experience.

PURPOSE: To investigate the potential of magnetic resonance (MR) imaging in patients with nipple discharge. MATERIALS AND METHODS: Between February 1992 and December 1998, 23 patients with nipple discharge underwent contrast material-enhanced MR imaging at 1.5 T. Mammographic findings were negative in 22 of 23 patients and revealed asymmetry in one patient. Galactography was attempted in two patients, with negative findings in one patient and no success in the other. Fifteen of 23 patients underwent excisional biopsy-seven of 15 with MR imaging-guided localization, and one of 15 with mammographic localization. Eight of 23 patients were followed up clinically (range, 7-24 months; mean, 20 months). RESULTS: In 11 of the 15 (73%) patients who underwent excisional biopsy, MR imaging findings correlated with histopathologic findings. MR imaging demonstrated four of six benign papillomas and one of two fibroadenomas as circumscribed, enhancing subareolar masses. Findings of one MR imaging examination were negative, and benign tissue was found at excisional biopsy. MR imaging findings were suspicious in six of the seven patients with excisional biopsy findings of malignancy (regional enhancement [n = 2], ductal enhancement [n = 2], peripherally enhancing mass [n = 1], and spiculated mass [n = 1]). In one of the seven patients, a benign-appearing intraductal mass was identified at MR imaging; excisional biopsy revealed a benign papilloma with an adjacent focus of DCIS. CONCLUSION: MR imaging can help identify both benign and malignant causes of nipple discharge. It potentially offers a noninvasive alternative to galactography.

Adult↗
PubMed2000

Adaptation and survival of surface-deprived red blood cells in mice.

The consequences of lost membrane area for long-term erythrocyte survival in the circulation were investigated. Mouse red blood cells were treated with lysophosphatidylcholine to reduce membrane area, labeled fluorescently, reinfused into recipient mice, and then sampled periodically for 35 days. The circulating fraction of the modified cells decreased on an approximately exponential time course, with time constants ranging from 2 to 14 days. The ratio of volume to surface area of the surviving cells, measured using micropipettes, decreased rapidly over the first 5 days after infusion to within 5% of normal. This occurred by both preferential removal of the most spherical cells and modification of others, possibly due to membrane stress developed during transient trapping of cells in the microvasculature. After 5 days, the cell area decreased with time in the circulation, but the ratio of volume to surface area remained essentially constant. These results demonstrate that the ratio of cell volume to surface area is a major determinant of the ability of erythrocytes to circulate properly.

Adaptation, Physiological↗
PubMed2000

Quantitative vascularity of breast masses by Doppler imaging: regional variations and diagnostic implications.

Seventy-four biopsy proven breast masses were imaged by color and power Doppler imaging to evaluate vascular pattern of malignant and benign breast masses. The images were analyzed for vascularity. The measurements were made over the entire mass as well as regionally at its core, at its periphery, and in the tissue surrounding it. The surgical specimens were analyzed for microvessel density. The diagnostic performance of Doppler sonographic vascularity indices was evaluated by receiver operating characteristic analysis. The malignant masses were 14 to 54% more vascular than the benign masses. Both types of masses were more vascular by ultrasonography than the tissue surrounding them. Whereas benign masses were 2.2 times more vascular than the surrounding tissue, the malignant masses were 5.0 times more vascular. In a subset of patients the regional vascularity at the core, periphery, and surrounding tissue by Doppler imaging exhibited a strong correlation (R2 > 0.9) with the corresponding histologic microvessel density measurements. Although the malignant masses exhibited a strong gradient in vascularity, core > periphery > surrounding tissue, the benign masses had relatively uniform distribution of vascularity. The area under the receiver operating characteristic curve (A(Z)) for the Doppler indices ranged from 0.56 +/- 0.07 to 0.65 +/- 0.07. A nonlinear analysis including age-specific values of Doppler indices improved the diagnostic performance to A(Z) = 0.85 +/- 0.06. In conclusion, quantitative Doppler imaging when used in combination with a nonlinear rule-based approach has the potential for differentiating between malignant and benign masses.

Adult↗
PubMed1999

Breakpoints of the t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma lie within or near the previously undescribed gene MALT1 in chromosome 18.

Lymphomas arising in mucosa-associated lymphoid tissue (MALT) are indolent B-cell tumors that have a predilection for epithelial sites and often develop in a setting of chronic inflammation or autoimmunity. As many as 50% of low-grade MALT lymphomas contain an (11;18)(q21; q21) chromosomal translocation. Using fluorescence in situ hybridization, we have analyzed the position of recombination within chromosome 18 DNA in three examples of MALT lymphoma bearing this translocation. In all three cases, the breakpoint maps to DNA in BAC b357H2, covering about 150 kb of sequence. A previously undescribed, ubiquitously expressed gene, which we refer to as MALT1, was identified within this sequence and was found to be broken in one case for which we have definitively located the position of recombination between chromosomes 18 and 11. The sequence of this gene indicates the presence of two immunoglobulin-like C2 domains and a region of partial homology to caspases, suggesting a possible role for MALT1 in the regulation of apoptosis.

Amino Acid Sequence↗
PubMed1999

Inhibition in the human motor cortex is reduced just before a voluntary contraction.

OBJECTIVE: To examine inhibition in the human motor cortex before and during voluntary movements. METHODS: The balance between the excitation and inhibition of corticospinal neurons in the human motor cortex was tested by conditioning the motor evoked potentials (MEP) evoked in forearm muscles by transcranial magnetic stimulation with a preceding subthreshold stimulus delivered through the same coil. RESULTS: When normal individuals (n = 9) made a tonic wrist extension, inhibition of the forearm extensor MEP decreased, whereas that of the forearm flexors was unchanged. When these individuals made a tonic wrist flexion, inhibition of the forearm flexor MEP diminished, whereas that of the forearm extensors was unchanged. When normal individuals (n = 10) made a phasic wrist extension in response to an auditory signal, inhibition of the extensor MEP began to decline about 95 msec before the onset of the agonist EMG activity. CONCLUSIONS: The changes in balance of excitation and inhibition of corticospinal neurons associated with a voluntary movement precede the movement and are directed at the corticospinal neurons projecting to the agonists. These changes may help to select the population of cortical neurons responsible for the movement.

Action Potentials↗
PubMed1999

Outcomes in breast cancer patients relative to margin status after treatment with breast-conserving surgery and radiation therapy: the University of Pennsylvania experience.

PURPOSE: To evaluate the significance of final microscopic resection margin status on treatment outcomes in women with early breast cancer who are treated with breast-conserving surgery and definitive breast irradiation. METHODS AND MATERIALS: An analysis was performed of 1021 consecutive women with clinical Stage I or II invasive carcinoma of the breast treated with breast-conserving surgery and definitive breast irradiation. Complete gross excision of tumor was performed in all cases, and an axillary staging procedure was performed to determine pathologic axillary lymph node status. The 1021 patients were divided into four groups based on the final microscopic margin from the tumor excision or from the re-excision if performed. These four groups were: (a) 518 patients with negative margins; (b) 124 patients with focally positive margins; (c) 96 patients with focally close margins (< or = 2 mm); and (d) 283 patients with unknown margins. RESULTS: Local failure was not significantly different in patients with negative, focally positive, focally close or unknown final pathologic margins of resection at 8 years (8% vs. 10% vs. 17% vs. 16%, respectively, p = 0.21). The 8-year outcome also was not different among the four groups for overall survival (86% vs. 83% vs. 88% vs. 81%, respectively, p = 0.13), cause-specific survival (89% vs. 86% vs. 88% vs. 83%, respectively, p = 0.14), no evidence of disease survival (81% vs. 73% vs. 86% vs. 77%, respectively, p = 0.09), and freedom from distant metastases (85% vs. 75% vs. 86% vs. 79%, respectively, p = 0.08). CONCLUSION: These results demonstrate that selected patients with focally positive or focally close microscopic resection margins can be treated with breast-conserving surgery and definitive breast irradiation with 8-year local control rates and survival rates that are similar to those seen in breast-conservation patients with negative or unknown final resection margins.

Adult↗
PubMed1999

Immunohistochemistry with pancytokeratins improves the sensitivity of sentinel lymph node biopsy in patients with breast carcinoma.

BACKGROUND: Sentinel lymph node (SLN) biopsy is being investigated as a staging procedure for breast carcinoma. The authors evaluated whether immunohistochemical (IHC) analysis improves the sensitivity of this procedure. METHODS: Forty-four women with breast carcinoma were recruited for SLN biopsy. Preoperative lymphoscintigraphy was followed by intraoperative localization using a handheld gamma probe and blue dye. After SLN identification, an immediate complete axillary lymph node dissection was performed in all patients. All lymph nodes were subjected to routine histology (hematoxylin and eosin [H&E]) and IHC using antibody to cytokeratins. RESULTS: The SLN was identified in 41 of 43 patients (95%). Successful SLN identification was independent of biopsy technique (open surgical [95%] vs. fine-needle aspiration/core needle biopsy [96%]). Twelve of 41 patients (29%) had evidence of lymph node metastasis in the SLN by routine histology. Of the twenty-nine patients with H&E negative SLN, 3 were found to have metastasis by IHC for a conversion rate of 10%. Fifteen of 41 patients (37%) had evidence of metastasis in SLN. All 26 patients with H&E and IHC negative SLN had negative nonsentinel lymph nodes by routine histology and IHC (100% negative predictive value). All patients with tumors < 2 cm and micrometastasis to the SLN had no additional lymph node disease, in contrast to patients with lesions > 2 cm or patients with macrometastasis to the SLN (P = 0.007). CONCLUSIONS: These results confirm that SLN biopsy is extremely accurate for patients with breast carcinoma, even after open surgical biopsy. IHC analysis or serial sectioning of SLN improves the sensitivity of this staging technique.

Adult↗
PubMed1999

On the focal nature of inhibition and facilitation in the human motor cortex.

OBJECTIVE: To find the area of the human cortex from which inhibition and facilitation of corticospinal neurons could be obtained. METHODS: A patient with seizures had an array of 64 electrodes placed over the left fronto-temporal cortex. The motor evoked potential (MEP) elicited by stimulating through one pair of electrodes was conditioned by stimuli that were subthreshold for a MEP given through adjacent pairs of electrodes. RESULTS: The MEP recorded over the right abductor pollicis brevis produced by stimulating over the hand area of the left cortex could be inhibited (at intervals less than 5 ms) and facilitated (at intervals greater than 5 ms) by subthreshold conditioning stimuli delivered through neighbouring pairs of electrodes. The inhibition and facilitation were only obtained when the conditioning stimuli were delivered within 1-2 cm of the test site. The sites producing inhibition and facilitation were not identical. Conditioning stimuli over the face area did not inhibit the MEP produced by stimulating the hand area or vice versa. CONCLUSION: The inhibition and facilitation of corticospinal neurons projecting to a given muscle arise from small areas close to those corticospinal neurons.

Electric Stimulation↗
PubMed1999

Sampling of grossly benign breast reexcisions: a multidisciplinary approach to assessing adequacy.

The widespread use of breast-conserving therapy in the treatment of early-stage breast cancer has resulted in increasing numbers of reexcision specimens requiring histologic assessment for residual disease and margin status. Because many reexcisions are performed for only microscopically positive or close margins, reexcision specimens often appear grossly negative and directed tissue sampling cannot be performed. The issue of adequate sampling in these specimens has not been addressed in the literature. A multidisciplinary approach to identifying the clinically important lesions in breast reexcisions and a cost-effective approach to tissue sampling are needed. We reviewed 97 consecutive cases of grossly negative breast reexcisions in which all tissue had been embedded. Forty-seven specimens contained residual invasive or in situ carcinoma and 50 were histologically negative. Detailed histologic findings were presented to a medical oncologist, a radiation oncologist, and a surgeon, who assessed the clinical impact of each diagnosis. Of the 47 positive specimens, 30 resulted in a major change in patient management (recommendation for additional surgery), 10 resulted in minor changes (alteration in radiation dose or adjuvant chemotherapy regimen), and 7 did not alter management. A total of 1867 blocks were submitted. If one block per centimeter of maximal tissue dimension had been submitted and the remainder of the specimen examined only if initial sections revealed invasive or in situ carcinoma, then 901 blocks would have been processed (52% reduction), but we would have missed an average of 3.7 cases resulting in a major change in therapy, and 3.3 cases resulting in a minor change. In contrast, two blocks per centimeter would have missed an average of less than one case each of diagnoses resulting in major and minor therapy changes (0.9 and 0.8 cases, respectively), and 315 (17%) fewer tissue blocks would have been processed. We recommend submitting two blocks per centimeter in grossly benign reexcisions, and examining the remainder of the tissue only if carcinoma is detected on initial sections.

Adult↗
PubMed1999

Histopathologic effects of radiofrequency catheter ablation in previously infarcted human myocardium.

INTRODUCTION: The use of catheter-based radiofrequency (RF) ablation for the treatment of ventricular tachyarrhythmias due to previous myocardial infarction has been steadily increasing. The histopathologic changes caused by this technique are not well described in humans. METHODS AND RESULTS: Three patients with hemodynamically tolerated ventricular tachycardias (VTs) due to previous myocardial infarction underwent endocardial mapping and catheter based RF ablation. All patients received between 5 and 11 RF lesions each of 60-second duration. One patient underwent myocardial resection of a left ventricular aneurysm 1 day following RF ablation, one expired 7 days after RF ablation, and one expired 9 months after RF ablation. None of the deaths occurred as a result of RF ablation. Pathologic specimens obtained early after RF ablation revealed areas of focal acute inflammation and fibrin deposition. Later specimens revealed several focal areas of fibrosis and granulation tissue. Specimens obtained late after RF ablation revealed a dense band of fibrosis, measuring 17 x 17 x 5 mm (1,250 mm3). CONCLUSION: Catheter-based RF ablation of ischemic VT in humans causes lesions that initially resemble coagulation necrosis. This is followed by the development of an inflammatory infiltrate and, finally, the development of fibrosis. Repeated application of RF ablation may result in much larger lesions than have been previously reported.

Aged↗