Athanasios Theologides

Distinctive Chromosomal Abnormalities in Histologic Subtypes of Non-Hodgkin's Lymphoma

Using a new high-resolution technique for chromosomal analysis, we have successfully studied biopsy specimens of lymph nodes from 42 of 44 patients with non-Hodgkins lymphoma and have categorized them using the new international histologic formulation and immunologic markers. Abnormalities of the clonal chromosomes were detected in all 42 patients. Three recurrent chromosomal aberrations were found to correlate with certain histologic types: a translocation between chromosomes 18 and 14 in 16 of 19 patients with follicular lymphomas (small cleaved cell, mixed cell, and large cell); a translocation between chromosomes 8 and 14 in 5 of 6 patients with small noncleaved-cell (non-Burkitts) or large-cell immunoblastic lymphoma; and a trisomy 12 in 4 of 11 patients with small-cell lymphocytic lymphoma. Our findings suggest that characteristic chromosomal defects occur in certain lymphoma subtypes and that high-resolution chromosomal analysis promises to become an important tool in improving our basic understanding of lymphoid cancers.

Multiple recurrent genomic defects in follicular lymphoma. A possible model for cancer.

Several steps in the clinical evolution of human neoplasia are associated with a variety of recurrent chromosomal defects that could prove essential to the understanding of cancer. We found 15 types of nonrandom chromosomal abnormalities in a study of 71 patients with follicular lymphoma; 10 of the types appeared to influence the histopathological findings, clinical course, or response to treatment. A translocation, t(14;18), observed in 85 percent of all patients appeared to be the main determinant of a follicular pattern. Ten patients with a t(14;18) as a single defect had the histologic features of follicular small cleaved-cell lymphoma. Most did not require treatment for one to four years, because their tumors had an initial indolent course. In contrast, patients with follicular small cleaved-cell lymphoma with t(14;18) and deletion 13q32 acquired the hematologic features of leukemia and had an acceleration of the disease. A deletion 6q together with a complete or partial trisomy 7 or trisomy 12 (or both) was associated with the clinically more aggressive follicular mixed small- and large-cell or large-cell histologic type, which often evolves from follicular small-cell lymphoma. A complete or partial trisomy 3, 18, or 21 correlated almost exclusively with follicular large-cell lymphoma. In all follicular stages, a trisomy 2 or duplication 2p often accompanied an accelerated clinical course and a poor response to treatment. This study suggests that several discrete genomic defects may govern the evolution of a patients malignant disease.

Recurrent chromosomal defects are found in most patients with non-Hodgkin's-lymphoma

Using methotrexate cell synchronization, we successfully analyzed chromosomal preparations of 40 lymph node biopsies and one bone marrow sample from 44 patients with non-Hodgkins, non-Burkitts lymphoma. All of the 41 patients successfully analyzed showed clonal chromosomal abnormalities. In 25 of the 41 (61%), the defects were found to be consistent with (A) a deletion 6q in five of seven patients with diffuse large cell lymphoma, (B) a t(11;14), a del 11q, or a + 12 in seven of nine patients with small cell lymphocytic lymphoma, and (C) a t(14;18) in 12 of 15 patients with follicular lymphoma (small cleaved and mixed small and large cleaved) and in a single case of diffuse large cell lymphoma. In three patients with small cell lymphocytic lymphoma whose biopsies exhibited a t(11;14), lymphocytes were cultured and chromosomes examined for the presence of fragile sites. In two, frequent breaks at band 11q13.3 were observed. Such findings suggest a possible relationship between a fragile site and a predisposition to a specific chromosomal rearrangement in human neoplasia.

Pathogenesis of cachexia in cancer. A review and a hypothesis

The clinical features of cachexia characterized by anorexia, marked asthenia, significant loss of body fat, protein and other components, anemia, water and electrolyte abnormalities and increased basal metabolic rate and energy expenditure despite the reduced dietary intake are just the most obvious manifestations of a profound systemic derangement of the host metabolism. A hypothesis to explain the pathogenesis of cancer cachexia is proposed.

Comparative Studies of Blood Coagulation and Platelet Aggregation in Patients with Cancer and Nonmalignant Diseases

Abstract Blood coagulation and platelet function was evaluated in 106 hospitalized patients with cancer and compared with 40 patients with nonmalignant diseases and 50 normal subjects. The mean val...

Unfavorable Signs in Patients with Chronic Myelocytic Leukemia

Abstract The prognosis of an individual case of chronic myelocytic leukemia may be uncertain. The criteria for predicting the course of the disease, the response to chemotherapy, and the life expec...

THE ANOREXIA‐CACHEXIA SYNDROME: A NEW HYPOTHESIS

Anorexia is a common symptom in cancer. It can occur as an early manifestation of the disease, or it may appear as the malignant neoplasm grows and spreads. The direct relationship of the anorexia to cancer is appreciated better when it is present prior to the diagnosis of the cancer and when the anorexia disappears after a curative resection. After the diagnosis, psychological, emotional, and therapeutic factors can be incriminated for the anorexia, and the direct contribution of the tumor becomes less clearly defined. The decreased food intake that results from the anorexia plays a major role in the progressive weight loss and advancing cachexia of cancer, but, as can be demonstrated by forced feeding, paired feeding, and caloric restriction experiments in tumor-bearing animals, the malnutrition alone cannot account entirely for the progressive cachexia.’“ This is supported by clinical observations in which the hyperalimentation of the cancer patient by tube feeding resulted in improvement of his nutritional status,5~6 although this improvement was transient and could not be sustained for long periods; in approximately 50% of these patients, the forced feeding actually had a detrimental effect.‘ Though significant progress has been made in our understanding of the genesis of hunger and satiety, the signals that initiate and the mechanisms that co.itrol food intake have not been fully elucidated.8-21 A brief review of theories proposed for the regulation of hunger and satiety will facilitate the discussion of potential abnormalities of the regulatory mechanisms in the cancer patient.

Daunomycin inhibition of DNA and RNA synthesis

Daunomycin is a new antibiotic with antitumor activity against a variety of solid and ascites forms of transplantable animal tumors. It is effective in acute leukemias and certain solid tumors in children. Daunomycin has been considered to inhibit preferentially RNA synthesis, with inhibition of DNA only at higher concentrations, therefore having a biologic mechanism of action similar to actinomycin. The effect of this antibiotic on the 32P incorporation into DNA and RNA of 6C3HD ascites tumor in vitro and in vivo and also on the regenerating mouse liver after partial heptectomy has been studied. These observations indicate that Daunomycin is a more effective inhibitor of the synthesis of DNA than RNA, and hence the biologic mechanism of action of this antibiotic is probably different from that of actinomycin.

Combination versus successive single agent chemotherapy in lymphocytic lymphoma.

Fifty‐three patients with advanced lymphocytic lymphoma were randomly assigned to treatment with the combination cyclophosphamide, vincristine, and prednisone (CVP) or the same agents used successively in maximal doses (C‐V‐P). Complete remissions occurred in 68% with CVP and 48% with C‐V‐P. For patients with nodular lymphoma, the complete remission rate was 81% with CVP and 46% with C‐V‐P. In patients with diffuse lymphoma a complete remission rate of 50% was obtained with both regimens. The median duration of response was longer for patients who obtained complete remission with CVP (37+ months) than for those entering remission with C‐V‐P (25+ months). More patients treated with CVP still survive. Current results suggest that CVP is a better induction regime than C‐V‐P in patients with nodular lymphoma. However, in patients with diffuse lymphocytic lymphoma, neither regimen results in more than 50% complete remissions or significant numbers of prolonged responses. More effective therapy is needed.

Studies on the neutropenia of cancer chemotherapy

Cancer patients who are receiving chemotherapy are considered to be at an increased risk of infection when the peripheral neutrophil count falls below 2000 cells/mm3. To protect them from such risk, the treatment is discontinued. The size of the marginal neutrophil pool, the extent of marrow neutrophil reserves, the patients ability to develop a tissue neutrophil and mononuclear cell response to a non‐specific inflammatory stimulus, and the in vitro metabolic activity of neutrophils were measured in 25 patients with solid tumors betore and after a course of chemotherapy. Results indicate that infection only occurred with a depression of marrow neutrophil reserves and/or a depression in the tissue neutrophil and mononuclear cell response to non‐specific inflammation. The functional capability of neutrophils, as measured by the in vitro metabolic responses to phagocytosis of latex particles, remained intact despite peripheral neutropenia. Chemotherapy may be safely continued, despite peripheral neutropenia, as long as the marrow reserves and tissue leukocyte inflammatory responses remain intact.