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Circulating lymphocytes and the spread of myeloma. Review of the evidence.

Patients with myeloma harbour circulating lymphocytes which bear the idiotypic determinants (SIg-id+ cells) of their own myeloma protein. Circulating white cells with abnormal karyotypes have been found in other patients with this disease. SIg-id+ lymphocytes have also been identified in the peripheral blood of myeloma-tumour-bearing mice. Murine myelomas have been propagated in vivo from circulating mononuclear cells that possessed myeloma-tumour-associated antigens. This and other evidence reviewed here points strongly to the involvement of circulating lymphocyte-like stem cells in the spread of human myeloma.

Animals

Clonal origin of a T cell lymphoproliferative malignancy.

A woman with a T cell lymphoproliferative malignacy and heterozhgosity at the X chromosome-linked locus for glucose-6-phosphate dehydrogenase (G-6PD) isoenzymes was studied to find the clonal origin of her circulating neoplastic T cells. The red blood cells, polymorphonuclear cells, whole mononuclear cells, and T cell-depleted mononuclear cells contained both A and B isoenzymes of G-6-PD. In contrast, the tumor cells, separated by using their capacity to form rosettes with sheep red blood cells, contained only the B isoenzyme of G-6-PD. This observation strongly suggests the monoclonality of this T cell malignancy.

Adult

Metastatic carcinoma with carcinocythemia mimicking leukemia.

Carcinoma metastatic to the bone marrow may present with peripheral blood and bone marrow changes and a clinical picture difficult to distinguish from leukemia. It is important to make an accurate diagnosis since the management is different. We have described a patient with circulating primitive cells and diffuse marrow involvement by similar cells. The pathologic process may be identified without cell markers by careful attention to the pattern of distribution, as well as the cytologic features of the neoplastic cells in the bone marrow biopsy.

Biopsy

Ultrastructural and immunocytochemical characterization of circulating mononuclear cells in patients with myelomatosis.

The ultrastructure of blood mononuclear cells from two IgG myeloma patients was studied, and cells reacting with anti-idiotypic serum and polyspecific anti-Ig serum were characterized by immunoperoxidase techniques. Abnormal, mononuclear cells were present in the blood of both patients, which morphologically were classified as atypical small to medium-sized lymphocytes, polymorphic immature lymphocytes (lymphoblasts), predominantly of the lymphoplasmocytic type and atypical, plasmocytic cells or myeloma cells. Immunocytochemical observations showed that most of the abnormal cells, including atypical small to medium-sized lymphocytes, reacted with anti-idiotypic and polyspecific anti-Ig serum. Periods of relapse and remission were correlated with an increase and decrease, respectively, of the number of abnormal cells and cells which reacted with anti-idiotype and anti-Ig serum. The observations indicate that circulating lymphoid cells are part of the myeloma clone.

Fluorescent Antibody Technique

Induction of metastasizing carcinoma in rats and their biological characteristics.

Induction of a spontaneously metastasizing carcinoma in rats was attempted. Four-week-old Sprague-Dawley female rats were thymectomized or/and splenectomized and fed 200 mg (20 mg times 10) of 3-methylcholanthrene from 7 weeks of age. In addition to these treatments, the early-appearing tumors were excised in order to select by isoimmunity the late-appearing ones that were less antigenic. The latter were easily transplanted into normal syngeneic female rats with metastasis to remote organs. This metastasizing capacity of the tumor became an inherent character in syngeneic normal rats from generation to generation of transplantation. With one of these tumors (MRMT-1) many cancer cells were histologically detected in circulating blood 3 days after tumor transplantation and arrested in capillary beds of lungs. The spontaneous metastasis to lymph nodes and lungs was macroscopically found within several weeks after tumor transplantation.

Adenocarcinoma

Carcinocythemia (carcinoma cell leukemia) due to metastatic carcinoma of the breast: report of a case.

A patient with a 17-year course of metastatic lobular carcinoma of the breast is described who developed large numbers of circulating carcinoma cells which were easily detectable in several routine peripheral blood smears shortly before death. This rare complication of carcinoma has been called "carcinocythemia." Carcinocythemia is probably due to widespread infiltration of many bone marrow sites and may also be related to splenectomy, which may impair reticuloendothelial clearance of circulating tumor cells. The differential diagnosis of carcinocythemia from superimposed acute myelogenous leukemia, which can complicate radiotherapy and chemotherapy for the primary tumor, is discussed. Cytomorphology, histochemistry, and electron microscopy of abnormal circulating cells should aid in the distinction of these two processes.

Adenocarcinoma

Osteosarcoma: improved survival with anticoagulation and amputation.

A study of warfarin anticoagulation as an adjunct to amputation of osteosarcomas was undertaken after finding dramatic results in experimental systems. Anticoagulation was started 7 days preoperatively, continued during the operation, and for up to six months postoperatively. Three of 21 (14%) non-anticoagulated control patients are alive at 5-11 years. Five of 9 (56%) of the anticoagulated patients remain alive 5-8 years. The presumed mechanism of increased survival is an inhibition of fibrin deposition around circulating tumor cells, thereby preventing their adherence to capillary endothelium to initiate metastasis formation.

Adolescent

Rhabdomyosarcoma presenting as carcinocythemia.

A case of rhabdomyosarcoma presenting with circulating tumour cells (carcinocythemia) is discussed. Tumor cells must be differentiated from leukemic cells or a leukemoid reaction. If the abnormal cells appear as syncytia, tumor should be strongly suspected. Cytochemical and/or histochemical stains should also be employed to differentiate tumor cells from hematopoietic cells.

Abdominal Neoplasms

Entry of metastatic malignant cells into the circulation from a subcutaneously growing myelogenous tumor.

The initial stage of metastasis formation, i.e., the entry of metastatic cells from a malignant subcutaneously growing myelogenous tumor into the circulation, was observed by means of transmission electron microscopy and scanning electron microscopy in Long-Evans rats. The transmural passage of malignant cells occurred through the walls of intact venules within the tumor. The malignant cell penetrated the endothelial cell body by making a temporary migration pore. The migration pore closed after the malignant cell entered the vascular lumen. The endothelial vascular lining remained continuous. The entry of malignant cells into the circulation was not the result of the general invasive and destructive properties of malignant tumor cells, but the consequence of a specific action of the tumor cells on the abluminal plasma membrane of the endothelium.

Animals

Destruction of circulating leukemia cells by phagocytosis in rats with myelogenous leukemia.

Acute myelogenous leukemia was induced in outbred Long-Evans rats by iv injections of leukemia cells from a subcutaneous tumor of Shay myelogenous leukemia. In rats with this leukemia the peripheral white blood cell (WBC) counts varied from 2.4 to 700 X 10(9)/liter. No differences were found in the bone marrow of the rats with the high WBC counts and that of rats with low WBC counts. This observation could explain the large variations in the number of circulating leukemia cells caused by differences in cell proliferation or delivery of cells into the circulation. Massive phagocytosis of leukemia cells occurred in animals with low WBC counts (less than 12 X 10(9)/liter) but not in animals with high WBC counts (greater than 150 X 10(9)/liter). This phagocytosis was directed against circulating leukemia cells. The main phagocytes were Kupffer's cells of the liver and macrophages of the spleen parenchyma. In addition, phagocytosis occurred in the spleens and bone marrow by intravascular macrophages, which were derived from extravascular sites. The endothelium of the postcapillary venules of the lymph nodes participated in the phagocytosis of circulating leukemia cells while continuing to be the locus of lymphocytic return from circulation to lymphatic parenchyma. The factors underlying the differences in macrophage activity between the rats with high and low WBC counts were unknown.

Animals

[Lymph node pathology during dermatoses with circulating Sézary cells].

The authors reported 12 cases of patients with cutaneous involvment associated with the presence of Sezary cells in the peripheral blood and specific lymph node involvment. They classify these cases as partial, early segmentary types, advanced types and diffuse types. either leukemic or sarcomatous. This study, once again, suggests the possibility that the Sezary syndrome and mycosis fu ngoïdes are different expressions, either predominantly leukemic, or predominantly sarcomatous, of the same chronic malignant hemopathy of "T" lymphocytes.

Aged

[About tumor cell findings in the peripheral venous blood, blood-borne metastases and the incidence of thromboembolic episodes in patients with carcinoma of various localisations (author's transl)].

In a retrospective study the frequency distribution of positive screenings for free-floating cancer cells in the peripheral venous blood of patients with cancers of the larynx, the abdomen and the lung was related to the frequency of blood-borne metastases and the incidence of thromboembolic episodes within 5 years of observation. Carcinomas of the larynx which were characterized by a very low frequency of blood-borne metastases are related with a high level of free-floating cancer cells in the venous blood. In contrast abdominal and lung cancers have a high frequency of blood-borne metastases, but a lower level of circulating cancer cells in the peripheral venous blood. Also there is a significant correlation between the initial presence of circulating cancer cells and the incidence of thromboembolic episodes in patients with abdominal and lung cancers, in contrast to patient with cancers of the larynx who lack this coincidence. On the basis of our observation we assume that the circulating tumor cells of the patients with abdominal and lung cancers have a high stickiness, therefore displaying a strong tendency to attach to the vascular endothelium. Only lodged cancer cells are able to penetrate the vessel wall and to develop metastases in the interstitial tissue. Remote and more or less generalized effects of cancer on blood coagulation are observed. In certain instances a disseminated intravascular coagulation results, almost exclusively due to remote effects of clotting factors elaborated by cancer cells, sometimes leading to micro- or macrothrombosis.

Abdominal Neoplasms

Isolation and characterization of a neuroblastoma cell line from peripheral blood in a patient with disseminated disease.

Circulation in the blood stream of neuroblastoma cells was confirmed by establishment of a cell line from the peripheral blood of a child with disseminated disease. The morphologic, enzymatic, and chromosomal pattern of this cell line was similar to a cell line established from the primary tumor on a previous occasion. The peripheral blood smear did not demonstrate tumor cells but increased numbers of atypical monocytes; lymphoblasts were evident, which may have been unrecognized neuroblasts.

Acetylcholinesterase

Some aspects of blood borne tumour emboli associated with thrombosis.

The ultrastructural morphology of the tumour cycle which has as one of its features the blood-borne tumour embolus associated with thrombosis is illustrated by examples of four phases. (1) The intrinsic vasculature of tumours influences the process of intravasation of tumour cells to form bloodborne emboli. Scanning electron microscopy of melanoma tumours reveals channels containing erythrocytes which are sinusoidal in appearance. (2) The reaction of the circulating blood to the villi and folds of tumour cells is to coat the surface with plasma proteins and platelets. Walker 256 carcinoma cells become encrusted with platelets following agitation with rat platelet rich plasma. (3) Damaged endothelium appears to provide a more secure adhesional site for the tumour embolus. Platelets on a damaged site may provide an active adhesional region for the platelets on the passing embolus. (4) Tumour cells migrate through the endothelial layer from the adherent embolus and can be held up at the level of the basement membrane of the endothelium.

Animals

Mismatch-introduced crRNA guided PCR-CRISPR/Cas12a platform improves EGFR point mutation detection in single tumor cell.

Dynamic monitoring of epidermal growth factor receptor (EGFR) mutations is essential for the early identification of resistance and treatment adaptation. Single-cell heterogeneity analysis is crucial for precision cancer medicine, yet sensitive and specific detection methods for individual tumor cells remain challenging. Here, we develop a PCR-CRISPR/Cas12a platform enhanced by the incorporation of mismatched base in crRNA at specific site for single-cell point mutation detection. This platform demonstrated high specificity and sensitivity, detecting point mutation at a frequency of 0.1% and in as low as 1.02 ng of genomic DNA, which represents an improvement over the amplification-refractory mutation system PCR (ARMS-PCR). Notably, the accuracy of the platform is highly consistent with next-generation sequencing (NGS), as evidenced by Kappa test values surpassing 0.9. By utilizing a conical-pore membrane with optimized porosity for single circulating tumor cell (CTC) enrichment, our platform enables point mutations detection in individual tumor cells, offering potential enhancements in precision and reliability for EGFR mutation analysis. This novel methodology holds potential for more accurate and personalized cancer treatment strategies.

Humans