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Amyloidosis is a rare systemic disease caused by extracellular deposition of an insoluble protein. Although it is usually seen in a systemic form, 10%-20% of cases can be localized. Systemic amyloidosis is subclassified into an idiopathic primary form and a secondary or reactive form. Patients with primary amyloidosis have no underlying condition or disease. Men are affected more than women, and the mean age at presentation is 55-60 years. Some causes of secondary amyloidosis are multiple myeloma (10%-15%), rheumatoid arthritis (20%-25%), tuberculosis (50%), or familial Mediterranean fever (26%-40%). Radiographic studies of 90 patients with biopsy-proved primary or secondary amyloidosis were reviewed. Computed tomographic (CT) scans demonstrated a wide spectrum of disease in the cardiothoracic, gastrointestinal, genitourinary, and musculoskeletal systems. Amyloid deposition simulated both inflammatory and neoplastic conditions. Amorphous or irregular calcifications were occasionally identified within the amyloid deposit. Definitive diagnosis requires biopsy confirmation, as CT findings are nonspecific.

We report the clinical findings and analysis of the immunoglobulin (Ig) composition of the vitreous of a 10-year-old girl with juvenile rheumatoid arthritis-associated uveitis. The vitreous had a schlieren appearance at the time of pars plana lensectomy and vitrectomy. Analysis of the vitreous fluid revealed marked elevation of IgG, IgM, IgA, and albumin levels relative to vitreous fluids from control patients without uveitis. The immunoglobulin coefficients were also elevated for the IgG and IgM classes of immunoglobulins. Immunofixation electrophoresis of the vitreous fluid revealed 2 distinct bands of restricted electrophoretic mobility. These studies suggest that there may be local (intraocular) production of immunoglobulins as an immunologic response in ocular inflammatory diseases such as juvenile rheumatoid arthritis-associated uveitis and that this immunologic response may be monoclonal (possibly biclonal or oligoclonal) in nature.

Atypical vancomycin pharmacokinetics were observed in an immunoglobulin A myeloma patient. Drug concentrations in serum were extremely elevated, the elimination half-life was prolonged despite normal renal function, and the vancomycin therapy was ineffective. Extensive binding of vancomycin, presumably by high concentrations of an aberrant immunoglobulin A protein, may have accounted for these observations.

Two patients with multiple myeloma in relapse after allogeneic BMT received donor lymphocyte infusions (DLI) but later required chemotherapy for treatment of myeloma-related complications. In both patients, recovery from chemotherapy-induced aplasia was accompanied by manifestations of graft-versus-host reactions. The first patient developed grade II acute GVHD and a complete remission which has lasted >22 months. The second patient developed grade III acute GVHD but died with co-existing GVHD and extensive extramedullary myeloma. These results demonstrate that chemotherapy does not nullify the ability of donor lymphocytes to mediate graft-versus-host reactions.

Amyloidosis is a rare cause of myopathy. Its prominent or presenting feature may be respiratory failure. Physiological measurement of transdiaphragmatic pressure and biopsy specimens of muscle show the pathological mechanism to be diaphragm weakness due to amyloid infiltration of the diaphragm rather than parenchymal lung involvement. Thus amyloid myopathy even without the typical macroglossia and muscle pseudohypertrophy should be considered as one of the neurological causes of respiratory failure.

Hydroxyethyl starch (HES), a glucopyranose polymer used to enhance the yield of granulocytes during leukapheresis, was detected by periodic acid-Schiff (PAS) staining of 1-microliter samples following electrophoresis on thin agarose film. HES migrated with restricted electrophoretic mobility in the far gamma region, and the intensity of staining was found to be concentration dependent. Densitometer scanning showed a linear curve from 30 mg to 600 mg per dl, although bands were identified at concentrations lower than 30 mg per dl. Sera from 46 leukapheresis subjects showed the same restricted bands. HES measured retrospectively in sera obtained on days 1 to 400 following apheresis ranged from 675 to 30 mg per dl. The clearance of HES from the sera of four donors measured serially appeared biphasic with the first T1/2 of 0.4 to 6.4 days and the second T1/2 of 58 to 240 days. HES also was detectable in urine concentrated 100fold for as long as 7 days following leukapheresis . This simplified, and sensitive PAS glycoprotein staining method can be used to detect and follow HES concentrations in serum and may provide a new tool for the study of HES in leukapheresis donors.

Malignant plasma cell proliferation and induced humoral stimulatory activity (HSA) occur in vivo at a predictable time following drug administration. Sequential sera from 11 patients with poor-risk multiple myeloma (MM) undergoing treatment with Cytoxan (CY) 2400 mq/sq m were assayed for their in vitro effects on malignant bone marrow plasma cell tritiated thymidine (3HTdR) incorporation. Peak HSA was detected day 9 following CY. Sequential changes in marrow malignant plasma cell 3HTdR-labeling indices (LI) paralleled changes in serum activity, with peak LI occurring at the time of peak HS. An in vitro model of chemotherapy demonstrated that malignant plasma cell proliferation was enhanced by HSA, as determined by 3HTdR incorporation assay, 3HTdR LI, and tumor cells counts, and that stimulated plasma cells were more sensitive to cytotoxic effects of adriamycin (ADR) than were cells cultured in autologous pretreatment serum. Based on these studies, we designed a clinical trial to treat 12 CY-refractory poor- risk patients with MM in which ADR (60 mg/sq m) was administered at the time of peak HSA and residual tumor cell LI (day 9) following initial CY, 2400 mg/m (CY1ADR9). Eight of 12 (67%) responded to timed sequential chemotherapy with a greater than 50% decrement in monoclonal protein marker and a median survival projected to be greater than 8 mo duration (range 4–21+ mo). These clinical results using timed sequential CY1ADR9 compare favorably with results obtained using ADR in nonsequential chemotherapeutic regimens.

We have modified the periodic acid-Schiff staining technique for glycoproteins for use with thin agarose-film electrophoresis membranes. With this procedure, carbohydrate-rich proteins can be detected with negligible background staining and insignificant staining of nonglycoproteins such as albumin and nonglycosylated Bence Jones proteins (free light chains). On the other hand, carbohydrate-rich M components of immunoglobulins M and A in serum and in cerebrospinal fluid from patients with plasma cell dyscrasia are readily detected. The technique is two- to threefold more sensitive than Ponceau S. Glycoproteins in serum and body fluids can be determined as a routine analytical procedure.

We report an infant with abnormally elevated levels of TSH determined in the Maryland State Laboratory for Neonatal Thyroid Screening, but normal levels in three other laboratories. The TSH level in the infant normalized by six months of age. The mother, who had a history of sarcoidosis, also had factitious hyperthyrotropinemia in the Maryland State Laboratory. Gel chromatography and ammonium sulfate precipitation of maternal serum demonstrated that the factor responsible for the factitious hyperthyrotropinemia was an immunoglobulin G. Maternal TSH levels in the Maryland State Laboratory were normalized by treatment of serum with polyethylene glycol. However, protein electrophoresis, immunoglobulin levels and immunofixation electrophoresis were all normal. We conclude that a subclass of immunoglobulins G, probably resulting from sarcoidosis, interfered with the precipitation of the TSH-antibody complex in the TSH radioimmunoassay of the Maryland State Laboratory.

Mixtures of BALB/c bone marrow (5 X 10(6) and LPC-1 myeloma (2 X 10(6) cells have been purged in vitro with 100 microM 4-hydroperoxycyclophosphamide (4HC) for 30 min at 37 degrees C. Elimination of tumor cells was assessed by monitoring newly synthesized tumor-specific IgG 2a kappa in vitro and by reinjecting the cells subcutaneously into the hindlegs of mice. Drug-treated LPC-1 cells had no detectable tumor production and did not reproduce tumors. Untreated cells regrew as solid tumors and killed the host within 3-4 weeks. Bone marrow cell suspensions purged of tumor cells were then used to reconstitute lethally pretreated mice injected 24 h earlier with 300 mg/kg cyclophosphamide (CY). Mice injected with CY alone died within 10 days. Those reconstituted with bone marrow cells or with purged bone marrow-tumor cell mixture lived longer than 7 months. Mice reconstituted with untreated bone marrow-tumor cell suspension grew tumors, had detectable tumor-specific IgG 2a kappa in their serum, and died by day 44. These studies demonstrate that the success of myeloma cell purging can be determined by monitoring newly secreted tumor protein and that 4HC successfully eliminates malignant plasma cells in vitro without impairment of normal bone marrow stem cell functions.

1. The clinical manifestations, laboratory data and renal histologic features of acute renal failure occurring in 14 patients with multiple myeloma are reviewed and contrasted with the data from 29 previously reported cases. 2. Whereas other reports have stressed the role of intravenous pyelography and dehydration in the development of acute renal failure in multiple myeloma, the most common etiologic factor in our experience was hypercalcemia (7 patients). Other factors included potentially nephrotoxic antibiotics (3 patients) and volume depletion (2 patients). Intravenous pyelography could be clearly implicated in ony one patient. 3. The unusually high incidence of Bence Jones proteinuria in these patients is consistent with the possibility that Bence Jones protein excretion is associated with an increased susceptibility to renal injury. This could be due to an adverse effect of Bence Jones proteins on the renal tubules or their tendency to precipitate in tubular lumina during periods of reduced tubular flow. 4. The prognosis of patients with multiple myeloma who develop acute renal failure is poor; only 5 of our 14 patients survived the early period of acutely impaired renal function, and 4 of these subsequently died within 2 months. Preventive measures particularly the prompt correction of hypercalcemia and volume depletion, are the most important aspects of patient management.

The early phase of LPC-1 plasmacytoma development was studied by in vivo labeling with [6-14C]arginine using its M component (immunoglobulin G 2a,kappa) as marker. At a time when M component was not detected or faint by protein staining of electrophoretograms, significant labeling of M component was detectable by autoradiography. Labeling of the M component was fairly constant for the first 10 hr but was markedly decreased from Days 1 to 7. Nadir (0 to 3% of initial 30-min value) was observed on Day 3. Recovery of M component labeling to the 30-min level was complete by Day 13. This period of marked reduction or "eclipse" in newly synthesized M component was shortened by 2 days when mice were pretreated with pristane or cyclophosphamide prior to tumor cell transfer. The eclipse period was also 2 days shorter in athymic BALB/c-nu/nu mice than in normal BALB/c mice. The eclipse period corresponds to the classical "lag" following tumor cell transfer before tumor growth can be detected by conventional methods. The sensitivity of the [6-14C]arginine pulse permits the in vivo detection of small numbers of tumor cells (as few as 10(6) cells) over the early time periods after cell transfer. Modification of eclipse by manipulating host and/or tumor cells may elucidate the accompanying cellular and biochemical events.

A simple and reproducible histochemical method for distinguishing different chemical types of amyloid is described. The method is based on the affinity of amyloid for Congo red dye after exposure to potassium permangenate and dilute sulfuric acid. The permanganate method represents a modification of the Romhanyi trypsin technique. It yields comparable results while obviating some of the technical difficulties associated with the latter method. The permanganate reaction was applied to a series of amyloid samples of known amino acid composition, to amyloid samples fixed in a variety of different preservatives, and to tissues obtained at autopsy from 67 amyloidosis patients whose disease had been previously subclassified on the basis of clinical presentation and autopsy observations. This method distinguished amyloid protein AA from other varieties of amyloid and proved effective when applied to amyloid samples preserved in any of several commonly used fixatives. This simple histochemical method proved useful in subclassifying amyloid type in the patient series particularly when used in conjunction with the available clinical history and the organ distribution of amyloid accumulation.

Serum protein electrophoresis (SPEP) data obtained at diagnosis were available for 98 of 342 patients with chronic lymphocytic leukemia (CLL) identified in a population-based case-control epidemiologic study. Patients tested with SPEP at diagnosis were significantly younger, more likely to have lymphadenopathy, and more likely to have had their conditions diagnosed at a university hospital than those not tested. Four categories of electrophoretic patterns were identified: normal (N = 56), hypogammaglobulinemia (N = 28), hypergammaglobulinemia (N = 11), and monoclonal gammopathy (N = 3). A higher proportion of those with hypergammaglobulinemia were black, and patients with hypergammaglobulinemia and monoclonal gammopathy were more likely to die within the first year following diagnosis than patients in the other SPEP groups. No association was found, however, between SPEP pattern and a clinical staging classification for CLL. These findings suggest that SPEP may be a useful adjunct in categorizing possible subtypes of CLL and developing future clinical staging classifications.

We have modified the periodic acid-Schiff staining technique for glycoproteins for use with thin agarose-film electrophoresis membranes. With this procedure, carbohydrate-rich proteins can be detected with negligible background staining and insignificant staining of nonglycoproteins such as albumin and nonglycosylated Bence Jones proteins (free light chains). On the other hand, carbohydrate-rich M components of immunoglobulins M and A in serum and in cerebrospinal fluid from patients with plasma cell dyscrasia are readily detected. The technique is two- to threefold more sensitive than Ponceau S. Glycoproteins in serum and body fluids can be determined as a routine analytical procedure.

A 62-year-old black female with Kaposi's sarcoma associated with multiple myeloma is reported. The co-existence of the two entities in the same patient appears more than coincidental. The case is the first woman and only the fifth described with Kaposi's sarcoma associated with multiple myeloma.

Serum RNase levels were measured in 34 patients with multiple myeloma and compared with 51 normal controls and 28 non-myeloma patients on chronic hemodialysis. Nineteen of the myeloma patinets with creatinine clearance (CCr) greater than 50 ml/minute had mean serum RNase levels that were statistically indistinguishable from those of the normal controls. The 15 myeloma patinets with CCr less than 50 ml/minute had mean RNase levels much higher than normal controls or myeloma patients with normal renal function. Patients without myeloma but on hemodialysis for chronic renal failure of varied etiologies had markedly elevated serum RNase levels. A strong correlation between RNase levels and renal insufficiency, as measured by CCr, has thus been demonstrated. In addition, case histories of 5 representative myeloma patients were analyzed in greater detail; they illustrated the rise and fall of RNase levels as a function of the status of their renal insufficiency, regardless of the extent of the underlying myeloma. We concluded that the serum RNase level was an indicator of renal function, and was not a biomarker either for the presence or extent of the plasma cell tumor.

A case of multiple myeloma in a 41-year-old white man that resulted in chronic renal failure is discussed. During the period of hemodialysis treatment, remission of the patient's myeloma was induced by chemotherapy. Thereafter a transplanted cadaver kidney functioned well for 3.5 years despite episodes of sepsis, administration of nephrotoxic chemotherapeutic agents, and recurrence of the myeloma with intermittent excretion of Bence Jones protein in the urine. The results of this fully documented case, as well as two other cases we have previously reported, support the strategy of offering cadaver renal transplantation to carefully selected individuals who require long-term dialysis and whose myeloma is in remission after chemotherapy.

Two unusual cases of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD), with progression to immunoblastic lymphoma (IL) and prominent gastric involvement are presented, and detailed immunohistologic studies described. In one case, Bence Jones proteinuria of the kappa type was observed during the course of AILD and was identified immunohistochemically in lymph node biopsy specimens and at autopsy. The potential significance of an M component and the importance of recognizing gastric involvement by AILD are discussed.

To expand on the findings from previous clinical trials that the growth of residual tumor is increased at a predictable time following initial drug administration, malignant plasma cells from bone marrows of patients with multiple myeloma (MM) were examined for changes in proliferation and clonogenicity induced in vivo by cyclophosphamide and in vitro by drug-induced humoral stimulatory activity. Peak plasma cell [3H]thymidine labeling index (LI) occurred predictably following drug and paralleled changes in agar colony formation by marrow cells obtained during therapy. Colony-forming capacity of pretreatment MM marrow populations was enhanced when those cells were cultured with humoral stimulatory activity, similar to the increased colony formation detected in Day 9 postcyclophosphamide marrows at the time of peak plasma cell LI. To further define a relationship between proliferative plasma cells and colony-forming tumor cells, MM marrows were fractionated by sedimentation on an isokinetic gradient. Enrichment of a proliferative tumor cell cohort was achieved, evidenced by [3H]thymidine LI. Colony-forming cells were also enriched by isokinetic gradient sedimentation, and agar colony formation by MM marrow cell fractions correlated with the kinetic characteristics of the isolated subpopulations. These studies of whole and fractionated human MM marrow cell populations suggest that the kinetically active cells which are induced to proliferate in vivo and in vitro are closely related to the clonogenic tumor cells which produce colonies in agar and which, like those cells measured by [3H]thymidine LI, respond to growth stimulation by drug-induced humoral stimulatory activity.

In a population-based case-control study carried out in the Baltimore, Maryland metropolitan area, family cancer history for 342 chronic lymphocytic leukemia cases diagnosed in 1969-1982 revealed significantly higher risks of leukemia as well as other hematolymphoproliferative neoplasms and breast cancer among their first-degree relatives compared with reported occurrence of these neoplasms in first-degree relatives of 342 matched cancer controls and 342 matched controls without cancer. Siblings of case subjects also had a significant elevation of kidney cancer compared with siblings of controls. Only one of the affected case families (and no control family) included more than one additional member with leukemia. The results suggest a genetic component for leukemia occurrence in several case families, although the majority of cases of chronic lymphocytic leukemia appeared to be sporadic. The similarity of findings between the two comparisons (cases vs. cancer controls and cases vs. controls without cancer) diminishes the likelihood of recall bias as an explanation for the observed excess risks.

The Eastern Cooperative Oncology Group evaluated cyclophosphamide 600 mg/m2 intravenously daily X 4 (total dose each cycle 2400 mg/m2) as an aggressive approach to the treatment of patients with advanced multiple myeloma. The overall objective response rate is 43%. This includes a 38% response rate for all previously treated patients and a 29% response rate for patients refractory to prior therapy with cyclophosphamide. The objective response duration was 3 months and the survival of responding patients 9 months. A subjective response rate of 63% was observed, characterized by effective pain relief and improved performance. Sixty-nine percent of patients experienced leukocyte cell nadirs less than 500/mm2 with a mean time to marrow recovery of 17 days. Thrombocytopenia was less severe but required platelet transfusion in 43% of patients. Bone marrow toxicity was encountered in all patients, and death in aplasia is a significant risk. Strict adherence to entry criteria, and a systematic plan for hospitalization for antibiotic and blood component support is required for treatment with this regimen.

[6-14C]arginine, injected intraperitoneally into normal rats, was cleared from the plasma with biphasic decay kinetics. Urinary excretion was efficient (32% of the 25-muCi dose within the first 24 hr) with no preferential tissue retention. In mice, the effective duration of the radiotracer's availability for protein biosynthesis was less than 30 min. When the tracer was administered i.v. to patients with multiple myeloma, it was similarly cleared from the plasma with biphasic kinetics, and was excreted rapidly in the urine (22% of the dose within the first 24 hr). In patients, the guanido-tagged arginine labeled only tumor M component, and the labeling was most intense in patients who had far advanced disease. Estimated radiation dose to humans from a 100-muCi injection was 10 mrads. These studies demonstrate the fesibility of in vivo labeling with [16 -14C]arginine, with minimal radiation hazard, thus providing a simple, sensitive, and specific method for monitoring the synthesis of the plasmacytoma M component in patients with multiple myeloma.

Murine LPC-1 plasmacytoma is sensitive to treatment with cyclophosphamide (CY), and animals bearing this tumor in advanced stages can be cured with doses as small as 60 mg/kg. With repeated transfer of LPC-1 cells followed by subcurative CY therapy, we have developed from this CY-sensitive parent line (CY-S) a stable CY-resistant subline (CY-R) that is unaffected by doses as large as 250 mg/kg. Stability of this induced CY resistance in the absence of CY treatment has been demonstrated for greater than 14 transfer generations. The CY-R subline has been compared to the CY-S parent line and shown to be similar with respect to morphology, growth kinetics, survival time, synthesis of IgG 2a kappa M component, and DNA content and distribution. The CY-S parent line responds in vivo to CY analogs (ifosfamide and trofosfamide), as judged by decreased tumor mass and increased survival; the CY-R subline is resistant to the CY analogs. The response to carmustine (BCNU) was tested, and resistance to CY did not predict for response to this alkylating agent since the effect on both CY-S and CY-R lines was equal. The significance of the development of this CY-resistant subline and the implications for future research into the mechanisms of such resistance are discussed.

Tables are presented for the thermodynamic properties of air from 90 to 1500 K using (1) temperature and pressure and (2) temperature and density as independent variables. The pressure tables range from 1 to 1200 atmospheres, whereas the density tables extend from 10 to the -7th power to 400 relative atmospheres (or amagat units). The tabulated properties are the compressibility factor Z, the dimensionless functions E/RT, H/RT and S/R, together with pressure and density. The tables account for the so-called real gas effects (van der Waals' effects) at high pressures, but do not include the effects of the small amounts of dissociation at low pressures and high temperatures. The sources for the tables as well as the final tables are discussed.

Waldenstrom's macroglobulinemia (WM) is a rare disorder of lymphoid and plasma cells characterized by an immunoglobulin M (IgM) monoclonal gammopathy, clinical and immunopathologic similarities with other lymphoproliferative neoplasms, but the etiology of which is unknown. We undertook the first case-control study of this disorder among 65 cases, comprising 87% of all WM patients diagnosed during 1969-1983 in the greater Baltimore, Maryland area. Compared with 213 hospital controls without cancer, cases were slightly better educated, but there were otherwise no differences in sociodemographic factors, history of prior medical conditions, medication use, cigarette smoking, alcohol consumption, specific occupational exposures, employment in any particular industries or occupations, or familial cancer history. Cases were more likely than controls to have first-degree relatives with a history of pneumonia, diphtheria, rheumatic fever, and diabetes mellitus. An exploratory evaluation of immunologic profiles of first-degree relatives of 48% of families of cases revealed that relatives of two cases had asymptomatic IgM (750 mg/dl) monoclonal gammopathy and close to 40% of the 109 evaluated had diverse immunologic abnormalities. Larger population-based case-control studies are needed to further evaluate the suggestive evidence of immune dysfunction among families of WM cases.

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