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BALB/c mice with the plasmacytoma MOPC 104E producing monoclonal IgM-lambda; with antibody activity to α-1,3 dextran were found to have B lymphocytes with surface immunoglobuhins with the immunochemical characteristics of in4E IgM capable of binding a-1,3 dextran. RNA extracted from this plasmacytoma induced the synthesis of such surface immunoglobulins on normal H lymphocytes in vitro and in vivo. Injection of 200μg of MOPC I04E RNA into normal mice 72 hr prior to the administration of the antigen kept the immune response to dextran-S intact, but suppressed that to other antigens, such as DNP-Ficoll and LPS, T cell-independent antigens, and SRBC and BSA which are T cell-dependent. The effect of the RNA was abolished by RNase but not by pronase and DNase. RNA extracted from LPC-1 tumour (γ2a-k without known antibody activity) significantly suppressed the immune response to dextran-S and to other antigens in normal mice. Thus, opposite effects to MOPC 1041'" RNA on the response to specific and non-specific antigens strengthen the hypothesis that the immune deficiency in plasmacytoma hearing mice is due to the conversion of normal surface immunoglobulin of a population of B lymphocytes to the idiotype of the respective myeloma globulin. [ABSTRACT FROM AUTHOR]

The previous findings were confirmed that RNA extracted from murine plasma-cytoma alters the character of the lymphocyte surface immunoglobulins (Slg) to express the idiotypic specificity of the Ig of the plasmacytoma from which the RNA was derived (cell conversion). RNA extracted from spleens of plasmacytoma-RNA-injected BALB'c mice also had converting activity, and if injected into other mice, caused the appearance of RNA active in cell conversion in spleens of the second set of mice. This activity was lost only after two additional transfers. When splenic cells from animals 1 hr after injection with RNA extracted from MOPC 300. LPC-1 or MOPC 104E, were cultured for 7 days, the proportion of cells with the Sig specific for these tumours increased. The cell-converting activity of the RNA extracted from the cultured cells after 7 day incubation (`7-day' RNA) was higher than that of RNA extracted from cells alter 1 hr incubation (`immediate' RNA). 'Seven-day' RNA could be used for sequential transfers without marked loss of activity in cell conversion for at least five transfers. The repetitive transferability of the phenomenon by the injection of plasmacytoma-RNA suggests the possibility of RNA replication in the recipient cells. [ABSTRACT FROM AUTHOR]

The increase in serum immunoglobulins in aged NZB mice is associated with the appearance of a monoclonal IgM. The decrease in the proportion of circulating lymphocytes with normal receptors (IgM and lgG) of the aging NZB mouse is due to the replacement of these surface immunoglobulins by a monoclonal IgM. RNA extracted from spleen and plasma of aging NZB mice induced the development of such monoclonal receptors on normal lymphocytes in vitro and in vivo. RNA was detected in plasma of aging NZB mice bound to an α-globulin. Evidence is presented suggesting that the mediating factor in the development of monoclonal receptors is plasma RNA. Receptor conversion, previously also detected in plasmacytoma of mice appears to be a cause of B-cell dysfunction interfering with the normal sequence of the immune response. [ABSTRACT FROM AUTHOR]

Light chain receptors on human circulating lymphocytes of thirty-three normal individuals were visualized by the immunocyto-adhesion reaction in which human (anuclear) erythrocytes coated with κ chains and chicken (nucleated) erythrocytes coated with λ chains (or vice versa) were used, 4.4 (±2.3)% of the lymphocytes had κ and 4.15 (±2.4)% had λ receptors, when the lymphocytes were sensitized with antisera to either κ and λ chains. When both antisera were used simultaneously only 5.3 (±3)% were found to have receptors and the majority of cells carried both κ and λ receptors. These findings suggest that in these cells the genes for the constant regions of both light chains are active. [ABSTRACT FROM AUTHOR]

Patients with intravascular large B-cell lymphoma often pose a significant diagnostic challenge, particularly in the early stages of the disease, but use of fluorodeoxyglucose-positron emission tomography could result in a more timely diagnosis., Competing Interests: Author disclosures The authors report no actual or potential conflicts of interest with regard to this article.

Purpose: Zoledronic acid decreases the risk for skeletal-related events (SREs) in men with castration-resistant prostate cancer and bone metastases but its role earlier in the natural history of the disease is unknown. This phase III study evaluated the efficacy and safety of earlier treatment with zoledronic acid in men with castration-sensitive metastatic prostate cancer., Patients and Methods: Men with castration-sensitive prostate cancer and bone metastases whose androgen-deprivation therapy was initiated within 6 months of study entry were randomly assigned in a blinded 1:1 ratio to receive zoledronic acid (4 mg intravenously every 4 weeks) or a placebo. After their disease progressed to castration-resistant status, all patients received open-label treatment with zoledronic acid. The primary end point was time to first SRE, defined as radiation to bone, clinical fracture, spinal cord compression, surgery to bone, or death as a result of prostate cancer. Target accrual was 680 patients. Primary analysis was planned after 470 SREs. The study was discontinued prematurely (645 patients; 299 SREs) after the corporate supporter withdrew study drug supply., Results: Early zoledronic acid was not associated with increased time to first SRE. The median time to first SRE was 31.9 months in the zoledronic acid group (95% CI, 24.2 to 40.3) and 29.8 months in the placebo group (95% CI, 25.3 to 37.2; hazard ratio, 0.97; 95% CI, 0 to 1.17; one-sided stratified log-rank P = .39). Overall survival was similar between the groups (hazard ratio, 0.88; 95% CI, 0.70 to 1.12; P = .29). Rates of adverse events were similar between the groups., Conclusion: In men with castration-sensitive prostate cancer and bone metastases, early treatment with zoledronic acid was not associated with lower risk for SREs.

Purpose: US veterans have been shown to be a vulnerable population with high cancer rates, and cancer care quality in Veterans Affairs (VA) hospitals is the focus of a congressionally mandated review. We examined rates of surgery and chemotherapy use among veterans with colon cancer at VA and non-VA facilities in California to gain insight into factors associated with quality of cancer care., Methods: A retrospective cohort of incident colon cancer patients from the California Cancer Registry, who were > or = 66 years old and eligible to use VA and Medicare between 1999 and 2001, were observed for 6 months after diagnosis., Results: Among 601 veterans with colon cancer, 72% were initially diagnosed and treated in non-VA facilities. Among veterans with stage I to III cancer, those diagnosed and initially treated in VA facilities experienced similar colectomy rates as those at non-VA facilities. Stage III patients diagnosed and initially treated in VA versus non-VA facilities had similar odds of receiving adjuvant chemotherapy. In both settings, older patients had lower odds of receiving chemotherapy than their younger counterparts even when race and comorbidity were considered (age 76 to 85 years: odds ratio [OR] = 0.18; 95% CI, 0.07 to 0.46; age > or = 86 years: OR = 0.17; 95% CI, 0.04 to 0.73)., Conclusion: In California, older veterans with colon cancer used both VA and non-VA facilities for cancer treatment, and odds of receiving cancer-directed surgery and chemotherapy were similar in both systems. Among stage III patients, older age lowered odds of receiving adjuvant chemotherapy in both systems. Further studies should continue to explore potential health system effects on quality of colon cancer care across the United States.

Objectives: To study the effect of zoledronic acid on patients with pre-existing osteoporosis on androgen deprivation therapy (ADT), who are at highest risk for fracture. Zoledronic acid is a potent bisphosphonate that can prevent osteoporosis in patients with nonmetastatic (M0), prostate cancer (CaP) who are initiating ADT. The effect of zoledronic acid on patients with pre-existing osteoporosis on ADT, who are highest risk for fracture, has not been adequately studied., Methods: We enrolled 28 patients with M0 CaP on ADT with severe osteopenia or osteoporosis (baseline bone-mineral density (BMD) T score < -2.0) in this open-label, single-arm trial to assess the effect of zoledronic acid on BMD. All patients also received supplemental calcium and vitamin D, and were counseled about lifestyle modifications. Patients received zoledronic acid (4 mg) intravenously every 3 months for 4 treatments. BMD was measured by dual energy X-ray absorptiometry scan at enrollment, 6 and 12 months. Primary endpoint was percent change in lumbar spine BMD., Results: This was a high-risk patient population-primarily older Caucasians (mean age, 73 years), former smokers, and moderate users of alcohol. Mean duration of ADT was 2.4 years. Pre-existing osteopenia or osteoporosis was observed in a single site in 9 patients and multiple sites in 19 (68%). After 12 months of zoledronic acid, lumbar spine BMD increased 4.17% (P < .0001), and BMD increased significantly (P < .05) in both hips and the right femoral neck. Seven patients (25%) experienced improved BMD into the nonosteoporotic range (T score > -2.0). Zoledronic acid infusion was well tolerated and without substantial renal toxicity., Conclusions: Zoledronic acid improves BMD in men with M0 CaP on ADT with severe osteopenia or osteoporosis (T scores < 2.0). This novel finding identifies a high-risk patient population that can potentially benefit from bisphosphonate therapy., (Copyright 2010 Elsevier Inc. All rights reserved.)

Context: Randomized trials suggest adjuvant chemotherapy is effective for older patients with stage III colon cancer. However, older patients are less likely to receive this therapy than younger patients, perhaps because of concern about adverse effects., Objective: To evaluate adjuvant chemotherapy use and outcomes for older patients with stage III colon cancer from well-defined population-based settings and health care systems., Design: Observational study of adjuvant chemotherapy use and outcomes by age using Poisson regression to estimate the number of adverse events adjusted for demographic and clinical factors, including comorbid illness and specific elements of chemotherapy regimens documented with clinically detailed medical record reviews and patient and surrogate surveys., Setting: Five geographically defined regions (Alabama, Iowa, Los Angeles County, northern California, and North Carolina), 5 integrated health care delivery systems, and 15 Veterans Affairs hospitals., Patients: Six hundred seventy-five patients diagnosed with stage III colon cancer from 2003 through 2005 who underwent surgical resection and were followed up for as long as 15 months postdiagnosis., Main Outcome Measures: Chemotherapy regimen, dose, duration, and annualized mean number of adverse events stratified by age., Results: Of 202 patients aged 75 years and older, 101 (50%) received adjuvant chemotherapy compared with 87% of 473 younger patients (difference, 37%; 95% confidence interval [CI], 30%-45%). Among patients who received adjuvant chemotherapy, 14 patients (14%) aged 75 years and older and 178 younger patients (44%) received a regimen containing oxaliplatin (difference, 30%; 95% CI, 21%-38%). Older patients were less likely to continue treatment, such that by 150 days, 99 patients (40%) aged 65 years and older and 68 younger patients (25%) had discontinued chemotherapy (difference, 15%; 95% CI, 7%-23%). Overall, 162 patients (24%) had at least 1 adverse clinical event, with more events among patients treated with vs without adjuvant chemotherapy (mean, 0.39 vs 0.16; difference, 0.23; 95% CI, 0.11-0.36; P < .001). Among patients receiving adjuvant chemotherapy, adjusted rates of late clinical adverse events were lower for patients 75 years and older (mean, 0.28) vs for younger patients (0.35 for ages 18-54 years, 0.52 for ages 55-64 years, and 0.45 for ages 65-74 years; P = .008 for any age effect)., Conclusion: Among patients with stage III colon cancer who underwent surgical resection and received adjuvant chemotherapy, older patients in the community received less-toxic and shorter chemotherapy regimens, and those treated had fewer adverse events than younger patients.

Purpose: Androgen deprivation therapy for prostate cancer is associated with osteoporosis and increased fracture risk. Previous studies of zoledronic acid demonstrated bone loss prevention in patients initiating androgen deprivation therapy. There are limited data on patients on prolonged androgen deprivation therapy or in Veterans Affairs patients with multiple risk factors for osteoporosis., Methods: We randomized 93 patients with M0 prostate cancer in this placebo controlled trial in the Veterans Affairs health care system. Preplanned strata included 50 patients on androgen deprivation therapy for less than 1 year (stratum 1) and 43 on androgen deprivation therapy for greater than 1 year (stratum 2). In each stratum patients were randomized to 4 mg zoledronic acid intravenously every 3 months for 4 treatments or intravenous placebo. The primary end point was the percent change in bone mineral density at the lumbar spine at 12 months., Results: Age, race, body mass index and osteoporosis risk factors were similar for the 2 treatments. Most patients were former smokers, had moderate alcohol intake, were not on calcium/vitamin D supplements and were relatively sedentary at baseline. In stratum 1 spine bone mineral density increased 5.95% in the zoledronic acid arm and decreased 3.23% in the placebo arm (p = 0.0044). In stratum 2 spine bone mineral density increased 6.08% in the zoledronic acid arm and only increased 1.57% in the placebo arm (p = 0.0005). Treatment was well tolerated with minimal impact on renal function., Conclusions: Zoledronic acid improved bone mineral density in patients with M0 prostate cancer on androgen deprivation therapy for 1 year or less, or greater than 1 year. This finding indicates that bisphosphonate therapy remains effective when initiated later in the course of androgen deprivation therapy and is efficacious in Veterans Affairs patients with multiple risk factors for osteoporosis.

Hemolytic anemia is uncommon in the general population; however, drug-induced hemolysis is not rare in hospitalized patients. We report a case of unrecognized subacute hemolytic anemia due to ceftriaxone in a geriatric patient requiring multiple blood transfusions before a correct diagnosis could be established.

Background: For patients at high risk of function-limiting or life-limiting disease, the time elapsed between first clinical presentation, diagnosis, and treatment can influence the likelihood of treatment success., Methods: A systematic change in the management of high-risk patients was undertaken. This approach includes identifying primary provider responsibility, establishing communication expectations between providers, developing a tracking system to actively monitor patients (patient traffic control), and using a time guideline to assess patient progression. A 60-day time frame was established for the time from first clinical presentation to diagnostic exclusion or treatment initiation., Results: In a one-year period, 288 high-risk patients were entered into patient traffic control, 211 (73%) of whom were monitored in the primary care setting. The median time to diagnostic exclusion or treatment was 43 days (mean, 58.5 days). Sixty-six percent of all patients achieved diagnostic exclusion or treatment by 60 days. Of the 95 patients monitored for > 60 days, 56% had delays caused by patient noncompliance or because of the appropriate need for long-term serial radiographic monitoring. Thirty-eight patients (13.1%) demonstrated problems with appointment nonadherence. None were lost to follow-up., Discussion: The patient traffic control approach enabled the management of the majority of high-risk patients within 60 days of presentation.

Purpose: Improving chemotherapeutic efficacy in non-small cell lung cancer (NSCLC) will require the development of new drugs or new strategies to better use currently available agents. Sequential administration offers an opportunity to increase drug diversity while maintaining dose intensity. On the basis of the data indicating the activity of taxanes as second-line therapy and the lack of efficacy for more than three cycles of platinum-based therapy, this randomized Phase II study tested the concept of planned sequential chemotherapy in advanced NSCLC., Experimental Design: Patients with selected stage IIIb (pleural effusion)/stage IV NSCLC, performance status of 0-1 and normal organ function were eligible., Therapy: arm 1, carboplatin (area under the curve = 5.5 mg/ml x min day 1) and gemcitabine (1000 mg/m(2) days 1 and 8 every 21 days x 3) followed by paclitaxel (225 mg/m(2) every 21 days x 3) or arm 2, cisplatin (100 mg/m(2) day 1), vinorelbine (25 mg/m(2) days 1 and 8 every 21 d x 3) followed by docetaxel (75-100 mg/m(2) every 21 days x 3)., Results: Two-hundred four patients were accrued, of whom, 178 were eligible and evaluable. Eighty percent of patients were stage IV on arm 1 and 85% on arm 2. Response rates were 21 and 28% on arms 1 and 2, respectively. Median, 1-year and 2-year survivals were 9 months, 34 and 13%, and 9 months, 36 and 8%, on arms 1 and 2, respectively., Conclusions: Sequential therapy, as used in this study, resulted in comparable efficacy to previous Southwest Oncology Group trials of two drug combinations in this population; however, it failed to meet criteria for further study.

Background: The current study was conducted to assess the activity and toxicity of high-dose ifosfamide and mesna with recombinant human granulocyte-colony-stimulating factor (rhG-CSF), given in an outpatient setting, in the treatment of patients with unresectable malignant mesothelioma., Methods: Between September 1994 and September 1996, 41 patients with histologically verified, unresectable malignant mesothelioma were registered, 38 of whom were analyzable (2 were ineligible and 1 was nonanalyzable). Patients received intravenous ifosfamide at a dose of 2.8 g/m2 over 3 hours (total dose of 14 g/m2), plus mesna at a dose of 0.56 g/m2 prior to and at 4 hours and 8 hours after ifosfamide infusion daily for 5 days every 21 days. rhG-CSF at a dose of 5 microg/kg/day was administered subcutaneously on days 6-15., Results: Response assessment could be determined adequately in 21 patients. Two patients obtained responses; 1 was a confirmed partial response (3%; 95% confidence interval [95% CI], 0-14%) and 1 was an unconfirmed response (3%; 95% CI, 5-14%). Eleven patients had stable disease (29%), 7 patients developed disease progression (18%), 1 patient had an early death (3%), and 17 patients had inadequate assessment (45%). At the time of last follow-up, 36 of the 38 eligible patients had developed disease progression, with a median progression-free survival of 5 months (95% CI, 3-7 months) and 34 patients had died with a median survival of 7 months (95% CI, 6-9 months). Twenty-four patients (63%) and 7 patients (18%), respectively, had Grade (according to Southwestern Oncology Group Toxicity Criteria) 4 hematologic toxicities and Grade 4 nonhematological toxicities. There was one treatment-related death, the result of infection, pulmonary edema, and renal failure., Conclusions: This regimen demonstrated a low overall objective response rate with substantial toxicity, and in the opinion of the authors does not warrant further investigation in the treatment of patients with unresectable malignant mesothelioma., (Copyright 2003 American Cancer Society.)

Elevated levels of serum antibodies to neurofilament proteins have been associated with a variety of neurological diseases, including autoimmune disorders such as neuropathy with monoclonal gammopathy of undetermined significance (MGUS). The pathological significance of anti-neurofilament antibodies in sera of affected patients, however, remains unclear. In this study, we report our findings of polyclonal antibodies in sera from 4 of 16 IgG MGUS neuropathy patients that react strongly on immunoblot with a high molecular weight neurofilament protein (NFH). The effect of anti-NFH polyclonal antibody on peripheral nerve function was tested in vivo by intraneural injection. Sera containing anti-NFH antibody, but not sera from age-matched control subjects, injected into the endoneurium of rat sciatic nerve significantly attenuated proximal-evoked motor nerve compound muscle action potential (CMAP) amplitudes in a complement-dependent manner. In contrast, ankle-evoked CMAP amplitudes were unaffected by intraneural injection of sera containing anti-NFH antibody. Anti-NFH serum-injected nerves showed changes in both axon caliber (shrinkage) and myelin ultrastructure (vesiculation and ovoid formation), suggestive of intramyelinic edema. Preincubation of sera containing anti-NFH antibody with purified NFH protein abolished immunoreactivity to NFH protein and neutralized the serum-mediated toxicity. The data suggest that anti-NFH polyclonal antibodies occurring in sera of some patients with IgG MGUS neuropathy may elicit peripheral nerve conduction block independent of the patients' IgG paraprotein. Anti-neural polyclonal antibodies in sera of IgG MGUS neuropathy patients may have a greater pathological significance than previously anticipated.

Monoclonal gammopathy of unknown significance (MGUS) is a monoclonal B cell expansion characterized by high levels of circulating monoclonal antibody that affects 3% of individuals over the age of 70. Although this is considered benign, a high percentage of MGUS patients develop a debilitating peripheral autoimmune neuropathy and have a significantly increased risk for progression to multiple myeloma. Here we show that the relative numbers of the CD30(+) T cell subset and levels of CD30 expression are elevated in activated lymphocytes from normal aged individuals (> or =60 years) and in MGUS patients, when compared to younger controls. PBL from MGUS patients and age-matched controls produced comparable levels of IL-6 when activated with anti-CD3 plus IL-2, and costimulation with a soluble form of CD30 ligand (sCD30L/CD8alpha) augmented anti-CD3 inducible IL-6 production similarly in both groups. However, MGUS PBL also produced measurable IL-6 when activated with sCD30L/CD8alpha alone. This capability was associated with the unique presence of CD30(+) T cells in the peripheral blood of MGUS patients. Furthermore, a higher percentage of activated MGUS T cells express CD30 when activated by incubation with idiotype-expressing autologous serum (68 +/- 13) than those activated by anti-CD3 plus IL-2 (43 +/- 7). These results indicate that quantitative alterations in CD30(+) T cells accompany aging and MGUS and that these cells may contribute to the chronic activation of B cells though the production of IL-6., (Copyright 2001 Academic Press.)

Extraskeletal Ewing's sarcoma (EES) is a round-cell malignancy that manifests most commonly in the paravertebral and intercostal regions. It occurs predominantly in adolescents and young adults, between the ages of 10 and 30 yr, and follows an aggressive course with a high recurrence rate. Distant metastasis is also common. The tumor is often confused with other round, small-cell neoplasms, including primitive neuroectodermal tumor, neuroblastoma, embryonal rhabdomyosarcoma, and lymphoma. This report pertains to a fine-needle aspiration cytologic diagnosis of EES, supported by clinicopathologic and fine structural correlations in a 56-yr-old man who presented with a rapidly growing, massive, right groin mass. The smears showed a diffuse cellular population of malignant round cells composed of two types: one group of larger cell exhibiting a thin-rim, pale cytoplasm, less hyperchromatic nuclei, nucleoli, and diffusely dispersed chromatinic nuclear details; and the second group of smaller and darker cells with highly hyperchromatic and almost smudged nuclei. These are chief cells and dark cells, respectively. Special studies revealed significant intracytoplasmic glycogen and positive vimentin and HBA-71 immunostaining. Cytogenetic findings of chromosomal 11;22 translocation is also supportive of the diagnosis of EES.

This case report concerns an embryonal rhabdomyosarcoma of the testis in a 31-yr-old white male patient who underwent radical left orchiectomy, followed by combined irradiation and chemotherapy, and who 2 yr later presented with dyspnea at rest, nonproductive cough, and lower back pain for 1 wk. Chest radiographs demonstrated a bilateral pleural effusion and diffuse infiltrating lesion of the pleurae, mimicking a mesothelioma. The pleural fluid displayed noncohesive, malignant, small, round cells about 2-5 times larger than mature lymphocytes. They had large, darkly stained, pleomorphic nuclei and bubbly cytoplasm with poorly defined borders. The diagnosis of embryonal rhabdomyosarcoma was supported by a positive myosin immunostaining and ultrastructural findings of intracytoplasmic actin and myosin-type microfilaments. Our case is also notable in that the tumor was a pure rhabdomyosarcoma involving a testicular origin, and the patient is the oldest reported in the literature.

Vincristine has been shown to reduce the amplitude of postreceptoral electroretinographic components in the isolated arterially perfused cat eye. We examined whether a similar effect occurs in vincristine chemotherapy. In the three patients tested, cone-mediated electroretinograms recorded before and after vincristine chemotherapy were not different. This observation is likely to reflect the lower doses of vincristine used therapeutically.

The effect of repeated injections of busulfan, an alkylating agent, on immune response of CAF1 mice was studied. A single injection of busulfan or acetone (vehicle to solubilize busulfan) acutely suppressed mitogenic and allogenic responses that normalized at two weeks. Repeated injections of busulfan (four injections), on the other hand, showed a transient suppression of the mitogenic responses. Natural killer (NK) activity during the first ten days after busulfan or acetone injections remained normal. NK activity diminished significantly after two injections of busulfan, remained low after four injections, and did not recover within four months of rest. Prolonged suppression of NK activity may be implicated as playing a role in the emergence of T-cell lymphomas in mice injected with busulfan.

The efficacy of leukocytapheresis in a pancytopenic patient with hairy cell leukemia in postsplenectomy stage is reported. Cytapheresis as the only therapy was effective on more than one occasion in inducing remission and reducing transfusion requirements. Fourteen months after the last leukocytapheresis, the patient's hemoglobin and hematocrit remain normal. The leukocyte concentrates removed contained 90 percent lymphocytes consisting of 75 percent T cells, 15 percent B cells, and only 2 to 4 percent hairy cells. Thus, the removal of a large number of lymphocytes, not necessarily hairy cells, induced a sustained clinical improvement and indicated that cytapheresis may be a useful alternative to chemotherapy for these patients.

We report the immunological studies on three transplantable lymphoma lines that developed when CAF1 mice were injected with busulfan and chloramphenicol. The lymphoma cells displayed Thy-1.2, brain associated antigen, and H-2d alloantigen. They were negative for surface IgM and Ia antigens. Expression of T cell differentiation antigens differed among the three lines. The 508 tumour line displayed only Thy-1.2: 408 tumour line displayed Thy-1.2, Lyt-2.2 and TL; and 808 tumour line was positive for Thy-1.2, Lyt-1.2, Lyt-2.2 and TL antigens. We established in vitro culture lines from 508 and 808 lymphoma cells. The lymphoma cells did not respond to mitogens and antigens. The splenic cells from mice bearing 508 or 808 had decreased phytohaemagglutinin (PHA), concanavalin A (Con A) and mixed leucocyte responses (MLR). When mitomycin-C treated lymphoma cells from the tumour bearing mice were cocultured with normal splenic mononuclear cells, the 808 lymphoma cells suppressed the mitogenic responses of the normal cells more profoundly than 508 lymphoma cells. Adherent cells from both tumours suppressed the Con A responses of normal spleen cells. Cells from in vitro 508 or 808 cell lines had no effect on mitogenic responses of normal cells. Plasma from tumour bearing mice, but not the supernatants taken from cultures of these lymphoma cells, suppressed the mitogenic responses of normal lymphocytes. Spleen cells from normal CAF1 mice responded in mixed leucocyte tumour reactions (MLTR) when cocultured with lymphoma cells. Mice immunized with mitomycin-C treated tumour cells had greater response. Responder cells taken from mice with established 508 or 808 tumors had suppressed MLTR responses. Although prior immunization with tumor antigen increased the MLTR response, injection of live tumour cells into immunized mice resulted in a more rapid tumour growth and suppression of MLTR response.

The carboxylic esterase (E.C. 3.1.1.1) isoenzymes from cases of acute myeloid leukemias were separated by analytical isoelectric focusing on horizontal thin-layer gels. One isoenzyme consisting of one or two components (bands) could be completely and selectively inhibited by addition of 40 mM sodium fluoride (NaF) to the staining bath. The 105 cases were classified into the groups M1-M6 according to the FAB proposals. The NaF-sensitive isoenzyme was not detected in cases of FAB groups M1/2 (acute myeloblastic leukemia without or with maturation), group M3 (acute promyelocytic leukemia) or group M6 (erythroleukemia). Thirty-one out of 33 cases in the FAB group M4 (acute myelomonocytic leukemia) and 9/9 cases in FAB group M5 (acute monocytic leukemia) expressed the NaF-sensitive isoenzyme. The NaF-sensitive isoenzyme was found at different staining intensities; all M5 cases showed the isoenzyme at strong or very strong intensity, whereas most of the M4 cases displayed the isoenzyme at weak, medium or strong staining intensity. The data presented are further evidence that the presence of the NaF-sensitive esterase isoenzyme indicates monocytic involvement or differentiation in cases of myeloid leukemias. The easy and fast to perform method of isoelectric focusing can be used to distinguish the monocytic variants among the acute myeloid leukemias and can supplement the morphological analysis of these cases.

A long-acting somatostatin analog, SMS 201-995, is now available to treat the hormonal manifestations of islet cell tumors. We report its use in a patient with a metastatic glucagonoma refractory to conventional therapy. This patient, who was severely disabled by the rash of necrolytic migratory erythema and brittle diabetes mellitus, allowed us to evaluate the therapeutic efficacy of SMS 201-995 and to gain insight into the origin of the rash. SMS 201-995 was administered subcutaneously (.05 mg twice a day). The rash improved markedly within 48 hours and was completely resolved within 1 week of treatment. Insulin requirements decreased from 90 U/day to zero during the first week of treatment. Corresponding to improvement in clinical symptoms circulating glucagon levels showed a marked decrease. There was no substantial change in plasma or urinary levels of zinc or in plasma amino acid levels. When SMS 201-995 was stopped, the rash recurred within 36 hours and it improved within 48 hours of readministration. The rash and diabetes have remained well controlled during 8 months of therapy but no change in tumor size has been seen on CT scan. The rapid changes in the rash related to the administration of SMS 201-995 indicate that the pathogenesis of necrolytic migratory erythema is probably due to circulating hyperglucagonemia or some other hormonal substance produced by the tumor.

The expression of myeloid-associated cell surface antigens detected by monoclonal antibodies (MoAb: MCS-2, MCS-1, MY7, MY9, Leu-M1, OKM1, VIM-D5, Mol, My-1, MY8, MY4, Leu-M3, VIM-D2, Mo2) of the HLA-DR/Ia-like antigen and of the Fc-receptor was determined on the blast cells from 91 patients with acute myeloid leukaemias classified as M1-M5 in the French-American-British (FAB) system. The surface antigen analysis revealed a highly heterogeneous reaction profile. Nevertheless, distinctive patterns of marker expression referring to morphologically defined subgroups were delineated. Several MoAb (especially MCS-2 and MY7 which were positive in most cases of the five FAB subgroups) appear to be useful for the recognition of myelomonocytic cells regardless of the commitment to either the granulocytic or monocytic cell lineage whereas other Mo Ab (especially MY4, Leu-M3, VIM-D2, Mo2) react predominantly with the monocytic variants and are helpful in the identification of monocytic commitment. The 91 cases could be divided into three immunologically defined phenotypes (Types I-III) corresponding to sequential differentiation levels. Correlations of these MoAb-defined phenotypes with the FAB subtyping showed that immunological and morphological classifications are not completely concordant and that only the parameters Type I and FAB M1 were significantly related. A scheme of early myeloid differentiation sequences based on the expression of surface antigens is presented.

A subcellular fraction from murine plasmacytoma cells was shown to suppress the primary antibody response when injected into normal mice. The active subcellular fraction copurified with intracisternal A-particles. The RNA extracted from subcellular fractions enriched in A-particles was also immunosuppressive. This activity was due to a population of RNA molecules that contained polyadenylic acid. Upon fractionation on a sucrose gradient, two populations of immunosuppressive RNA were obtained with sedimentation velocities of 12 to 18S and 40 to 50S. The 40 to 50S RNA was shown to be a thermolabile aggregate of molecules that contained the 12 to 18S RNA molecules. Plasmacytoma-derived material with similar physicochemical characteristics had previously been shown to induce in normal mouse lymphocytes surface immunoglobulins with the plasmacytoma idiotype, supporting the possibility that one of the mechanisms responsible for the development of immunological deficiency is the change of surface immunoglobulins of nonmalignant B-cells.

Busulfan causes long-lasting defects in the hematopoietic stem cells and in the immune system of mice. We designed studies to determine whether chloramphenicol further damaged the already defective hematopoietic stem cells of mice that were pretreated with busulfan, and we unexpectedly observed that mice given injections of the combination of busulfan and chloramphenicol developed lymphomas in relatively high incidence. The disease is invariably associated with splenomegaly and enlargement of the thymus. Leukocytosis with lymphoblasts in the peripheral blood occurred in some affected mice. The malignant cell is a lymphoblast of thymic origin. Thirteen of 37 mice which received both busulfan and chloramphenicol developed lymphomas. An additional five of the remaining 24 mice without proven lymphoma died and were not autopsied. Twelve of the 13 proven lymphomas developed within 280 days from the start of the experiment. Four of the 35 mice treated with busulfan alone developed lymphomas, and an additional five of the remaining 31 died but were not autopsied. Two of 41 mice treated with only chloramphenicol developed lymphomas. Of the mice treated with either busulfan or chloramphenicol alone that developed lymphomas, all did so more than 280 days from the start of the experiment. None of the control mice developed lymphoma. We conclude that both busulfan and chloramphenicol may induced lymphomas in mice that are not known to develop them spontaneously. The combination of both busulfan and chloramphenicol increased the frequency and accelerated the onset of the disease.

Repeated injections of busulfan (Bu) in CAF1 mice caused a long-lasting (greater than 16 weeks) decrease in their natural killer (NK) cell activity and impaired their resistance to transplantable lymphoma. Bu-treated mice had fewer spleen cells capable of binding to NK-sensitive YAC-1 target cells and reduced lymphokine-activated killer (LAK) cell activity as compared to normal age-matched controls. In contrast, interleukin 1 (IL-1) and interleukin 2 (IL-2) production were normal. Transplantation of normal bone marrow cells into Bu-treated mice resulted in an elevation of IL-2 production as well as in complete restoration of NK activity, target cell binding, and partial restoration of LAK activity. Resistance to transplantable lymphoma was equal to that of age-matched control mice. Polyinosinic-polycytidylic acid (Poly I:C) treatment resulted in immunomodulation in both control and Bu-pretreated mice. Twenty-four hours after Poly I:C injection, control and Bu-treated mice had higher levels of NK activity than did normal age-matched control mice, but the NK activity of Poly I:C/Bu-treated mice remained significantly lower than that of Poly I:C/control mice. The super-normal levels of NK activity in control and Bu-treated mice following Poly I:C administration were attributable, in part, to endogenous LAK activity. The generation of splenic LAK cells in vitro and target binding cells, which were reduced in Bu-pretreated mice, normalized following treatment with Poly I:C. Poly I:C treatment caused an increase in both IL-1 and IL-2 production in control and Bu-pretreated mice and in the ability of the treated mice to reject transplanted lymphoma cells. These results suggest that repeated injections of Bu decrease NK and LAK activity, but do not eliminate NK and LAK precursor cells. Thus, treatment with agents that increase IL-2 and/or interferon production can activate these cells to become effective killers and counter the long-lasting immunosuppressive effects of chemotherapy.