Biomedical subjects

D L Weaver

Publications and source records attributed to D L Weaver.

At least 19 recordsLinked to original sources

PubMed1999

Limitation in gamma probe localization of the sentinel node in breast cancer patients with large excisional biopsy.

BACKGROUND: Radiolocalization and selective biopsy of the sentinel node to correctly predict the status of remaining lymph nodes may provide an alternative to axillary dissection in selected breast cancer patients with clinically negative lymph nodes. STUDY DESIGN: In a nonrandomized, multicenter clinical trial, gamma probe localization for lymphatic mapping and sentinel node biopsy along with axillary dissection was performed on 75 patients with invasive breast cancer and clinically negative lymph nodes. The accuracy of the sentinel node biopsy to correctly predict the status of the remaining axillary lymph nodes was established through standard pathologic investigation. RESULTS: A sentinel node was identified in 70 of 75 patients with a technical success rate of 93%. Of these 70 patients, 21 (30%) had axillary nodal metastases identified pathologically. Four of these 21 (19%) had sentinel nodes negative for metastases. All 4 false-negative patients had prior excisional biopsies. The false-negative group had a larger mean maximal biopsy dimension than the true-positive group. Eleven of the 21 patients with axillary metastases had a diagnosis made by core needle biopsy with no false negatives. CONCLUSIONS: The accuracy of the sentinel node biopsy in correctly predicting the status of remaining axillary lymph nodes may be limited in patients with large excision before radiolocalization of the sentinel node. Our findings suggest that excisional biopsy should be avoided prior to lymphatic mapping for sentinel node biopsy.

Adult↗

PubMed1998

Estrogen-receptor-related protein p29 in primary nonsmall cell lung carcinoma: pathologic and prognostic correlations.

BACKGROUND: Estrogen-dependent intracellular processes are important in the growth regulation of normal tissue and may play a role in the regulation of malignancies. Utilization of estrogen receptor assays in breast carcinoma is well established, but the role of such evaluation in other cancers largely is unknown. In this study, immunohistochemical expression of estrogen receptor (ER) and the ER-related protein p29 was correlated with survival of patients with nonsmall cell carcinoma of the lung. METHODS: All patients with a tissue diagnosis of primary nonsmall cell bronchogenic carcinoma diagnosed over a 6-year period at the Medical Center Hospital of Vermont were reviewed. Assays for p29 and ER using a streptavidin-biotin immunoperoxidase method were performed on each tumor. Results were correlated with clinical data, including survival. RESULTS: Of 111 tumors examined, 109 (98%) were positive for p29 whereas none of the tumors reacted with ER (ER1D5). The relation between p29 expression and survival time was different for men and women. A statistically significant negative relation for women was observed; this relation was most pronounced in patients with Stage I and II tumors. A positive but not statistically significant relation was observed for men. CONCLUSIONS: The ER-related protein p29 commonly is expressed in nonsmall cell carcinomas of the lung. The relation between p29 and survival time is different for males and females, suggesting the presence of gender specific factors that may influence tumor growth and overall patient survival, especially in patients with early stage lung carcinoma.

Adenocarcinoma↗

PubMed1998

Localization of regional lymph nodes in melanomas of the head and neck.

OBJECTIVES: To study the efficacy of gamma-probe radiolocalization of the first draining (sentinel) lymph node (SLN) in stage N0 melanoma of the head and neck and to evaluate its potential role in the staging and treatment of this disease. DESIGN: Gamma-probe radiolocalization, a new alternative to blue-dye lymphatic mapping, uses a scintillation (gamma) probe to identify radiolabeled SLNs. In a consecutive sample clinical trial, gamma-probe radiolocalization of the SLN is compared with lymphoscintigraphy and blue-dye lymphatic mapping. Follow-ups ranged from 1.7 years to 4 years, with a mean follow-up of 2.5 years. SETTING: Tertiary and private care teaching hospital. PATIENTS: Between June 1993 and November 1995, 23 patients with stage N0 intermediate-thickness melanoma of the head and neck were enrolled in this volunteer sample. INTERVENTIONS: Twenty-four hours prior to surgery, a radioactive tracer was intradermally injected around the circumference of a primary melanoma. Twelve patients also had blue dye injected just prior to surgical resection. Using a handheld gamma probe, radiolabeled lymph nodes were identified and selectively removed with minimal dissection. In patients with nodes with histologic evidence of metastases, a regional lymphadenectomy was performed. MAIN OUTCOME MEASURES: The successful identification of radiolabeled SLNs, the correlation of SLN radiolabeling to lymphoscintigraphy and blue-dye mapping, and the long-term development of regional metastases. RESULTS: Surgeons successfully resected the radiolabeled SLNs in 22 (96%) of 23 patients. The success rate of blue-dye lymphatic mapping was 8 (75%) of 12 patients and lymphoscintigraphy was 20 (91%) of 22 patients. One hundred percent of blue-stained lymph nodes were radiolabeled. The one patient in whom no SLN could be identified developed regional disease at 17 months. CONCLUSIONS: Gamma-probe radiolocalization and resection of the radiolabeled SLN is a simple and reliable method of staging regional lymph nodes and determining the need for elective lymphadenectomy.

Adult↗

PubMed1998

The early folding kinetics of apomyoglobin.

The folding pathway of apomyoglobin has been experimentally shown to have early kinetic intermediates involving the A, B, G, and H helices. The earliest detected kinetic events occur on a ns to micros time scale. We show that the early folding kinetics of apomyoglobin may be understood as the association of nascent helices through a network of diffusion-collision-coalescence steps G + H <--> GH + A <--> AGH + B <--> ABGH obtained by solving the diffusion-collision model in a chemical kinetics approximation. Our reproduction of the experimental results indicates that the model is a useful way to analyze folding data. One prediction from our fit is that the nascent A and H helices should be relatively more helix-like before coalescence than the other apomyoglobin helices.

Apoproteins↗

PubMed1998

Desmoplastic small round cell tumour of unknown primary origin with lymph node and lung metastases: histological, cytological, ultrastructural, cytogenetic and molecular findings.

Desmoplastic small round cell tumour (DSRCT) is an extremely aggressive neoplasm belonging to the family of "small round blue cell tumours", which includes primitive neuroectodermal tumour (PNET), Wilms' tumour and Ewing's sarcoma. DSRCT is considered to be a neoplasm derived from a primitive cell. It is immunohistochemically reactive with epithelial, neuronal and mesenchymal cell markers, demonstrating divergent differentiation along three cell lines. Originally thought to arise from serosal surfaces, the tumour has recently been reported in the central nervous system and ovary. The tumour in this case is a neoplasm that meets the histological, immunohistochemical, cytological and cytogenetic criteria of DSRCT; it is not associated with serosal membranes, and it has supraclavicular and axillary lymph node deposits and multiple pulmonary and brain metastases. Tumour cells from our case show cytogenetic similarities with Ewing's sarcoma and PNET. Electron microscopic findings suggest similarities between DSRCT and Wilms' tumour. Cloning and sequencing of PCR products showed in-frame fusion of EWS exon 7 to WT1 exon 8.

Adult↗

PubMed1997

Three-dimensional reconstruction by confocal laser scanning microscopy in routine pathologic specimens of benign and malignant lesions of the human breast.

Confocal laser scanning microscopy (CLSM) has become an exciting new instrument because of its increased resolution over conventional wide-field microscopy and its high performance three-dimensional (3D) optical sectioning. Although CLSM has been used extensively in cell biology, few applications have been reported in routine clinical pathology. In this study, 3D reconstruction was performed on routine formalin-fixed, paraffin-embedded tissues of normal mammary duct, simple ductal hyperplasia, intraductal papillary hyperplasia, ductal carcinoma in situ, invasive carcinoma, and lymph node metastatic carcinomas of the human breast by using computer-assisted CLSM in conjunction with a 3D reconstruction software package (microVoxel). The selected specimens were sectioned at 30 microns, mounted on glass slides, and stained with the DNA fluorescent probe, YOYO-1 iodide. The nuclear DNA and chromatin texture were clearly demonstrated after pretreatment with RNAase and hydrolysis with 2 N HCl. High quality 3D images were obtained by processing the optical section stacks with volume render and surface display parameters in microVoxel. 3D morphologic characteristics of different breast lesions were examined in various orientations by angular image rotation. The clearly benign lesions (simple ductal hyperplasia and intraductal papillary hyperplasia) revealed similar 3D morphologic features, including: (1) smooth nuclear surface and homogeneous chromatin fluorescence intensity; (2) hyperplastic cell nuclei showing similar shape and volume; and (3) clearcut margin of basement membrane defined by spindle-shaped myocytes of the ductal outer layer. In contrast, carcinomas displayed remarkably different features in 3D morphology, including: (1) irregular nuclear surface: (2) marked nuclear pleomorphism (irregular, angulated and indented shape of nuclear volume); (3) irregular and coarse chromatin texture; (4) chaotic arrangement of tumor cell nuclei; and (5) absence of myocytes, indicating no clear margin at the site of infiltration of cancer cells. In conclusion, nuclear structure, specifically demonstrated by CLSM of YOYO-1 iodide fluorescently stained cells, used in tandem with 3D volume morphologic reconstruction, may provide a useful research diagnostic tool in pathology.

Benzoxazoles↗

PubMed1997

Osteocalcin and osteonectin immunoreactivity in the diagnosis of osteosarcoma.

Osteosarcomas (OSAs) can be difficult to distinguish histologically from tumors with significantly different biologic potentials and treatment protocols. The correct diagnosis of OSA relies on identification of malignant osteoblasts that are capable of producing neoplastic bone. To determine the use of immunohistochemistry for the diagnosis of OSA, 106 tumors from the Massachusetts General Hospital and the University of Vermont were immunostained with monoclonal antiosteocalcin (OC) and antiosteonectin (ON) antibodies. They included 42 OSAs, 25 non-bone-forming sarcomas, 24 other malignant tumors including lymphomas, carcinomas, and melanomas, and 15 benign bone tumors. Cytoplasmic staining with OC showed 70% sensitivity and 100% specificity, while staining with ON showed 90% sensitivity and 54% specificity for bone-forming tumors, consistently staining cell types other than osteoblasts. Of the OSAs, 83% demonstrated matrix staining with one or both antibodies, whereas dense collagen was negative for both antibodies in all tumors. We conclude that tumor cell cytoplasmic staining with monoclonal OC may be helpful in distinguishing OSAs from other malignancies, and staining of extracellular matrix for OC and ON antibodies concurrently may help distinguish bone matrix from dense collagen.

Antibodies, Monoclonal↗

PubMed1997

Diagnostic accuracy of a rural live video telepathology system.

Accuracy of diagnoses rendered using a live video telepathology network was assessed for permanent sections of surgical pathology specimens. To determine accuracy, telepathology diagnoses were compared with those obtained by directly viewing the glass slide using a standard microscope. A total of 294 cases were read via both telepathology and glass slide by attending pathologists at a tertiary care medical center. Overall accuracy was defined as exact concordance between diagnoses. Clinically insignificant differences in diagnoses were excluded to determine clinically significant accuracy. For the 285 cases with complete data, the overall accuracy for telepathology was 0.912 (95% confidence interval [CI], 0.872-0.941), whereas the overall accuracy for glass slide readings was 0.968 (95% CI, 0.939-0.985). This difference is statistically significant (p = 0.009). When focusing on clinically significant discrepancies, where the difference in diagnosis might affect therapeutic decisions, the video accuracy was only slightly less than the glass slide accuracy (0.965 [95% CI, 0.934-0.982] vs. 0.982 [95% CI, 0.957-0.994], respectively), but this difference is not statistically significant (p = 0.302). Most of the cases with clinically significant differences involved lesions with inherently high interobserver variation. Certainty of diagnosis did not differ between video and glass slide readings (p = 0.911), but there was an association between certainty of diagnosis and diagnostic accuracy for video (p = 0.003 for clinically significant accuracies). Based on these findings, we recommend when using this telepathology system that only preliminary diagnoses should be given in the following situations: for diagnostic areas with known high interobserver variability; when the consultant has any degree of uncertainty about the presence or absence of the lesion in question; and when there is insufficient experience using telepathology as a diagnostic medium.

Crohn Disease↗

PubMed1996

A positive, systematic approach to improve inpatient medical record completion in a family practice residency program.

BACKGROUND AND OBJECTIVES: Timely completion of medical records is a concern for many reasons. For physicians, incomplete records may result in loss of hospital privileges and income and increased legal liability after entering practice. Traditionally, medical record delinquencies have been dealt with punitively. We developed a multifaceted approach to inpatient medical record completion and implemented it at our hospital. METHODS: The intervention involved posting weekly lists of physicians who were in compliance or noncompliance with medical records completion requirements, giving positive rewards (candy bars) for those who were in compliance, and increasing faculty contact with residents over issues of medical records completion. RESULTS: This approach reversed an increasing hospital record delinquency rate that had exceeded 50% and reduced the rate to 10%-30%. Residents' views of the various components of the intervention were positive. CONCLUSION: Medical records completion rates can be increased with positive, rather than punitive, measures.

Data Collection↗

PubMed1995

Minimal-access surgery for staging of malignant melanoma.

OBJECTIVE: To develop a simple, minimally invasive technique of determining whether regional node metastasis has occurred in patients with melanoma. SETTING: Teaching hospital tertiary care and private practice settings. PATIENTS: Between February 1993 and October 1994, 121 patients with invasive malignant melanoma and clinically negative lymph nodes were enrolled in this clinical trial. DESIGN: Consecutive sample clinical trial. Within 24 hours prior to lymph node resection, a radioactive tracer was injected into the dermis around the site of the primary melanoma. Forty-four patients also had blue dye injected immediately prior to surgical resection. Measurement of radioactivity in the lymph nodes and surgical localization were made using a handheld gamma detector. Radiolabeled nodes were selectively removed with the least dissection possible. In patients with pathologically positive radiolabeled nodes, regional lymphadenectomy was performed. OUTCOME MEASURES: Successful identification of radiolabeled sentinel lymph nodes, correlation of radiolabeling with injection of blue dye, and regional node recurrence rate. RESULTS: Surgeons successfully resected the radiolabeled sentinel lymph nodes in 118 (98%) of 121 patients. One hundred percent of blue-stained lymph nodes were successfully radiolabeled. Fifteen patients had pathologically positive sentinel lymph nodes. In 10 patients, the sentinel node was the only node with metastasis. Two systemic and one regional node recurrences occurred during a mean follow-up of 220 days. CONCLUSIONS: Selective gamma probe-guided resection of the radiolabeled sentinel lymph node is possible in over 95% of patients with melanoma. This technique offers a simple and reliable method of staging of regional lymph nodes in these patients without performing a regional lymphadenectomy.

Adolescent↗

PubMed1995

Strategies and rationales for the de novo design of a helical hairpin peptide.

The de novo design of alpha t alpha, a helical hairpin peptide, is described, alpha t alpha (alpha-helix/turn/alpha-helix) was developed to provide a model system for protein folding at the level of secondary structure association and stabilization. According to the prevailing models of protein folding, the second step in the folding process is the association and stabilization of secondary structural elements or microdomains. A brief description of the design, along with CD and NMR evidence confirming the conformation of the peptide in solution, has been published (Fezoui Y, Weaver DL, Osterhout JJ, 1994, Proc Natl Acad Sci USA 91:3675-3679). The present work includes a full description of the design process, including the trade-offs that were made during the development of the peptide, a discussion of recent experimental results that were not available at the time of the original design, indications of areas where, in retrospect, the design might have been done differently, and a discussion of how the present work fits into the field of de novo protein design.

Amino Acid Sequence↗

PubMed1995

Von Hippel-Lindau disease presenting as pancreatic neuroendocrine tumour.

A 21-year-old woman with a family history of von Hippel-Lindau disease presented with a mass in the head of the pancreas. Light microscopic features of the tumour suggested neuroendocrine differentiation and although it displayed positive immunostaining for the antigens expected in a neuroendocrine neoplasm, S-100 staining was also present. This unusual feature prompted further evaluation by routine and post-embedding protein-A gold immunoelectron microscopy, which demonstrated the presence of neuroendocrine granules. Tumour cell DNA content was normal by flow cytometry. Although this patient exhibited no other signs of von Hippel-Lindau disease, the presence of a pancreatic tumour with neuroendocrine differentiation demonstrated that she was affected. Future surveillance and genetic counselling will be influenced by this diagnosis.

Adult↗

PubMed1995

Comparison of DNA content, S-phase fraction, and survival between medullary and ductal carcinoma of the breast.

Medullary carcinoma (MC) of the breast has been regarded as a subtype of breast carcinoma with a relatively favorable prognosis despite its high nuclear grade and high mitotic index. High nuclear grade and high mitotic index have been correlated with DNA aneuploidy and high S-phase fraction (SPF) by flow cytometry. Generally in breast cancer, these histologic and DNA content features predict a less favorable prognosis. To address this paradox, all cases of MC of the breast (20 of 1,365 carcinomas [1.5%]) diagnosed between 1968 and 1982 were compared to age- and stage-matched cases of infiltrating ductal carcinoma (IDC) diagnosed during the same time period. All of the MC and 80% of the IDC had one or more DNA aneuploid stem lines. Average total SPF was 8.1% for MC and 4.8% for IDC. DNA analysis was performed from paraffin blocks (average CV: 4.5% DNA diploid; 4.1% DNA aneuploid), and subjected to computer modeled analysis. Statistically significant differences between presence or absence of DNA aneuploidy (P = .035) and total SPF (P = .029) were demonstrated between the two groups. Thirteen of 20 patients (65%) with MC (average followup 130 months) were alive at the end of the study period compared to 12 of 20 patients (60%) with IDC (average follow-up 160 months). The difference in crude survival was not statistically significant (P = .867). However, there was a tendency toward early death in MC and late death in IDC. Within the TNM stage-matched patients, no significant difference was demonstrated for tumor size or nodal status when these variables were examined separately. In conclusion, statistically significant differences in DNA content and proliferative fraction exist between medullary carcinoma of the breast and ductal carcinoma. The biologic and clinical differences demonstrated in this analysis warrant careful consideration before including cases of medullary carcinoma in studies evaluating newer prognostic variables in breast cancer.

Adult↗

PubMed1995

Mature teratoma of the uterine cervix with pulmonary differentiation.

Teratomas of the uterus are very rare, and a uterine teratoma with pulmonary differentiation has not, to our knowledge, been described previously. In this article, we report such a case in a 33-year-old woman, who presented with heavy vaginal bleeding and a polypoid mass of the uterine cervix. The cervical lesion was composed entirely of mature lung tissue, including bronchial, bronchiolar, and alveolar structures. The presence of well-differentiated respiratory epithelial cells, ie, Clara cells and alveolar type II cells, is confirmed by immunohistochemistry. The patient had no history of dilatation and curettage; therefore, implantation of fetal tissue could be excluded from the differential diagnoses. Since this is a newly developed mass in an adult individual, we favor a neoplastic process over heterotopia and interpret the lesion as unilateral lung development in an extragonadal mature teratoma.

Adult↗

PubMed1994

De novo design and structural characterization of an alpha-helical hairpin peptide: a model system for the study of protein folding intermediates.

The de novo design and structural characterization of an alpha-helical hairpin peptide (alpha-helix/turn/alpha-helix, alpha t alpha) are reported. The peptide is intended to provide a model system for the study of the interactions of secondary structural elements during protein folding. Both the diffusion-collision and framework models of protein folding envision that the earliest intermediates in protein folding are transient secondary structures or microdomains which interact and become mutually stabilizing. Design principles for the alpha t alpha peptide were drawn from the large body of work on the structure of peptides in solution. Computer modeling was not used in the design process. Study of alpha t alpha by circular dichroism and two-dimensional nuclear magnetic resonance indicates that the designed peptide is monomeric, helical, and stable in aqueous solution at room temperature. Analysis of two-dimensional nuclear magnetic resonance experiments indicates that the two helices and the turn form in the intended positions and that the helices associate in the designed orientation. Development of alpha t alpha represents an advance in protein design in that both the secondary structural elements and designed tertiary interactions have been realized and can be detected in solution by nuclear magnetic resonance. The resulting model system resembles a protein folding intermediate and will allow the study of interacting helices in a context that approximates an early stage in protein folding.

Amino Acid Sequence↗

PubMed1994

Protein folding dynamics: the diffusion-collision model and experimental data.

The diffusion-collision model of protein folding is assessed. A description is given of the qualitative aspects and quantitative results of the diffusion-collision model and their relation to available experimental data. We consider alternative mechanisms for folding and point out their relationship to the diffusion-collision model. We show that the diffusion-collision model is supported by a growing body of experimental and theoretical evidence, and we outline future directions for developing the model and its applications.

Diffusion↗

PubMed1994

MacMolecular: a program for visualization of molecular structures on the Macintosh.

MacMolecular displays small- to medium-sized biomolecules, with particular emphasis on peptides. It has been developed to run on color Macintosh computers. The display can be stick, ball and stick, depth cued by thickness stick, or several types of space-filling representations. The program takes input from standard PDB files, simple Cartesian coordinate files, and, in addition, from Kinemage files in which atom information has been included. The program allows color changes of various types as well as the normal functions of translation, rotation, and zooming. In addition, animation files may be produced for subsequent display. Bonding of atoms is done by a distance algorithm (standard) or sequentially to properly display C alpha traces and traces of peptides containing simplified representations of amino acids. Stereo viewing is available, and manipulated structures which were drawn from PDB files can be written out to new PDB files. In addition, PICT files of the drawing window can be generated.

Alanine↗

PubMed1993

Simulation of alpha-helix-coil transitions in simplified polyvaline: equilibrium properties and Brownian dynamics.

A quantitative understanding of helix-coil dynamics will help explain their role in protein folding and in folded proteins. As a contribution to the understanding, the equilibrium and dynamical aspects of the helix-coil transition in polyvaline have been studied by computer simulation using a simplified model of the polypeptide chain. Each amino acid residue is treated as a single quasi-particle in an effective potential that approximates the potential of mean force in solution. The equilibrium properties examined include the helix-coil transition and its dependence on chain position and well depth at the coil-helix interface. A stochastic simulation of the Brownian motion of the chain in its solvent surroundings has been used to investigate dynamical properties. Time histories of the dihedral angles have been used to study the behavior of the helical structure. Auto and cross-correlation functions have been calculated from the time histories and from the state (helix or coil) functions of the residues with relaxation times of tens to hundreds of picoseconds. Helix-coil rate constants of tens of ns-1 were found for both directions of the transition.

Amino Acid Sequence↗