Richard A. Rudders

Primary extranodal lymphoma: response to treatment and factors influencing prognosis.

The cumulative 10 year lymphoma experience of a teaching hospital and two of its affiliated institutions was reviewed. From this group, a series of 39 cases of regionally localized primary extranodal lymphomas (Ann Arbor Stages IE and IIE) were selected for study. This group of patients was analyzed for response to initial curative treatment and factors influencing prognosis. The disease‐free survival rate following initial treatment is 41% and the rate is 51% if those treated for a single relapse are included. Factors which clearly influence prognosis in this group are stage (extent of disease) at presentation and Rappaport histologic subclassification. The relationships of anatomic site and age to prognosis independent of other factors are unclear. There appears to be an association between sites of involvement in Waldeyers Ring and the gastrointestinal tract seen both initially and in sites of relapse. An analysis of relapse patterns revealed that 33% of relapses occur as solitary extranodal “skip” recurrences that when treated with radical local treatment may result in long disease‐free survival. The latter is one of several findings which suggest that a modification of the current Ann Arbor staging system may be necessary to encompass certain unique features of this group of tumors.

Phase I evaluation of recombinant interleukin-2 in patients with advanced malignant disease.

Seventeen patients with refractory malignant tumors were treated with recombinant human interleukin-2 (IL-2) administered by weekly bolus intravenous (IV) injection in a phase I dose escalation trial. Patients received 10,000 to 1,000,000 U/m2 per injection over a course of 3 to 33 weeks. Toxicity was dose related and consisted primarily of fever, chills, nausea, and vomiting. Hypotension was observed at doses of 500,000 U/m2 or higher and in one instance was sufficiently severe to require pressors. No tumor regression was seen and all patients eventually developed progressive disease. Blood levels of cortisol, ACTH, prolactin, and growth hormone as well as the acute phase reactant C-reactive protein (CRP) increased after the administration of IL-2 in most patients. Serum IL-2 levels in excess of 250 U/mL were detected five minutes after an IV injection of 1,000,000 U/m2, after which the levels declined with a half-life of approximately 25 minutes. No alteration in lymphocyte surface phenotype or enhancement in natural cell-mediated cytotoxicity against natural killer (NK)-sensitive and resistant tumor cell lines was observed when these parameters were measured weekly just before the IL-2 injections. However, a dramatic but transient decline in circulating lymphocytes and NK activity was noted within hours of receiving IL-2. This effect was independent of fever and was not abrogated by pretreatment with ibuprofen or metyrapone. The majority of patients developed serum IgG antibodies of IL-2 detectable with a sensitive enzyme-linked immunosorbent assay (ELISA) and a nitrocellulose dot blot assay. The development of anti-IL-2 antibodies was not associated with symptoms suggestive of serum sickness, reductions in serum complement levels, or deterioration in lymphocyte tumoricidal activity. This investigation provides insight into the in vivo actions of this potent biological response modifier and will assist in the design of future studies with IL-2 administered alone or in conjunction with other treatment modalities.

Lymphocyte Subsets in Primary Biliary Cirrhosis

To ascertain whether abnormalities of circulating T-cell subsets are a cause or effect of primary cirrhosis, we analyzed peripheral blood lymphocytes from 44 patients at various stages of disease. The percentages of total T cells and helper/inducer cells were normal in early disease whereas the percentage of suppressor/inducer cells was increased. The percentage of all T-cell subsets fell steadily as the disease progressed histologically. The percentages in late (cirrhotic) disease were the same as those in patients with other types of cirrhosis. We conclude that most of the previously reported abnormalities of circulating T cells are secondary to the histologic progression of primary biliary cirrhosis.

Nodular non‐Hodgkin's lymphoma (NHL): Factors influencing prognosis and indications for aggressive treatment

In this study we have analyzed a group of 86 consecutive previously untreated patients with nodular lymphoma in order to determine those factors which adversely effect survival. Sixty‐two percent of these patients are still living; 23 patients for greater than 36 months. In contrast, 38% have died; 28% of them within 24 months of diagnosis. Striking correlations with short survival were seen with histiocytic cell type, Ann Arbor B symptoms and advanced age. Survival also declined with advanced stage but was A or B symptom dependent. The group was further subdivided into those with exclusively nodular and those with mixed nodular and diffuse histology in order to determine whether the presence of a diffuse component had a negative influence. No significant differences were found in survival patterns between these 2 groups. Our results clearly define a subgroup of nodular lymphoma patients with a poor prognosis which is likely to benefit most from aggressive treatment. The remaining patients are surviving for longer periods of time (albeit many not disease free) and the appropriate treatment for this group remains controversial.

Infectious mononucleosis in an adult progressing to fatal immunoblastic lymphoma.

We report a case of infectious mononucleosis progressing to fatal immunoblastic lymphoma. The patient, a 44-year-old man who may have had an immunoregulatory defect, failed to have an appropriate T-cell response to his Epstein-Barr (EB) viral infection. His active EB viral infection was manifest by seroconversion of IgM-viral capsid antibody and a greater than four fold rise in IgG-viral capsid antibody. Also, he transmitted his EB viral infection to his wife who became ill 1 month after his death. Clinically the patients illness was characterized by waxing and waning lymphadenopathy, persistent fever, diarrhea (similar to that associated with cholera), a coagulopathy, and gastrointestinal bleeding. The patient had pathologic findings of a diffuse immunoblastic lymphoma involving lymph nodes, small bowel, liver, pancreas, kidneys, lungs, and bone marrow. Immunologic cell markers showed the tumor to be polyclonal.

Clinical usefulness of 67gallium scanning in the malignant lymphomas

To determine the clinical usefulness of 67 gallium (Ga) scanning in the evaluation of patients with lymphomas, we reviewed 142 total body Ga scans performed on 44 patients with Hodgkins disease and 53 patients with non-Hodgkins lymphoma. Fifty-two per cent (123 of 236) of known disease sites were detected on scan. The false-positive rate was less than 5 per cent. The accuracy of detecting lymphoma varied in individual anatomic areas from 33 per cent in the axilla to 73 per cent in the thorax. In eight patients with bone involvement, all bone lesions were detected on scan. The size of the lesion appeared to influence accuracy, since tumors greater than 3 cm in diameter were more often positive.

Phenotypic and functional evaluation of suppressor cells in normal pregnancy and in chronic aborters

To evaluate the potential role of immunoregulatory cells modulating the maternal immunologic response during pregnancy, we carried out phenotypic and functional studies in patients with normal obstetrical histories during each trimester and in patients with chronic idiopathic spontaneous abortions. Using monoclonal antibodies (Ortho), total numbers of T cells (T3+) and T4+ cells progressively increased during pregnancy (compared to nonpregnant controls) and then declined in the third trimester. Increased percentages of T8+, T10+, and Ia+ cells were found in the third trimester. The relative decline in numbers of T4+ cells, with increased numbers of T8+ cells, led to a significantly reduced T4/T8 ratio in the third trimester. Histamine receptors on T cells were quantitated by an immunofluorescent technique. Significantly reduced numbers of H1-type receptors were noted during the second trimester of pregnancy and this was associated with a decreased H1/H2 ratio. Functionally, histamine-induced suppression was measured in a lymphocyte proliferation assay. Patients in the first and second trimester of pregnancy had greater histamine-induced suppression of phytohemagglutinin (PHA)-stimulated proliferation at high concentrations of histamine (10(-3) to 10(-7)) but less suppression at the lower concentrations (10(-9) to 10(-11) M), compared to nonpregnant controls. In contrast, patients studied in the third trimester failed to respond to any concentration of histamine. MLC-induced suppressor activity was generated by incubating the maternal cells with either paternal or third-party mononuclear cells for 2 or 6 days and assaying the cell-free supernatant for its suppressive effects on PHA-stimulated proliferation. Maternal responses to paternal cells did not result in significant suppression in 2-day supernatants during any trimester but by 6 days the suppressive activity was equivalent to non-pregnant controls in patients during the first and second trimester. Maternal responses to third party cells was greater during the second trimester than either the first or third trimesters in both 2- and 6-day supernatants. Patients with histories of chronic idiopathic spontaneous abortions, who were not pregnant at the time of study, exhibited normal numbers of T-cell subsets and T4/T8 ratios. Numbers of both H1 and H2 receptor bearing T cells were proportionally reduced, resulting in a normal H1/H2 ratio. Despite having decreased numbers of H1 and H2 receptor bearing cells, histamine-induced suppression of PHA-stimulated proliferation was comparable to nonpregnant controls over the concentration range (10(-3) to 10(-11) M) employed.(ABSTRACT TRUNCATED AT 400 WORDS)

Surface marker and histopathologic correlation with long‐term survival in advanced large‐cell non‐Hodgkin's lymphoma

Since 1974, a group of consecutive adult patients with non‐Hodgkins lymphoma have been prospectively analyzed for tumor‐surface membrane‐marker phenotype and histopathologic correlation with response to treatment and survival. The results are reported in a subset of 35 patients with advanced (Stages III‐IV) large‐cell variants, most of whom would be classified by Rappaport criteria as histiocytic. An attempt has been made to define those marker characteristics that will identify long‐term survivors in this diverse group who remain in continuous disease‐free remission. There were ten patients with complete remissions with intensive treatment. The most common subgroup within the complete responders were patients with cells that were nonexpressive (null) and were classified by Lukes‐Collins criteria as the large, noncleaved follicular center cell variant. Currently there are seven patients remaining in complete remission, five of whom have been in continuous disease‐free remission for more than two years (total survival 34+−42+ months) following cessation of all treatment. Of those five, four were in the null group and four were classified as large non‐cleaved. The actuarial survival curve for all null patients is characterized by a rapid initial decline and a subsequent plateau, which contains four of the long survivors. In contrast, the B‐derived group has a more graded decline in survival with time; this curve currently contains the remaining long survivor. Although the overall prognosis of B‐derived tumors appears to be superior to that of the null subset, the subgroup with the potential for cure at this point in our study includes patients with both null and B‐derived tumors, particularly those classified by Lukes‐Collins criteria as the large noncleaved follicular center cell variant.

Adult non‐Hodgkin's lymphoma. Correlation of cell surface marker phenotype with prognosis, the new working formulation, and the rappaport and lukes‐collins histomorphologic schemes

The interrelationships between histomorphologic classification, cell surface marker phenotype and prognosis were prospectively studied in 130 adults with non‐Hodgkins lymphomas. Within each of the classification schemes used there were certain histologic variants that exhibited heterogeneity of cell lineage as well as those that were extremely uniform. Diffuse lymphomas with cell populations consisting of large cells, or mixtures of large and small cells were the most heterogeneous phenotypically and were most resistant to precise definition of immunologic cell lineage. The new Working Formulation for Clinical Usage likewise exhibited considerable heterogeneity of phenotype even within well defined histomorphologic categories. Two immunologic phenotypic variables that conferred a significant favorable prognosis were the expression of surface membrane immunoglobulin (B derivation) and the simultaneous expression of a membrane μ and δ immunoglobulin heavy chain. The results of this study suggest that cell surface marker phenotypic determinations have well defined and potentially useful correlations with histomorphologic classification schemes, and are useful in predicting biologic behavior and prognosis. It is suggested that a knowledge of both immunologic phenotype and histomorphologic characteristics is necessary in formulating therapeutic decisions. Cancer 52:2289‐2299, 1983.

Non-hodgkin lymphoma arising in lower urinary tract

Primary involvement of the bladder and prostate by non-Hodgkin lymphoma is exceedingly rare. Usually bladder lymphoma can be cured by aggressive local therapy, but the prognosis of prostatic lymphoma is poor. The devastating clinical course of a young man with primary lymphoma involving the prostate and bladder base is reported to emphasize the heterogeneity of this group of tumors and to encourage precise tumor classification. Prognosis depends on the tumor stage and the specific lymphoma cell-type as defined by conventional histologic and immunologic criteria. Management should be tailored according to tumor grade, stage, and site.