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PubMed2003

Symptoms and signs of primary melanoma: important indicators of Breslow depth.

BACKGROUND: Operative management of patients with cutaneous melanoma is guided primarily by the pathologic determination of Breslow depth. Differentiating early from more advanced melanoma is not always straightforward and may be complicated by pathologic misdiagnosis, inappropriate biopsy techniques, or poor specimen handling. Inconsistencies between the patient's history and the pathologist's interpretation may alert the physician to the possibility of misdiagnosis. In this setting, awareness of the signs and symptoms (S/S) of thin versus intermediate or deep melanoma may be helpful in guiding management. The authors performed a prospective evaluation of the S/S reported by patients who presented at Memorial Sloan-Kettering Cancer Center with invasive primary melanoma. METHODS: The authors prospectively evaluated 369 patients with a detailed questionnaire regarding their S/S at the time of their initial visit. Multivariate logistic regression was employed to study the association between S/S reported by the patient and Breslow depth of the primary lesion, adjusting for gender, age, and anatomic site. Patients were grouped by the Breslow depth of their primary tumors into three categories for analysis: those with thin (< or = 1.0 mm), intermediate (1.0-4.0 mm), and thick (> or = 4.0 mm) lesions. RESULTS: Gender, age, and primary site were not significantly predictive of increasing category of Breslow depth. Most patients reported at least one S/S (n=278 [75%]). The most common S/S reported was an increase in size (n=187 [51%]), followed by a change in color (n=147 [40%]). Bleeding (n=95 [26%]), lump (n=86 [23%]), itching (n=83 [22%]), skin breakdown (n=66 [18%]), and pain (n=24 [7%]) were less common. In a multivariate analysis, the S/S most strongly associated with an increased category of Breslow depth was bleeding (odds ratio [OR] 7.5), followed by pain (OR 3.3), lump (OR 2.2), itching (OR 1.9), and change in size (OR 1.7). The only S/Ss not independently associated with an increasing category of Breslow depth were a change in color and skin breakdown. The presence of one or more S/S was associated significantly with an increased category of Breslow depth of the primary melanoma (1 or 2 S/S vs. no S/S: OR, 4; > or= 3 S/S vs. no S/S: OR, 24). CONCLUSION: Most S/Ss of cutaneous melanoma are associated with an increasing risk of a deep primary lesion. Understanding this relationship can be valuable in patient management, especially when pathologic data are incomplete or inconsistent with the patient's history.

Adolescent↗

PubMed1993

Prospective trial evaluating immunocytochemical-based sputum techniques for early lung cancer detection: assays for promotion factors in the bronchial lavage.

To confirm the results of a previous report on the use of monoclonal antibodies in immunocytochemical assays of sputums for the early detection of lung cancer, we designed a new prospective trial in an independent clinical trial population. Since well-characterized Stage I resected non-small cell lung cancer patients have a low rate of tumor relapse and a high (1-3%/year) chance of developing a second primary lung cancer, they comprise a very favorable group for conducting an early lung cancer detection trial. The rate of new lung cancer is about 10-fold in excess of a standard "high" risk population of smokers. To optimize the chance for a favorable outcome, all of the technical components for the trial have been systematically evaluated to ensure that optimal procedures are employed. For example, automated immunostaining of the sputum specimens will be performed. Bronchial lavages will be analyzed in a subset of the trial participants to define additional targets for early lung cancer detection. Two markers will be quantitated, including gastrin releasing peptide and peptidyl glycine alpha-amidating monooxygenase activity. These two markers assess the epithelium's capacity to produce growth factors which may be central to the biology of tumor promotion. Since these assays have not been performed in this context before, we attempted to optimize the specimen handling to permit the receipt of the material from a range of collaborating clinical sites in a condition that permits accurate quantitation of these two biomarkers. Efforts to standardize the assay endpoint stimulated the development of computer-assisted methods of immunocytochemical analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2003

Association between extent of axillary lymph node dissection and patient, tumor, surgeon, and hospital factors in patients with early breast cancer.

BACKGROUND AND OBJECTIVES: Axillary lymph node dissection (ALND) in patients with breast cancer is crucial for accurate staging, provides excellent regional tumor control, and is included in the standard of care for the surgical treatment of breast cancer. However, the extent of ALND varies, and the extent of dissection and the number of lymph nodes that comprise an optimal axillary dissection are under debate. Despite conflicting evidence, several studies have shown that improved survival is correlated with more lymph nodes removed in both node-negative and node-positive patients. The purpose of this study is to determine which patient, tumor, surgeon, and hospital characteristics are associated with the number of nodes excised in early breast cancer patients. METHODS: A random sample of 938 women with node-negative breast cancer was drawn from the Ontario Cancer Registry and the data supplemented with chart reviews. The extent of axillary dissection was studied by examining the number of nodes examined in relation to the patient, tumor, surgeon, and hospital factors. RESULTS: The mean number of lymph nodes excised was 9.8 (SD = 4.8; range, 1-31), and 49% of patients had >/=10 nodes excised. Lower patient age was associated with the excision of more lymph nodes (>/=10 nodes: 63% of patients <40 years vs. 38% of patients >/=80 years). Surgeon academic affiliation and surgery in a teaching hospital were highly correlated with each other and were significantly associated with the excision of >/=10 nodes. The number of nodes excised was not associated with any tumor factors, nor with the breast operation performed. These results were confirmed with multivariable models. CONCLUSIONS: Even though the number of lymph nodes found in the pathologic specimen can be influenced by factors other than surgical technique (e.g., number of nodes present, specimen handling, and pathologic examination), this study shows significant variation of this variable and an association with several patient and surgeon/hospital factors. This variation and the association with survival warrant further study and effort at greater consistency.

Academic Medical Centers↗

PubMed2006

Strategies for plasma proteomic profiling of cancers.

Despite a voluminous literature on potential protein biomarkers and a compelling need for diagnostic tests based on biomarkers to detect cancers at much earlier, more treatable stages, progress has been limited. New methods and new instruments for analysis of differences in gene expression, gene methylation, and proteomics are being employed to try to accelerate the discovery phase. Given the heterogeneity of tumor mechanisms and the limitations of analytical methods, it is likely that a variety of strategies will be needed and will be complementary. That is the basis of this review of proteomic approaches. This article adopts a systems biology view, starting with mRNA transcripts in tumors and cultured tumor cells to detect mRNA overexpression, some of which will be correlated with protein overexpression. Some of those proteins may be secreted or released into proximal biofluids and plasma. Detection of low-abundance tumor proteins in the complex and dynamic mixture that is plasma requires combinations of increasingly powerful technologies. The biological amplification of protein signals through the immune system offers autoantibodies as potential biomarkers. Higher abundance proteins, including acute-phase reactants, may have practical value, especially if the proteins are modified as part of the cancer processes. Low molecular weight proteins, fragments, and peptides may offer complementary biomarkers. Promising biomarker candidates must be confirmed in independent studies. Then they must be submitted to higher-throughput methods practical for large-scale validation studies and, hopefully, for clinical and epidemiological applications. Standardized operating procedures for specimen handling, design and use of various reference standards, care to avoid bias and confounding, and guidelines for reporting findings and contributing datasets should enhance the prospects for predictive proteomic profiling of people at risk for cancers.

Biomarkers, Tumor↗

PubMed2003

Plasma and red blood cell zinc in cystic fibrosis.

The objectives of this study were to measure plasma and red blood cell (RBC) zinc concentrations in patients with cystic fibrosis (CF), and examine their relationship to nutritional status and pulmonary function. Plasma and RBC zinc levels were compared in 53 CF patients ranging in age from 0.5-46 years. Their relationships to weight (% ideal weight) and forced expired volume in 1 sec (FEV(1)) (% predicted value) were examined. After excluding improperly handled specimens, RBC zinc levels in 51 patients and plasma zinc concentrations in 40 patients were included for analysis. Sixteen of 51 (31%) patients had low RBC zinc levels compared to 4 of 40 (10%) with low plasma zinc concentrations (P < 0.01). Thirteen of 38 patients (34%) in whom both values were obtained had low RBC zinc concentrations compared to 4 of 38 (11%) with low plasma zinc levels (P < 0.022). Neither low RBC nor plasma zinc levels correlated with nutritional status or lung function. In conclusion, about one third of patients with CF had low RBC zinc levels. Plasma zinc concentrations may not adequately reflect overall zinc status. This deficiency did not appear to be related to either nutritional status or lung function. The significance of low RBC zinc in CF is unknown.

Adolescent↗

PubMed1994

Large loop excision of the transformation zone (LLETZ): a pathologic evaluation.

Forty-six LLETZ cone biopsies were performed at the Medical College of Georgia from January 1991 through December 1991. All LLETZ cones were performed for diagnostic reasons following colposcopic biopsies. The majority of procedures were done by residents in obstetrics and gynecology with direct faculty supervision. All specimens were critically evaluated by one pathologist with regard to specimen orientation, thermal artifact, margins, histologic diagnosis, and overall specimen adequacy. The median number of specimens obtained per patient was two, with a maximum of eight. Sixteen patients had a separate endocervical specimen obtained. Thermal artifact was graded as slight in 16 cases, moderate in 18 cases, and severe in 12 cases. The transformation zone was identified in 33 cases. Margins were positive in 17 cases, negative in 21 cases, and nonevaluable in 8 cases. Only 13 LLETZ specimens were believed to compare in quality to a cold-knife cone biopsy. The main criticism about the specimens was the effect of thermal artifact on critical histologic evaluation. In three cases, the thermal artifact precluded an accurate enough evaluation to rule out microinvasion. Mucosa missing at the margins or inadequate representation of the transformation zone were major reasons to call a specimen inadequate. Endocervical specimens suffered the most thermal injury. Orientation of fragmented cone specimens present a problem in histologic evaluation. A major emphasis needs to be placed on the proper indications for LLETZ cone biopsy as well as education of practitioners and pathologists in proper specimen handling.

Artifacts↗

PubMed2001

Quality management in neuropathology.

Quality management will have an increasing impact on the field of clinical neurosciences. The neuropathological examination of surgical or autopsy samples obtained from the central nervous system (CNS) and related structures, cerebrospinal fluid, peripheral nerve or skeletal muscle serves three major purposes: to identify a structural correlate of the disease, provide a reliable basis for treatment strategies and to investigate underlying pathogenic mechanisms. In order to achieve histopathological diagnosis at a consistent quality, quality management and control have to be implemented at different levels. At the local site, these concern neuropathological services, such as acquisition of tissue specimens, handling and staining procedures as well as diagnostic examination. Training programs offered in slide seminars and diagnostic workshops are important tools to highlight new developments and maintain high standards. National reference centers for brain tumors, neurodegenerative disorders, prion or muscle and nerve diseases assist with a second opinion in difficult cases and support epidemiological as well as clinical therapy trials. An international panel of neuropathologists has established guidelines for the classification of brain tumors, recently updated during a WHO 2000 consensus conference. Finally, the standardized histopathological and cytological diagnosis of CNS disorders plays also an important role in providing quality control for associated fields of the clinical neurosciences, such as neuroradiology, neurology, psychiatry and neurosurgery.

Brain Neoplasms↗

PubMed2005

[Microbiologic diagnosis of selected skin infections].

Using as examples either common or important but less frequent bacterial skin diseases, detailed practice-oriented information is provided on microbiologic diagnostic procedures. Despite the availability of many advanced techniques, often the simplest measures can provide the correct diagnosis and help guide therapy. The practicing physician must also know what is required for more advanced diagnostic procedures; if they are used improperly, unnecessary costs accumulate. Conversely, the decision process and technical methods must be understandable for those without special background in microbiology. The value of all methods is discussed from the perspective of dermatology with emphasis on appropriate sampling and handling of specimens.

Bacteriological Techniques↗

PubMed2003

Localization of sucrose synthase and callose in freeze-substituted secondary-wall-stage cotton fibers.

Methods for cryogenic fixation, freeze substitution, and embedding were developed to preserve the cellular structure and protein localization of secondary-wall-stage cotton (Gossypium hirsutum L.) fibers accurately for the first time. Perturbation by specimen handling was minimized by freezing fibers still attached to a seed fragment within 2 min after removal of seeds from a boll still attached to the plant. These methods revealed native ultrastructure, including numerous active Golgi bodies, multivesicular bodies, and proplastids. Immunolocalization in the context of accurate structure was accomplished after freeze substitution in acetone only. Quantitation of immunolabeling identified sucrose synthase both near the cortical microtubules and plasma membrane and in a proximal exoplasmic zone about 0.2 microm thick. Immunolabeling also showed that callose (beta-1,3-glucan) was codistributed with sucrose synthase within this exoplasmic zone. Similar results were obtained from cultured cotton fibers. The distribution of sucrose synthase is consistent with its having a dual role in cellulose and callose synthesis in secondary-wall-stage cotton fibers.

Cell Wall↗

PubMed2005

Review of tonsillar lymphoma in pediatric patients from the pediatric oncology group: what can be learned about some indications for microscopic examination?

Financial considerations have led to suggestions that routine microscopic evaluation of tonsils and adenoids is neither cost effective nor clinically indicated. However, the possibility of tonsillar lymphoma must be carefully weighed when making institutional policy decisions. One way to find an appropriate algorithm for pathologic examination is to examine the characteristics of biopsy-proved tonsillar lymphomas. To investigate the clinicopathologic characteristics of tonsillar lymphoma, we performed a retrospective analysis of patients who had non-Hodgkin lymphoma (NHL) and large-cell or Burkitt lymphoma involving the tonsils and adenoids and were registered on Pediatric Oncology Group (POG) protocols. Seventy-seven (9%) of 832 POG cases of NHL involved the tonsils and adenoids. Review of the pathology reports available from 29 of these cases revealed that NHL was incidentally discovered by pathologic examination in only 5 cases, all of which had clinical evidence of unilateral tonsillar enlargement or size discrepancy by gross examination. The other 24 cases indicated a clinical suspicion of tonsillar cancer, as judged by a preoperative diagnosis or by a request for frozen-section examination. We conclude that in most cases there is a clinical suspicion of tonsillar NHL at the time of gross examination. With routine cases, we predict that the use of comparative organ weights, a clinical impression of tonsillar asymmetry, and review of clinical history will increase the recognition of tonsillar lymphoma when "gross-only" protocols are employed for specimen handling.

Adenoids↗

PubMed2004

Borderline ovarian tumors: diverse contemporary viewpoints on terminology and diagnostic criteria with illustrative images.

The National Cancer Institute sponsored a Borderline Ovarian Tumor Workshop held in August 2003 in Bethesda, MD. This report was developed from discussions at the Workshop. The participants acknowledged several areas of disagreement on basic terminology issues and agreed that a glossary with example images would help clarify many commonly misunderstood issues. This report defines terminology used in the pathological description of borderline tumors and their variants, and illustrates examples of each of the most common entities. It also addresses controversial aspects of the definitions and issues involving specimen handling and reporting. For those issues where there is disagreement, the terminology and diagnostic approaches reflecting the differing views are presented.

Cystadenocarcinoma↗

PubMed1984

Umbilical cord pH and PCO2: effect of interval from delivery to determination.

Determinations of umbilical blood pH and PCO2 can be useful for correlating intrapartum fetal heart rate patterns, intrapartum samples of scalp blood, and Apgar scores, for the retrospective evaluation of the management of a particular labor. Occasionally, such data can indicate and clarify needed resuscitative measures and intensive neonatal observation. Cumbersome techniques have been described for the handling of specimens of cord blood to ensure an accurate determination. This study was performed to determine the effect on cord blood pH and PCO2 of room temperature and time from delivery. One hundred five cord venous or arterial determinations had a linear pH decrease versus time at room temperature. The regression slope was -3.66 X 10(-4) per minute with a standard deviation of 1.37 X 10(-2). The PCO2 showed only a slight increase with time at room temperature, although the scatter was high, with a standard deviation of 3.8 torr. The conclusion is that samples of cord blood drawn for determination of pH and PCO2 can be kept at room temperature in plastic syringes for up to 30 minutes without significant alteration in these values, i.e., pH decrease no greater than 0.04 unit (p less than 0.05).

Apgar Score↗

PubMed1999

Impact of the fetal fibronectin assay on admissions for preterm labor.

OBJECTIVE: The aim of the study was to determine whether use of the fetal fibronectin assay would decrease the number of admissions to labor and delivery for diagnosis and treatment of preterm labor. STUDY DESIGN: A prospective cohort design was used to compare preterm labor admissions during a 12-month period of fetal fibronectin assay use (study) against a baseline period before fetal fibronectin assay was implemented as standard protocol. Patients coming to the physician's office or hospital with signs and symptoms of preterm labor had a sample obtained for fetal fibronectin assay per labeling criteria. Comparisons were made with the Mann-Whitney U test, independent Student t test, chi2 test, and Fisher exact test. P <.05 was considered significant. RESULTS: There was no difference noted in the number of deliveries between the baseline and study years. During the study year 251 of 330 patients evaluated for preterm labor met study criteria and had the fetal fibronectin assay completed. Eight patients did not have fetal fibronectin assay results available because of specimen handling errors, leaving 243 subjects available for study. Compared with the baseline year, the study year had significantly fewer admissions for preterm labor, preterm labor admissions per patient, and prescriptions written for tocolytic agents. In addition, the length of stay per admitted patient was significantly reduced. The study population had no differences in neonatal outcomes from the baseline population in terms of deliveries at <35.0 weeks' gestation, number of admissions to the neonatal intensive care unit, neonatal intensive care unit length of stay, or days of ventilatory support per patient admitted to the neonatal intensive care unit. CONCLUSIONS: Use of the fetal fibronectin assay resulted in significantly reduced preterm labor admissions, length of stay, and prescriptions for tocolytic agents. No negative impact on neonatal outcomes was observed. Reductions in admissions for preterm labor and in charges per admission resulted in approximately $486,000 saved during the study period. A trend toward increased corticosteroid administration (for neonates ultimately admitted to the neonatal intensive care unit) was noted.

Adolescent↗

PubMed1998

Analytical issues on prostate-specific antigen in relation to prostate cancer screening.

OBJECTIVE: Evaluation of the analytical performance of the Hybritech Tandem-E PSA assay as applied to the Rotterdam part of the European Randomized Study of Screening for Prostate Cancer (ERSPC) during 1994-1997. DESIGN AND METHODS: For assessment of test performance imprecision and accuracy contributing to clinical decision making was examined. Pre-analytical variables (specimen handling), long-term reagents stability and calibration check with the Stanford 90:10 PSA Calibrator were studied. RESULTS: Total prostate-specific antigen proved to be a stable marker. Provided correct storage at 4 degrees C, we were not able to find differences between samples analyzed directly after blood withdrawal and those analyzed the following day, with or without centrifugation. Day-to-day precision, we found during 1997 a coefficient of variation of 4.9% for concentration 1.8 micrograms/L and 4.2% for 4.8 micrograms/L (n = 182). The variation among the 21 Tandem-E reagent batches used during 1994-1997 proved to be small. Application of the Stanford 90:10 PSA Calibrator revealed 3% higher values for Tandem-E. CONCLUSION: The overall, long-term picture of Tandem-E PSA is reliable in our hands. Possible differences from the true PSA values, not specific for Tandem-E, need to be elaborated.

Humans↗

PubMed1989

Electron microscopy in the diagnosis of pediatric disease.

Electron microscopy, although not able to solve all diagnostic dilemmas, is an essential adjunct to the analysis of pathologic processes. The importance of correct specimen handling for ultrastructural study is highlighted. Some diseases encountered in pediatrics, in which the ultrastructural findings are well established, are illustrated. New technologies that show promise for wider application to problems in pathology also are considered in this article.

Child↗

PubMed2000

Small peripheral glandular lesions detected by screening CT for lung cancer. A diagnostic dilemma for the pathologist.

The early detection of lung cancer by helical CT provides an important opportunity for radiologic-pathologic and clinical correlation of borderline glandular lesions. Little is known about the clinical course of atypical adenomatous hyperplasia, solitary noninvasive, nonmucinous BAC, and early-phase invasive adenocarcinomas, therefore, a single protocol for specimen handling and a central tissue registry are essential. The most important separation among the various types of adenocarcinoma is the diagnosis of BAC, a potentially curable malignancy, from invasive adenocarcinoma. Therefore, for small lesions of 2 cm or less, the entire tumor should be processed. For larger lesions, one section per centimeter should be sampled, and if the initial sections show a purely lepidic growth pattern, additional sections should be taken to exclude an invasive component. If foci of invasion are identified, the tumor should be classified as an adenocarcinoma with bronchioloalveolar features. At the International Conference on Screening for Lung Cancer held in October 1997, it was recommended that an international panel be used to reach consensus on difficult lesions of the lung detected by CT screening, and that a tissue bank of these lesions be established to ensure further clinical, radiographic, light microscopic, immunohistochemical, and molecular studies of putative precursor lesions and small carcinomas. Through the collection of these lesions, we can further our understanding of the biologic behavior of lung cancer, particularly because little is known about the progression from a purely lepidic growth pattern to invasive adenocarcinoma.

Adenocarcinoma↗

PubMed2004

An automated method for the determination of montelukast in human plasma using dual-column HPLC analysis and peak height summation of the parent compound and its photodegradation product.

PURPOSE: To develop an assay to evaluate the bioequivalence of overcoated and marketed montelukast formulations, the former to be used for future blinded clinical studies. METHODS: The method used automated 96-well sample preparation and dual-column HPLC analysis for increased throughput. Regression analysis was performed using the total peak height of montelukast and its photodegradent, a cis-ethenyl geometric isomer. This approach successfully compensated for montelukast's light sensitivity, allowing both clinical specimen handling and bioanalytical laboratory analysis to be conducted without extensive precautions being taken to protect samples from UV light. To ensure a molar equivalent fluorescence response between the cis (Z) and trans (E) isomers, the emission wavelength and detector attenuation were both increased just prior to the elution of the montelukast peak (i.e., the trans isomer), effectively dampening the response of the stronger fluorophore. Plasma proteins were precipitated using acetonitrile, and 50 microl of supernatant was injected onto an HPLC system consisting of two C18 analytical columns connected to a 10-port switching valve. Injections were overlapped on alternating columns allowing twice as many samples to be processed during each analytical run. RESULTS: The calibration curve was linear from 5 to 2000 ng ml(-1). The inter-day and intra-day precision expressed as coefficient of variation (%CV), were 1.1-6.1% and 3.1-6.7%, respectively. The accuracy, reported as percentage bias, was less than or equal to +/-9.1%. The absolute recovery was determined to be 94.3% and 98.1% at 15 and 1500 ng ml(-1), respectively. CONCLUSIONS: This assay represents a rapid, accurate, and sensitive method for the determination of montelukast in human plasma. The method has been successfully used to demonstrate the bioequivalence of the overcoated montelukast formulations to their equivalent marketed tablets.

Acetates↗

PubMed2003

C-1 esterase inhibitor dysfunction localised to the periodontal tissues: clues to the role of stress in the pathogenesis of chronic periodontitis?

BACKGROUND: C1-esterase inhibitor (C1eIn) is an important modulator of complement activation via the classical pathway. Deficiencies or dysfunction involving this inhibitor underlie the condition of angioneurotic oedema. AIM: The purpose of this report is to describe a female patient who presented at the age of 24 years with an apparently aggressive form of periodontitis and severe oedema, localised to the free gingival tissues. After 21 years of repeated surgical reduction of the gingiva, a diagnosis of C1eIn dysfunction was made. METHODS: Exhaustive serological investigations were performed along with histopathology. RESULTS: All investigations were unremarkable, until the function of the C1eIn molecule was investigated. These demonstrated a functional activity of only 29% and a raised C1q at 157 mg/l. Subsequent repeated investigation with careful specimen handling demonstrated undetectable levels of C1eIn and normal C1q. A diagnosis of C1eIn dysfunction was made, although at present it is unclear whether this represents an unusual variant of hereditary dysfunctional C1eIn deficiency. The patient was managed by various means, including steriodal and non-steroidal drugs, the latter forming part of her maintenance regime. CONCLUSIONS: To our knowledge, this is the first case of angio-oedema localised to the free gingiva. The role of stress in the acute exacerbations of oedema and bone loss is discussed along with the diagnostic pitfalls associated with this case.

Adult↗