Lymphocyte studies in familial chronic lymphatic leukemia

Immunologic and morphologic studies were performed on peripheral blood mononuclear cells from a mother and son with chronic lymphocytic leukemia. Results showed striking similarities between the two patients. The cells from both lacked detectable surface immunoglobulin and did not form sheep erythrocyte rosettes; thus, neither are clearly B cell or T cell in origin. A significant percentage of cells from both patients formed EAC rosettes whereas only a few were phagocytic. Peripheral blood mononuclear cells from both patients demonstrated diminished response to phytohemagglutinin, concanavalin A and pokeweed mitogen. Cells from both patients showed low levels of cytotoxic activity against antibody-coated target cells (ADCC). By light and electron microscopy, both patients' cells were small lymphocytes. Both mother and son had undetectable serum immunoglobulin M (IgM), borderline low immunoglobulin G (IgG), and lacked skin test reactivity to four common antigens. Their clinical courses have also been similar, with prolonged asymptomatic survival without therapy (10 and 18 years since diagnosis) in the presence of marked lymphocytosis, mild anemia and intermittent thrombocytopenia. Lymphocyte counts, skin tests and serum immunoglobulin levels are within normal limits in three siblings of the son. Because the accumulating cells in mother and son share morphologic, functional and surface marker characteristics, and result in similar impairments of cellular and humoral immunity, they may have arisen from similar subpopulations of cells.     

Blast crisis as an initial or terminal manifestation of chronic myeloid leukemia. A study of 28 patients.

The clinical and morphologic features of nine patients who initially presented with blastic leukemia and the Philadelphia chromosome were studied. Corresponding features were evaluated at the time of diagnosis of blast crisis in 19 patients who had a previous history of chronic myeloid leukemia (CML). Although many of the presenting symptoms and signs were similar, infections, lymphadenopathy, tissue infiltration and central nervous system involvement were more common in patients who presented with blastic leukemia. Marked leukocytosis, basophilia and marrow hypercellularity were present in both groups. Although patients in both groups had morphologic patterns that resembled acute leukemia, cytology suggestive of acute lymphocytic leukemia was more frequent in patients who initially presented with blastic leukemia. Megakaryocyte, platelet and erythroid abnormalities were more frequent in patients with a prior history of CML. Although there were clinical and morphologic features in the patients who presented with blastic leukemia which suggested the diagnosis of CML in blast crisis, chromosome studies were necessary to identify some of these patients. In both groups of patients multiple therapeutic regimens were used. Complete remissions were obtained in two patients; both presented with blastic leukemia, had "lymphoblastic" morphology and were treated with chemotherapeutic agents generally used for the treatment of acute lymphocytic leukemia. It appears that morphology of the blast crisis may be important in choosing the treatment regimen.     

Post-transplant malignant lymphoma: Distinctive morphologic features related to its pathogenesis

Malignant lymphoma developed in two patients after renal transplantation. In both, the central nervous system was involved. Histologic study of the tumors showed that they were composed of a monomorphous proliferation of cells characterized by a large vesicular nucleus, prominent basophllic nucleolus and strongly pyroninophilic cytoplasm. The tumors thus would be classified as “diffuse large lymphoid lymphomas with pyroninophilia” or “immunoblastic sarcomas” as described in the literature. Tumor cells resembled cells observed in the paracortex of antigenically stimulated lymph nodes, cells from malignant lymphomas in mice that were antigenically stimulated and from malignant lymphomas in patients with immunodeficiency diseases or autoimmune disorders. The distinctive morphologic features of the tumors in the transplant recipients described provide further evidence that long-term antigenic stimulation may be important in their pathogenesis.     

Etiology and prognosis in acute post-transplant renal failure

During the last seven years we encountered 117 cases of acute renal failure after 492 renal transplants. The affected patients fall into two general groups that can be broadly identified by an ¹³¹I-Hippuran renogram: Those in whom low or no uptake is evident on the renogram (group 1) and those in whom good uptake is evident on the renogram (group 2). Fifty per cent of the patients in group 1 have renal arterial thrombosis or hyperacute rejection. These patients should have a renal arteriogram, and immediate nephrectomy may be necessary. The prognosis in these patients is very grave. In group 2, 89 per cent of the patients have acute tubular necrosis, and they do not differ prognostically from patients who experience immediate renal function. Invasive diagnostic procedures should be avoided in this group because they may increase the mortality rate. We believe that repeated renograms, a reduction in azathioprine dosage and careful dialysis is the only treatment necessary.     

Upper airway obstruction during head flexion in morquio's disease

Previous reports of pulmonary function in patients with Morquio's disease have emphasized the restrictive nature of their ventilatory defect. We describe a patient in whom pulmonary disability was secondary to upper airway obstruction from collapse of the trachea during head flexion. The same phenomenon was demonstrated in one of two other patients with Morquio's disease, both of whom were asymptomatic. Positionally dependent airway obstruction may be an important cause of pulmonary disability in Morquio's disease.     

Selection of vasodilator, inotropic or combined therapy for the management of heart failure

Vasodilator and inotropic drugs work through independent mechanisms in augmenting left ventricular pump function in patients with heart failure. The selection between these two classes of pharmacologic agents for an individual patient may be based on the control blood pressure as well as the underlying disease. Although vasodilator drugs are easiest and safest to employ in patients with normal or high arterial presure levels, even in relatively hypotensive subjects (systolic arterial pressure less than 105 mm Hg), a salutary hemodynamic effect can be achieved without an undue decrease in pressure. Inotropic drugs may be safest to administer to patients without coronary artery disease, but the oxygen-consuming effect of these drugs need not necessarily have an adverse effect on patients with ischemic heart disease. Combined vasodilator and inotropic drug therapy is the most potent pharmacologic means of restoring pump function in patients with severe heart failure. The long-term use of vasodilator and inotropic drugs in the treatment of heart failure is dependent on the availability of agents that will produce a sustained hemodynamic effect. Hydralazine, nitrates and prazosin have been employed alone or in combination and provide a promising approach to vasodilator treatment of heart failure. Better and more selective oral inotropic agents are needed to allow this therapeutic modality to be employed optimally.     

Association of renal allograft rejection with virus infections

Sixty-one immunosuppressed renal transplant recipients were systematically screened for virus infections and the findings correlated with their clinical course. Only herpesvirus (cytomegalovirus, herpes simplex and herpes zoster) were consistently isolated. The onset of virus infections could usually be associated with clinical syndromes. Patients without virus infections were usually asymptomatic. The clinical syndrome associated with virus infection consisted of fever, leukopenia and renal allograft rejection. Renal biopsy, performed at the time serum creatinine levels were elevated, revealed classic rejection; most rejections were reversed by increasing the dose of steroids. Patients continued to excrete virus even after antibody response and clinical recovery. Virus infections do not appear to be incidental findings in transplant patients except after recovery when the virus persists in the immune patient. The clear-cut association between virus infection and rejection episodes suggests a pathogenic relationship. The two mechanisms which seem to best explain the relationship are (1) the virus infection acting as an adjuvant and triggering the rejection of the allograft or (2) the allograft rejection activating a latent virus infection.     

Vinblastine, bleomycin and cis-diamminedichloroplatinum in the treatment of advanced testicular carcinoma. Possible importance of longer induction and shorter maintenance schedules

Twenty-eight patients with stage III or recurrent stage I or II testicular cancer were treated with four to six cycles of vinblastine, bleomycin and cis-diamminedichloroplatinum, and then with vinblastine maintenance for one year. With a median follow-up of more than 20.5 months for all patients, complete remission has been achieved with chemotherapy and operation in 23 (82 per cent). One of these 23 patients has had a relapse, and only three are still receiving maintenance therapy. The toxicity incurred by the extra cycles of chemotherapy in patients with extensive disease was no greater than that experienced by patients receiving smaller doses of drugs. These results confirm the high response rate reported for this combination of drugs and strongly suggest that some relapses after complete remission can be prevented by longer remission induction schedules. The value of maintenance therapy is questionable and needs further study.     

B and T cell lymphomas: Analysis of blood and lymph nodes in 87 patients

B and T cell populations were studied in blood and neoplastic tissues from 64 untreated and 23 treated patients with non-Hodgkin's lymphoma. This study was undertaken primarily to evaluate the relation of B and T cell markers in various lymphomas to the currently accepted morphologic classifications and to determine the utility of various tissues in defining the cell of origin of a lymphoma. When histologically involved blood, bone marrow, lymph nodes or body fluids were studied, a B or T cell origin of the lymphoma was identified in 26 of 28 (68 per cent) patients. A B cell origin was found in 17 adults classified as having nodular (N) or diffuse (D) poorly differentiated lymphocytic lymphoma (PDLL). One lymphoma of T cell origin was observed in an adult with poorly differentiated lymphocytic lymphoma-diffuse (PDLL-D). In contrast, all cases of PDLL-D in children were T cell in origin. The origin of American Burkitt's (stem cell) lymphoma in two children was the B cell. When histologically involved blood was studied, a B or T cell origin was demonstrated in 10 of 21 (48 per cent) adults. Evidence of a monoclonal proliferation of B lymphocytes in the blood was found two adults with more than 7 per cent lymphoma cells in Wright-Giemsa stained blood smears. When neoplastic lymph nodes were studied, the diagnosis of a B cell lymphoma was made in 8 of 12 (67 per cent) adults. Study of surface markers on malignant cells in cerebrospinal or serosal fluids frequently revealed a B or T cell origin of the lymphoma. B and T lymphocyte numbers in the blood did not correlate with immunoglobulin or skin test abnormalities. Abnormalities in circulating B or T cell percentages at diagnosis were a poor prognostic sign in patients with PDLL-D.     

Reversal of myelofibrosis in advanced breast cancer

Reversal of myelofibrosis and splenomegaly is described in a 41 year old woman with metastatic breast cancer. After intensive chemotherapy and hormonal therapy, the tumor regressed, the splenomegaly receded, the hemogram showed no abnormalities, and the dense collagen and reticulin fibers in the marrow disappeared. The severe thrombocytopenia and leukoerythroblastosis noted before therapy were not obstacles to clinical management. In our report we document that myelofibrosis associated with breast cancer is not an ominous sign. Patients may benefit from an intensive, but well titrated, therapeutic program.     

Immunodeficiency,xanthomas and obstructive liver disease

Chronic obstructive liver disease and secondary hyperlipidemia developed in an immunodeficient boy. Sequential addition of cholestyramine and phenobarbital to his medical regimen, following an initial response to bile drainage, resulted in the disappearance of xanthomas and pruritus, and the restoration of normal serum concentrations of liplds and bile acids. This improvement may result from shifting the bile acid pool from the peripheral blood compartment to the enterohepatlc circulation.     

Lack of age-dependent cisplatin nephrotoxicity

Cisplatin nephrotoxicity was evaluated by serial pretreatment and post-treatment 24-hour creatinine clearance determinations in 43 patients who received 295 monthly infusions of 60 mg/m2 of this drug. An aggressive standard hydration protocol was used without diuretic administration. Fourteen of these patients had a single kidney. Older patients and patients with a single kidney had lower pretreatment creatinine clearances when compared with younger persons with two functioning kidneys. Older and younger patients with two kidneys had an equal, progressive, dose-related deterioration of renal function. Renal function did not decline in persons with a single kidney but did so markedly in those with two kidneys. When administered at 60 mg/m2, cisplatin dose or schedule modification is not indicated on the basis of advancing age or decreased renal function secondary to the surgical loss or total ureteral obstruction of one kidney.     

Autoimmune hemolytic anemia in association with monoclonal IgM(kappa) with anti-i activity.

A patient with a warm autoimmune hemolytic anemia with an immunoglobulin G (IgG) panagglutinin, also had monocional IgM(kappa) cold agglutinin with anti-i activity. Ninety per cent of the peripheral blood lymphocytes had surface immunoglobulin and the number of T cells was diminished. A subpopulation of the patient's lymphocytes formed rosettes with cord (i) erythrocytes and not with adult (l) erythrocytes. The finding of increased lymphocytes bearing i-binding sites and a monoclonal antibody with anti-i activity could be related to shared idiotypic determinants between antigen-binding sites and serum antibody. The occurrence of two autoantibodies in this patient suggests an immune regulatory disorder.     

Comparison of effectiveness of thyrotropin-suppressive doses of d- and l-thyroxine in treatment of hypercholesterolemia

In an attempt to compare the cholesterol-lowering effects of equivalent doses of d- and l-thyroxine, 10 euthyroid, hypercholesterolemic subjects were treated with graded doses of each medication in a cross-over design using thyrotropin suppression following thyrotropin-releasing hormone administration as the end-point. The mean thyrotropin-suppressive dose of d-thyroxine was 2.4 ± 0.66 mg per day, which resulted in mean reductions of 10 percent in total plasma cholesterol, 10 percent in plasma low-density lipoprotein cholesterol, and 11 percent in plasma high-density lipoprotein cholesterol. The mean thyrotropin-suppressive dose of l-thyroxine was 135 ± 46 μg per day, which resulted in mean reductions of 7 percent in total plasma cholesterol, 6 percent in plasma low-density lipoprotein cholesterol, and 14 percent in plasma high-density lipoprotein cholesterol. The reductions in total, low-density, and high-density cholesterol achieved with d-thyroxine were not significantly different from those achieved with l-thyroxine. Neither medication produced a significant increase in heart rate or ventricular ectopy as determined by Holter monitoring. These data do not support the belief that d-thyroxine has a preferential cholesterol-lowering effect in humans when compared with equivalent doses of l-thyroxine. In addition, both d- and l-thyroxine reduced plasma high-density lipoprotein cholesterol.     

Successful renal transplantation in patients with prior history of malignancy

Eleven selected patients with a history of cancer have received renal transplants. In three patients the malignancies were diagnosed and treated before renal failure developed, two patients underwent bilateral nephrectomies for the treatment of bilateral renal malignancy. In six patients the malignancy developed while they were uremic, and they received transplants after treatment of the tumor. Recurrent tumor developed in only One of the 11 (9 per cent) patients after receiving the transplant. Thus, patients with a history of malignancy can receive a transplant without accelerating growth of the tumor. We recommend a minimum period of one year between tumor treatment and transplantation to observe for tumor recurrences or metastases. A longer period of observation may be necessary in patients who have tumors with a poorer prognosis.     

The role of complement,immunoglobulin and bacterial antigen in coagulase-negative staphylococcal shunt nephritis

We describe three patients with arrested hydrocephalus in whom glomerulonephritis developed secondary to Staphylococcus epidermidis bacteremia from an infected ventriculoatrial shunt. Investigation of the immune-mediated renal disease associated with this chronic infection showed that (1) complement depletion during the acute phase of bacteremia and nephritis was predominantly via the classic pathway; (2) rheumatoid factor was associated with bacteremia, fever, proteinuria and low complement levels; (3) early complement components (C1q, C4, C3), immunoglobulin (predominantly immunoglobulin M [IgM]), Staph. epidermidis antigen(s) and electron dense subendothelial deposits were localized within the renal glomerulus; (4) C1q and IgM derived from patient serums, were the most prominent in vitro immunoreactants to Staph. epidermidis cell walls; and (5) the causative organisms, Staph. epidermidis, shared common antigens with Staph. aureus, and antibody from patient serums cross reacted with extracts from both of these organisms.     

Fever in renal transplant recipients: causes, prognostic significance and changing patterns at the University of Minnesota Hospital

During a three year period in which 433 renal transplants were performed, 194 episodes of fever were documented in allograft recipients hospitalized at the University of Minnesota. Viral infections were responsible for over half of the febrile episodes, and 98 (51 percent) of the fevers were associated with cytomegalovirus (CMV), either occurring alone or in conjunction with allograft rejection or another systemic infection. Bacterial infections, fungal infections and rejection were other important causes of fever, accounting for 14 percent, 5 percent and 13 percent of the febrile episodes, respectively. Most fevers occurred in the first four months after transplantation; although about two thirds of these fevers were due to CMV, only 17 percent of fevers that occurred more than one year after the renal transplant were due to CMV. Bacterial and fungal infections and malignancy were important causes of these fevers. Of the febrile illnesses associated with transplant nephrectomy or death, a majority occurred in patients with CMV disease. Secondary bacterial and/or fungal infections were observed in a large majority of patients with lethal CMV disease. During the third year of this study there was a significant decrease in the proportion of febrile episodes due to CMV.     

Hypocellular acute leukemia

We examined the clinical features and therapeutic response of a group of patients with acute leukemia and hypocellular bone marrow. Therapists have generally avoided, delayed or modified therapy because of hypocellularity. We demonstrated not only that aggressive therapy is possible, but also that the remission rate is high (complete remission = 73 percent) and survival prolonged (x? > 40 months).     

Cellular immunologic studies of a patient with monocytic leukemia.

Cellular immunologic studies were performed on the leukemic cells of a 59 year old white man with monocytic leukemia. Morphologically, most circulating leukocytes were monocytes. They demonstrated Fc and C3 (third component of complement) receptors, phagocytized latex particles, showed In vitro cytoplasmic spreading and lysed antibody-coated chicken erythrocytes. Phagocytosis of, as well as rosetting with, C3-coated erythrocytes and very rapid cytoplasmic spreading suggested in vivo monocyte “activation.” The cells were easily maintained in primary culture for up to 13 weeks, with acquisition of typical macrophage morphology. In addition, nearly all cells demonstrated surface immunoglobulin (Slg) which was (1) trypsin-sensitive and did not regenerate in culture, (2) could be restored after trypsinization by incubation of cells In autologous or normal serum and (3) persisted in culture on 75 per cent of cells for at least seven days. Fluoresceinated monospecific antiserums showed an immunoglobulin G (IgG), kappa pattern on one occasion and an IgG, kappa, lambda pattern on another. Eluates of the cells prepared on three occasions showed only IgG and kappa reactivity using numerous antiserums. We concluded that most Slg was probably Fc-receptor bound with unusually high affinity and with greater representation of IgG (kappa) than IgG (lambda). These studies suggest that apparent “monoclonal” Slg does not necessarily indicate a truly clonal proliferation of B cell origin.     

24-hour mean pulse. Simple predictor of doxorubicin-induced cardiac damage

Nineteen adult patients with cancer received six to 10 monthly treatments of doxorubicin and cisplatin. Recumbent pulse was measured for 24 to 30 hours before each treatment. Treatment was stopped for disease progression or when a total doxorubicin dose of 550 mg/m2 was reached. Rising serial 24-hour pulse averages predicted congestive heart failure reliably. No patient had congestive heart failure during therapy, but three patients had congestive heart failure two to four months after receiving 540, 525, and 530 mg/m2 of doxorubicin. In these, two to six months before completion of therapy, the 24-hour rhythm-qualified mean (mesor) of pulse showed a positive slope by linear regression analysis (p less than 0.05) that was apparent at cumulative doxorubicin doses of 300, 420, and 240 mg/m2. All 19 patients received similar total doses of doxorubicin and were followed to death or 12 months after the last doxorubicin dose. In addition, a progressive rise in the 24-hour mean pulse coincided with histologically documented doxorubicin-induced lethal congestive heart failure in Wistar-Kyoto rats of both sexes.