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Biomedical subjects

A J Cochran

Publications and source records attributed to A J Cochran.

At least 55 records · Page 3Linked to original sources
PubMed1993

Frequency and distribution of occult micrometastases in lymph nodes of patients with non-small-cell lung carcinoma.

BACKGROUND: Accurate assessment of the presence and absence of tumor in the regional lymph nodes is critical in assessment of prognosis for patients with lung cancer. Development of sensitive immunohistochemical techniques and specific monoclonal antibodies has increased our capacity, in melanoma and breast cancer, to detect small groups of tumor cells or even single tumor cells in lymph nodes that appear to be tumor free in conventionally stained sections. PURPOSE: This retrospective study was designed to assess whether use of a polyclonal antikeratin reagent in immunohistochemical analysis offers any advantage over conventional histopathology in detection of regional lymph node metastases in non-small-cell lung cancer. METHODS: Paraffin-embedded tissue sections from regional lymph nodes of 65 patients with non-small-cell lung cancer were studied. We examined tissue from 588 nodes of 60 patients with a diagnosis of disease confined to the lung and from 72 nodes of five patients with a diagnosis of metastasis to some nodes. A polyclonal antikeratin antibody was applied to the lymph node tissue sections, using the avidin-biotin complex immunoperoxidase technique. RESULTS: Single tumor cells and small clusters of tumor cells (occult micrometastases) not visible on routine evaluation were readily detected in 38 (63%) of the 60 patients whose nodes appeared to be negative on examination of hematoxylin-eosin-stained slides. In the five patients with a diagnosis of node-positive non-small-cell lung cancer, five (10%) of 51 nodes that were tumor free on conventional examination contained metastases. Metastatic tumor cells were most often located in the subcapsular or medullary sinuses. The lymph nodes that contained occult tumor cells were those located nearest to the tumor, mainly in peribronchial and hilar locations. The median survival of patients with occult metastases (1977 days) was shorter than that of patients whose nodes contained no tumor (2456 days) but was longer than that of patients whose nodes contained metastases detectable on hematoxylin-eosin-stained slides (927 days). CONCLUSIONS: Our results suggest that, in patients with non-small-cell lung cancer, metastatic involvement of regional lymph nodes is more frequent than was previously determined by the conventional histologic method and substantially more frequent than in other tumor types, such as melanoma and breast cancer. IMPLICATIONS: The high frequency of occult nodal metastases in non-small-cell lung cancer makes it clear that, without immunohistochemistry, disease is understaged in many patients. Therefore, it seems essential that immunohistochemical evaluation of the lymph nodes be undertaken in clinical trials.

Adult↗
PubMed1993

Intratumoral interleukin-2 immunotherapy: activation of tumor-infiltrating and splenic lymphocytes in vivo.

Direct intratumoral injection of interleukin-2 (IL-2) was evaluated in a murine model. Balb/c mice received 5 x 10(4) Line 1 alveolar carcinoma cells (L1C2) by subcutaneous injection. On the third day following tumor implantation, mice received injections of IL-2 (5 x 10(3)-5 x 10(4) units) or diluent twice daily, either by i.p. or intratumoral injection, 5 days/week for 3 weeks. Intratumoral injection of 5 x 10(4) units IL-2 significantly reduced tumor volume (P < 0.05 versus control), increased median survival time (P = 0.0001), and resulted in a 23.5% cure rate (P = 0.008). There were no long-term survivors in the other treatment groups. Both tumor-infiltrating lymphocytes (TIL) and splenic lymphocytes isolated directly from IL-2-treated mice demonstrated enhanced cytolytic activity compared to diluent-treated controls. To determine whether non-T-cell-mediated antitumor responses were active in our model, intratumoral immunotherapy was evaluated in athymic Balb/c nu/nu mice. In order to decrease the recruitment of lymphocyte precursors, nude mice were splenectomized and received cyclophosphamide prior to tumor injection and IL-2 therapy. Intratumoral IL-2 immunotherapy also significantly decreased tumor volume in these immunodeficient mice (P < 0.02), but did not lead to long-term survival. We conclude that both TIL and splenic lymphocytes are activated in vivo in response to intratumoral IL-2 immunotherapy, suggesting that intratumoral therapy with IL-2 activates both local and systemic antitumor responses.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed1993

Dobutamine thallium-201 tomography for evaluating patients with suspected coronary artery disease unable to undergo exercise or vasodilator pharmacologic stress testing.

OBJECTIVES: The aim of this study was to assess the feasibility, safety and diagnostic accuracy of a high dose dobutamine infusion in conjunction with thallium-201 single-photon emission computed tomography in 144 patients (72 men and 72 women with a mean age of 65 +/- 10 years) unable to perform exercise or pharmacologic vasodilator stress testing. BACKGROUND: Dobutamine increases myocardial oxygen consumption by increasing heart rate, contractility and arterial blood pressure. In addition, it causes myocardial blood flow heterogeneity and thus may be a useful stress for noninvasive detection of coronary artery disease. METHODS: Dobutamine was administered intravenously at incremental doses of 5, 10, 20, 30 and up to 40 micrograms/kg per min at 3-min intervals. After 1 min of the maximal dose, 3 mCi of thallium-201 was injected and the infusion was continued for an additional 2 min. Thallium-201 tomography was performed 5 to 10 min after termination of the infusion and 4 h later. The images were visually assessed for the presence and vascular location of perfusion defects and the extent of thallium redistribution. Coronary angiography was performed in 84 patients, with a > 50% stenosis considered significant. RESULTS: Dobutamine significantly (p = 0.0001) increased the heart rate (from 75 +/- 14 beats/min to 120 +/- 23 beats/min), systolic blood pressure (from 136 +/- 23 mm Hg to 148 +/- 35 mm Hg) and the rate-pressure product (from 10,144 +/- 2,517 to 17,858 +/- 4,349) from baseline to peak infusion rate, respectively. Most patients (75%) experienced side effects during the infusion, but 74% tolerated a dobutamine dose of 40 micrograms/kg per min and 97% a dose of 30 micrograms/kg per min. The more common side effects were typical (26%) and atypical (5%) chest pain, palpitation (29%), flushing (14%), headache (14%) and dyspnea (14%). The overall sensitivity of dobutamine tomography was 86% in the patients who underwent coronary angiography and 84% in those with single-vessel, 82% in those with double-vessel and 100% in those with triple-vessel disease. Seventy-eight percent of vessels with severe (> or = 70%) stenoses were identified with dobutamine tomography. The specificity of dobutamine tomography was 90% for patients and 86% for individual vessels. CONCLUSIONS: A high dose dobutamine infusion in conjunction with thallium tomography appears to be a well tolerated and accurate method for diagnosing coronary artery disease in patients unable to perform exercise or vasodilator pharmacologic stress testing.

Adult↗
PubMed1993

S-100 protein remains a practical marker for melanocytic and other tumours.

S-100 protein, extracted from bovine brain, is the first described of the modern generation of marker molecules for melanocytic tumours. Despite the observation that many different types of cells express S-100 protein, detection of the molecule in tumour cells in appropriate clinical and pathological circumstances is a widely used and effective adjunct to the determination that a tumour is melanocytic. Antibodies to S-100 protein are best deployed as part of a package that includes antibodies to other melanoma-associated epitopes (HMB-45, NKI-C3/Beteb), cytokeratins and common leukocyte antigen. Antibodies to S-100 protein may also increase the accuracy of melanoma staging and permit detection of small numbers of metastatic tumour cells that are not detectable by conventional histology. Future applications will probably include the wider use of antibodies to the S-100 protein monomers (alpha and beta) and the detection and quantification of S-100 protein in body fluids and tissues.

Biomarkers, Tumor↗
PubMed1993

Variations in the distribution, frequency, and phenotype of Langerhans cells during the evolution of malignant melanoma of the skin.

We examined the frequency, distribution, and immunophenotype (S-100 protein, CD1) of epidermal Langerhans cells (LC) in the epidermis overlying primary melanoma, and dermal dendritic cells (DC) in the dermis deep to melanoma, and in adjacent normal skin. There is a substantial reduction in S-100+ LC and a lesser decline in CD1+ LC in the epidermis over melanoma. There is a simultaneous increase in the frequency of cells expressing these phenotypes in the dermis deep to tumor. Double-staining studies in progress show coexpression of S-100 and CD1 in most of these cells. The depletion of S-100+/CD1+ DC from the peritumoral epidermis is maximum in deeper (Clark level III-V) and thicker (> 0.76 mm) tumors. The reduction in total DC in peritumoral epidermis is, however, proportionally less than the reduction in S-100+/CD1+ DC owing to an increase in cells that are S-100-/CD1+. The proportion of S-100+/CD1+ dermal DC deep to tumor is similar to that in normal epidermis and dermis, suggesting that there is no increased migration of S-100-/CD1+ DC from tumor-associated epidermis to subjacent dermis. Non-dendritic leukocytes in the dermis deep to tumor were increased in frequency, maximally in the dermis deep to thinner and more superficial melanomas. Most such cells were T lymphocytes with helper/inducer cells predominating. The data presented show substantial alterations in the frequency, distribution, and phenotype of LC/DC as melanoma evolves, alterations that may be critical for development of effective tumor-directed immunity.

Antigens, CD↗
PubMed1993

Pathological evaluation of the regional lymph nodes in malignant melanoma.

The clinical implications of lymph node metastasis in patients with malignant melanoma remain serious. Five-year survival rate for clinical stage II disease is between 36% and 50% compared with more than a 80% 5-year survival rate for stage I melanoma. The purpose of this article is to review the known clinical and pathological risk factors for the development of lymph node metastasis in melanoma, to consider the prognostic significance of metastasis once it has occurred, and to discuss the histopathology and differential diagnosis of metastatic melanoma in lymph nodes. Our experience with selective lymphadenectomy for the detection of micrometastases is also presented.

Diagnosis, Differential↗
PubMed1993

Nevi, other than dysplastic and Spitz nevi.

Cutaneous nevi are common lesions that develop by proliferation of melanocyte-derived cells. The majority develop as junction nevi from melanocytes at the epidermo-dermal junction. Cells from this proliferation pass into the underlying dermis forming compound nevi. Later junctional melanocytic activity ceases, leaving an intradermal nevus. A minority of nevi, mainly blue nevi, arise from intradermal melanocytes. Histological variants of melanocytic nevi exist and can be the source of difficult diagnostic problems. Nevi are important as clinical and histological simulators of cutaneous melanoma, as precursor lesions for melanoma (although the actual chance of malignant transformation of an individual nevus is low) and as cosmetic problems (mainly large congenital nevi). Cutaneous nevi are to be separated clinically and histologically from melanomas that are comprised of nevocyte-like cells (minimal deviation melanoma).

Adult↗
PubMed1993

The histology and differential diagnosis of Spitz nevus.

We attempted to identify features by which Spitz nevi (SN) and melanomas that resemble SN may be distinguished, by examining the light microscopic features of 43 SN, using a multifactorial protocol. The data confirm that SN evolve in a manner similar to melanocytic nevi, with well-defined junctional, compound, and intradermal phases. Because of their growth kinetics most SN are excised at the compound stage, the most readily identifiable stage of evolution. However, almost 20% of SN are removed before or after the compound stage and at these stages they are recognized less readily. There are common characteristics of the histological features of the epidermis, junctional and dermal melanocytes, and stromal components at the different stages of SN evolution, but each stage additionally has unique characteristics. Each stage of SN has to be separated from different benign and malignant melanocytic lesions and criteria by which these separations may be made are discussed.

Diagnosis, Differential↗
PubMed1992

Variations in the ganglioside profile of uveal melanoma correlate with cytologic heterogeneity.

Gangliosides may play an important role in the proliferation and spread of human malignant melanoma. Because the frequency of metastases in uveal and cutaneous melanoma differs, it is possible that they may express different gangliosides. We analyzed the ganglioside profiles of primary uveal melanoma in 14 cases and of cutaneous melanoma metastasis in 19 cases. In cutaneous melanoma, GM3 ranged from 4.2% to 74.6% and GD3 from 22.1% to 91.8% of total lipid-bound sialic acid. GM2 (found in 13 of 19 cases, ranging from 0.5% to 11.7%), GD2 (11/19, 0.5%-22.0%) and 9-O-acetyl-GD3 (13/19, 0.5%-12.6%) were also frequently observed. By contrast, in 11 cases of uveal melanoma, GM3 was > 90%, GD3 was < 10%, GM2 was < 1.1%; neither GD2 nor 9-O-acetyl-GD3 were detected. The ganglioside profiles of these uveal melanomas were virtually identical to those of normal melanocytes obtained from foreskins. Histological examination of these 11 biopsies showed a monomorphous cell composition, but neither infiltration of lymphocytes or melanophages nor cell necrosis was observed. In 3 other cases, GD3 was increased to 19.5%-46.0%. Histological examination of these 3 biopsy specimens showed at least 2 populations of tumor cells that were separable based on morphological grounds, and mononuclear inflammatory cells interspersed among the tumor cells. An increase in GD3 appears to be related to tumor polyclonality and infiltration of the tumor by lymphocytes and macrophages. These results suggest that ganglioside expression of uveal melanoma is associated with host immune responses to the tumor. Furthermore, the low metastatic capacity of uveal melanoma, in contrast to the high metastatic rate of cutaneous melanoma, may be a result of its differentiated ganglioside expression, which is strikingly similar to that of normal melanocytes.

Gangliosides↗
PubMed1992

Technical details of intraoperative lymphatic mapping for early stage melanoma.

The initial route of metastases in most patients with melanoma is via the lymphatics to the regional nodes. However, routine lymphadenectomy for patients with clinical stage I melanoma remains controversial because most of these patients do not have nodal metastases, are unlikely to benefit from the operation, and may suffer troublesome postoperative edema of the limbs. A new procedure was developed using vital dyes that permits intraoperative identification of the sentinel lymph node, the lymph node nearest the site of the primary melanoma, on the direct drainage pathway. The most likely site of early metastases, the sentinel node can be removed for immediate intraoperative study to identify clinically occult melanoma cells. We successfully identified the sentinel node(s) in 194 of 237 lymphatic basins and detected metastases in 40 specimens (21%) on examination of routine hematoxylin-eosin-stained slides (12%) or exclusively in immunohistochemically stained preparations (9%). Metastases were present in 47 (18%) of 259 sentinel nodes, while nonsentinel nodes were the sole site of metastasis in only two of 3079 nodes from 194 lymphadenectomy specimens that had an identifiable sentinel node, a false-negative rate of less than 1%. Thus, this technique identifies, with a high degree of accuracy, patients with early stage melanoma who have nodal metastases and are likely to benefit from radical lymphadenectomy.

Adolescent↗
PubMed1992

Effect of epidermal Langerhans cells from melanoma patients on lymphoproliferative responses.

Langerhans cells (LC) are potent antigen-presenting dendritic cells essential for cutaneous immune responses. LC are reduced in number in the epidermis adjacent to primary melanomas and increase in number in the lymphoid infiltrate that accumulates in the dermis deep to such tumours. The present study was undertaken to assess whether the reduction in epidermal LC was accompanied by alterations in their functional competence. We evaluated the capacity of LC from melanoma patients to augment lymphocyte responses to phytohaemagglutinin (PHA), tetanus toxoid and melanoma-associated antigens. Using a panning method to bind Fc receptor positive (FcR+) cells we separated LC-enriched (FcR+) and depleted (FcR-) fractions of epidermal cells. Lymphocyte responses to PHA and tetanus toxoid were increased in the presence of LC-enriched cell populations, but not in the presence of LC-depleted epidermal cells. In preliminary experiments LC-enriched cell populations did not help initiate detectable in vitro lymphoproliferative responses to autologous metastatic melanoma cell lines, allogeneic HLA-DR+ metastatic melanoma cell lines, or a 180-190 kD melanoma tumour-associated antigen. Future studies will investigate the capacity of LC to augment responses to melanoma-associated antigens on autologous primary melanomas.

Antigens, Neoplasm↗
PubMed1991

Immunopathological features of human pulmonary tumors following low-dose interleukin-2.

We administered preoperative low-dose interleukin-2 (IL-2) to 10 patients undergoing thoracotomy for pulmonary tumors. The in vivo effect of IL-2 on tumor-associated lymphocyte activity was assessed in the resected specimens by immunohistochemistry and compared with observations in 45 patients who did not receive IL-2. H & E evaluation revealed an increase in intra- and peritumoral lymphocyte infiltration in the IL-2-treated patients. Immunopathological evaluation with monoclonal antibodies revealed that this lymphocyte infiltration was predominantly CD5-positive T cells. The amount of intra- and peritumoral lymphocyte activity correlated with the dose of IL-2 administered (6000-90,000 international units/kg every 8 h for 48 h. IL-2-treated patients showed increases in T-cell-associated activation markers (IL-2 alpha-receptor, transferrin receptor and HLA-DR) on peritumoral lymphocytes, but not on intratumoral lymphocytes. We previously reported that low-dose IL-2 increases the intrinsic natural killer cell cytotoxicity of intratumoral lymphocytes and suggest that this lymphocyte infiltration is further evidence that low-dose IL-2 can augment in vivo lymphocyte activity at the tumor site.

Aged↗
PubMed1991

Histopathologic diagnosis of dysplastic nevi: concordance among pathologists convened by the World Health Organization Melanoma Programme.

Dysplastic nevi are an important indicator of risk of cutaneous malignant melanoma. The study of and, particularly, international communication regarding this group of lesions have been hindered by a lack of precision in diagnosis. In an effort to broaden understanding, a panel of pathologists agreed upon a set of criteria for the diagnosis of dysplastic melanocytic nevi. Two major and four minor criteria were defined. The major criteria are (1) basilar proliferation of atypical nevomelanocytes (extending at least three rete ridges or "pegs" beyond any dermal nevo-cellular component), and (2) organization of this proliferation in a lentiginous or epithelioid-cell pattern. Minor criteria are (1) the presence of lamellar fibrosis or concentric eosinophilic fibrosis, (2) neovascularization, (3) inflammatory response, and (4) fusion of rete ridges. Diagnosis required presence of both major criteria and at least two minor criteria. One hundred fourteen histologic specimens of benign acquired nevi, dysplastic nevi, and radial-growth-phase melanomas were examined by the members of this panel; their diagnoses were compared to determine degree of concordance. The established criteria yielded 92% mean concordance overall.

Diagnosis, Differential↗
PubMed1990

Murine monoclonal anti-idiotype antibody (alpha) as a probe to detect human monoclonal antibody bound to human tumor tissues.

A new immunohistochemical assay was developed for the detection of human monoclonal antibody (HuMAb) bound to human biopsied tumor tissues. A murine anti-idiotype monoclonal antibody, alpha type, 18C6 (IgGl), was raised against an IgM HuMAb, L612, defining a tumor-associated ganglioside antigen (GM3) and used as a probe in a three step cell-binding assay (HuMAb + anti-id + biotinylated anti-mouse Ig). Anti-id 18C6 has an exclusive binding specificity for HuMAb L612, but does not interfere with the binding of L612 to antigen positive melanoma cell lines or to a purified antigen, GM3. The applicability of 18C6 in the three step cell-binding assay was tested first using a melanoma cell line, UCLASO-M12. L612 bound to M12 cells was specifically detected by 18C6 without any background reactivity in ELISA. When this assay was compared with the standard two-step cell-binding assay (HuMAb + peroxidase-conjugated anti-human IgM) using various cultured tumor cell lines, parallel reactivity was observed. The three-step cell-binding assay was then applied to various fresh-frozen human tumor sections. Positive reactivity was demonstrated on various histologic types of human tumor tissues: primary melanoma (10/10), metastatic melanoma (4/4), nevus (10/10), lung cancer (3/6), breast cancer (2/6), and colon cancer (1/1). Adjacent normal tissues were unstained. Control experiments included the cell-binding assay with L612 alone, 18C6 alone. L612 + unrelated mouse IgG, and unrelated IgM HuMAb (L72) + 18C6; but biotinylated anti-mouse IgG did not react with these control preparations. The results indicate that anti-id 18C6 is a highly specific probe to assess the expression of the ganglioside antigenic epitope recognized by the L612 HuMAb on biopsied human tumor tissues.

Animals↗
PubMed1990

Lymphocyte subset alterations in nodes regional to human melanoma.

The lymphocyte subpopulations in tumor-draining lymph nodes of melanoma patients were determined using two-color flow cytometry. Data were analyzed according to: (a) the staging of the melanoma; (b) whether or not the nodes contained tumor; and (c) their distance from the primary tumor. Compared with Stage I patients (without metastasis), uninvolved nodes of stage II patients (with nodal metastases) had a significant decrease in helper/inducer (CD4+) T-cells (P less than 0.001), with a corresponding increase in cytotoxic/suppressor (CD8+) cells (P less than 0.001) and Leu 19+ natural killer (CD56+) cells (P less than 0.01). In some patients the presence of tumor within a node was associated with a large decrease in CD3+ total T-cells, whereas in others tumor involvement had little influence on lymphocyte phenotypes. When analyzed by distance from the primary tumor, nodes closest to tumor in Stage I patients contained a smaller percentage of CD19+ B-cells. In Stage II, tumor-free nodes nearest to tumor showed an increase in CD19+ cells, but statistical significance was not reached. CD56+ natural killer cells increased progressively in nodes near tumor and were more numerous in Stage II uninvolved nodes compared with Stage I nodes. Alterations in phenotypically defined lymph node lymphocytes occur in nodes regional to melanoma as the disease progresses, as growth of metastases occurs, and in tumor-free nodes nearest to tumor. These alterations may be essential to the establishment and progression of metastases.

Adult↗
PubMed1990

Nuclear DNA measurements of metastatic melanoma by a computerized digital imaging system.

To determine the extent of nuclear DNA abnormalities and their relationship with prognosis of stage II malignant melanoma, metastatic melanomas in lymphadenectomy specimens of 22 patients were studied by a computerized digital imaging system. The DNA ploidy pattern was aneuploid in 86% of the cases and tetraploid in the remaining 14%. In metastatic melanomas, there was a single clone in one third of patients and multiple clones in the remaining two thirds. Poor survival rate was associated with multiple clones and greater than 30% of mean coefficient of variation of DNA content. With tumor progression stem-cell lines often became heterogeneous with the development of multiple clones and widespread DNA values. These abnormalities, determined by nuclear DNA ploidy analysis, provide useful prognostic information.

DNA, Neoplasm↗