B-cell prolymphocytic leukemia: a survey of 35 patients emphasizing heterogeneity, prognostic factors and evidence for a group with an indolent course.

We report a retrospective survey of 35 patients (18 males and 17 females) with B-Prolymphocytic leukemia (B-PLL) followed for a median of 63 months. Twelve patients fulfilled Galton's original clinical and hematological criteria, presented with prominent splenomegaly and hyperleukocytosis and showed rapid progression soon after diagnosis. Twelve cases with gradually increasing spleen size and prolymphocyte count had an indolent course. Seven of this group are alive 68 to 164 months after diagnosis, whereas five died from causes unrelated to PLL. Eleven patients who never developed impressive leukocytosis had a variable prognosis. In the group of 17 patients treated with chlorambucil and prednisone (CP) or cyclophosphamide, vincristine, prednisone (COP) 8 achieved a partial remission (PR) with a median response of 32 months. In the group of six cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) treated patients one achieved a complete remission and two PR (median response was maintained for 30 months). Three patients treated with 2CdA achieved good PR. Six patients remained untreated. Median survival was 65 months and the probability of overall survival for 3, 5, and 10 years was 63%, 56% and 35%, respectively. Anemia < 11 g/dl and lymphocytosis > 100 x 10(9)/l were predictors of shorter survival in this group of patients. Age over 70, gender, B-symptoms at presentation, spleen size, thrombocytopenia, low IgG and complement levels, presence of paraproteinemia and the pattern of bone marrow infiltrate were not significant. Our findings show that all B-PLL may not have such a poor prognosis as described in earlier reports. The existence of prior symptoms evolving gradually after years to obvious PLL and cases with mild prolymphocytosis could possibly lead to underdiagnosis of the entity. Identification and follow-up of such cases may suggest a different natural history, variable prognostic features and different survival curves for B-PLL patients. In the light of the above, we suggest that the therapeutic approach for B-PLL should always relate to the severity of the disease.

Neuroendocrinology of prolonged critical illness: effects of exogenous thyrotropin-releasing hormone and its combination with growth hormone secretagogues.

The catabolic state of prolonged critical illness is associated with a low activity of the thyrotropic and the somatotropic axes. The neuroendocrine component in the pathogenesis of these low activity states was assessed by investigating the effects of continuous intravenous infusions of TRH, GH-releasing peptide-2 (GHRP-2), and GHRH. Twenty adult patients, critically ill for several weeks, were studied during two consecutive nights. They had been randomly allocated to one of three combinations of peptide infusions, each administered in random order: TRH (one night) and placebo (other night), TRH + GHRP-2 (one night) and GHRP-2 (other night), or TRH + GHRH + GHRP-2 (one night) and GHRH + GHRP-2 (other night). The peptide infusions were started after a 1-microgram/kg bolus and infused (1 microgram/kg per h) until 0600 h. Blood sampling was performed every 20 min, and pituitary hormone secretion was quantified by deconvolution analysis. Reduced pulsatile fraction of TSH, GH, and PRL secretion and low serum concentrations of T4, T3, insulin growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS) were documented in the untreated state. Infusion of TRH alone or in combination with GH secretagogues augmented nonpulsatile TSH release 2- to 5-fold; only TRH + GHRP-2 increased pulsatile TSH secretion (4-fold). Average rises in T4 (40-54%) and in T3 (52-116%) were obtained with all three combinations, whereas reverse T3 levels did not increase, except when TRH was infused alone. Pulsatile GH secretion was amplified > 6- and > 10-fold, respectively, by GHRP-2 and GHRH + GHRP-2 infusions, generating mean increases of serum IGF-I (66% and 106%), IGFBP-3 (50% and 56%), and ALS (65% and 97%) within 45 h. The addition of TRH did not alter the GH secretory patterns. TRH infusion increased PRL release only when combined with GH secretagogues. No effects on serum cortisol were detected. In conclusion, the pathogenesis of the low activity state of the thyrotropic and somatotropic axes in prolonged critical illness appears to have a neuroendocrine component, because these axes are both readily activated by coinfusion of TRH and GH secretagogues.

Verapamil inhibits B-cell proliferation and tumor necrosis factor release and induces a clinical response in B-cell chronic lymphocytic leukemia.

Four B-CLL patients, treated with verapamil for cardiac problems, showed substantial reduction of lymphadenopathy in one, a 3- and 5-year stabilization of B-CLL in two patients, and a dramatic decrease in lymphocyte count, lymphadenopathy and splenomegaly in one stage IV patient. We therefore studied the effects of verapamil on B-CLL cells in vitro. In 13 samples we observed that verapamil strongly inhibited in vitro proliferation of pokeweed mitogen (PWM) stimulated and unstimulated cells. Using a cytotoxic bioassay, we found that verapamil markedly inhibited the spontaneous and PMW-induced release of tumor necrosis factor (TNF) by B-CLL cells. These findings suggest that verapamil may block B-CLL cell proliferation through inhibition of TNF release and thereby may contribute to the management of B-CLL.

Fragile X syndrome and myelodysplasia discovered during pregnancy.

We describe a female patient who presented at pregnancy with leucopenia and was found to suffer from both fragile X syndrome [Fra(X)] and myelodysplastic syndrome with cytogenetic abnormalities in bone marrow cells including 4q+ and deletion D13. To date only four cases of Fra(X) syndrome with malignant tumours (one haematological), all in male patients, have been reported. We believe that the occurrence of the myelodysplastic syndrome in this patient could be more than coincidental.

Involvement of Interleukin-6 in the Autocrine Stimulation of Chronic Lymphocytic Leukemia B Cells by Tumor Necrosis Factor.

Tumor necrosis factor α (TNFα) acts as an autocrine growth factor in chronic B cell malignancies. TNF also induces production of interleukin 6 (IL-6) which stimulates B cell growth and differentiation. We have previously demonstrated increased TNFα production by (Rai) stage 0 chronic lymphocytic leukemia (B-CLL) cells and the absence of TNF production by cells from stage IV patients. In an attempt to elucidate a possible role for TNF in the malignant progression of B-CLL we investigated the possibility of IL-6 involvment in the stimulatory action of TNF on B-CLL cells. We observed that: (1) the in vitro proliferative response of B-CLL cells to recombinant human (rh)THFα was consistently inhibited by a monoclonal antibody (MoAb) against IL-6, (2) the release of IL-6 by B-CLL cells could be augmented by rhTNFα, (3) no differences were detected in the foregoing parameters between stage 0 and stage IV-derived cells and (4) despite the inhibitory action of an anti-IL-6 MoAb on the TNF-induced proliferative response of B-CLL cells, IL-6 receptor expression was undetectable in these cells. Although these findings are suggestive of an autocrine or paracrine mechanism involving TNF and IL-6, the importance of the release and action of these cytokines in the regulation of B-CLL cell growth and malignant progression still remains to be elucidated.

Further characterization of prolymphocytic leukemia cells as a tumor of activated B cells.

Peripheral blood mononuclear cells from 24 patients with prolymphocytic leukemia (PLL) were isolated using a Ficoll-Hypaque gradient and stained by indirect immunofluorescence using a wide panel of monoclonal antibodies against B cell restricted and associated antigens, including HLA DR (Ia), CD19, CD21 (C3dR) surface membrane immunoglobulin (Slg), CD10 (CALLA), C3b, B5, CD25 (TAC), PCA1, T9, and T10. The cells were also tested for the FMC7, defined previously on PLL cells and the RAB1, a newly described hairy cell leukemia antigen. Thirteen out of the 24 samples expressed with variable intensity all the above antigens. While Ia, CD19, CD20, FMC7, and RAB1 were strongly or moderately expressed in all, the complement receptors (CD21 and C3b) were only weakly expressed in 12 cases; and the activation antigens B5, TAC, T9, T10, and PCA1 were found with variable intensity in two-thirds of the cases. In 50% of the cases tested, the CD5 antigen (usually strongly expressed on B CLL cells) was weakly to moderately expressed. These findings (absence or weak expression of complement receptors with variable expression of activation antigens) suggest that the PLL cells are activated B cells. When stimulated in vitro by anti-mu and TPA, (phorbol ester) tumor cells showed a decrease in CD21 and Slg and a stronger expression of CD25, T9, T10, and PCA1, with evidence of Ig secretion in four out of the seven cases studied. This confirms that the PLL cells arrested at an advanced stage of differentiation progressed narrowly to more differentiated cells. In view of our findings, we believe that the term prolymphocytic leukemia is inaccurate to define the stage of cell differentiation, and we suggest calling the disease preplasmacytic leukemia.

Hymenolepis diminuta: intestinal mast cell and eosinophil response of the mouse to infection.

It has been demonstrated that the rejection of Hymenolepis diminuta by the mouse is characterized by a humoral response in serum and intestinal lavage. Now the response is also shown to be accompanied by a mast cell and eosinophil response in the lamina propria of the intestine. The mast cell response is, in time and place, correlated with the rejection process of H. diminuta. With regard to the number of eosinophils in the lamina propria, a significant response was only found in the second half of the intestine. The eosinophil peroxidase (EPO) concentration in the intestinal lumen is correlated with the rejection of the parasite and illustrates the involvement of eosinophils in the rejection process. The course of the EPO response is identical to the mast cell response. This, together with other results, suggests that, as to other "systemic" worm infections, a mast cell-eosinophil response may be, at least in part, responsible for the rejection of H. diminuta from the intestinal lumen.

Carcinocythemia. Report of two cases, one simulating a Burkitt lymphoma.

Carcinocythemia is a rare complication of metastatic carcinoma, characterized by the presence of carcinoma cells in the peripheral blood, which may mimic acute leukemia. Two cases are reported in which the patients developed carcinocythemia several years after being treated for carcinoma of the breast. Cytologic examination of peripheral blood smears in both cases showed the presence of numerous large abnormal cells; in one case the cells simulated those of a Burkitt lymphoma. Cytochemical and/or immunologic marker studies ruled out a hematopoietic origin of the malignant cells in both cases and confirmed a diagnosis of carcinocythemia. The rapidly fatal outcome observed in these two cases was in accordance with the poor prognosis usually encountered with this rare phenomenon.

[T-cell lymphoma].

8 patients with lymphoproliferative disorders of T-cell origin were diagnosed during the years 1985-1987. They included 2 cases of so-called Lennert's lymphoma, 1 case of T-cell lymphoma simulating malignant histiocytosis and 1 case of T-cell lymphatic lymphoma with splenic T-cell lymphoma which survived 10 years. The other cases presented with peripheral T-cell lymphomas. Immunologic typing of malignant lymphomas with cell suspensions is of diagnostic value.

Effects of lung hyperinflation on mean arterial pressure and postsuctioning hypoxemia.

Our purpose was to determine the effect of five different lung hyperinflation volumes (tidal volume, 12 cc/kg, 14 cc/kg, 16 cc/kg, and 18 cc/kg lean body weight) on mean arterial pressure and postsuctioning hypoxemia (arterial blood gases). Subjects received three consecutive lung hyperinflations at one of the five randomly ordered volumes in 15 seconds via a ventilator "sigh" control at a fraction of inspired oxygen of 1.0. The three lung hyperinflations were followed by 10 seconds of continuous suction (flow rate 16 L/min). The procedure was repeated three times. The sample consisted of eight men and women 4 hours after coronary artery bypass graft surgery. Data indicated a statistically significant (by analysis of variance, p = 0.000) mean increase of 15 mm Hg in mean arterial pressure over the three lung hyperinflation sequences that was not volume dependent. There was a significant increase (p = 0.0001) in arterial oxygen pressure at 0 seconds after suctioning that increased with each increasing lung hyperinflation volume.

Hymenolepis murissylvatici: humoral response in intestinal lavages of the mouse.

Hymenolepis murissylvatici elicits a humoral response in serum and in the intestine of the mouse from which it is immunologically rejected. In serum, significant differences were recorded 3 days after reinfection, while in intestinal lavages it takes place from day 9 after reinfection. In serum the response is largely the result of IgG and IgM antibodies whereas in the intestine, IgA is the most abundant antibody. Although specific IgE could not be demonstrated in serum, it was present in intestinal lavages, although rather late (i.e. day 14 after reinfection). Treatment of young worms in vitro both with immune serum or intestinal lavages had no apparent effect on their viability. Immune serum produced a complement independent precipitation on the surface of the worms in vitro. This reaction did not affect viability or infectivity of the parasite, as demonstrated by the successful implantation of treated worms in recipient mice. The above-mentioned results, together with the knowledge that the Hymenolepis model has no tissue stages and causes no tissue damage, make it probable that further study of this model will reveal some specific intestinal immunological reactions.

Gray platelet syndrome in the elderly.

A 68-year-old male who suffered from thrombocytopenia and mild splenomegaly for 18 years was found to present agranular gray platelets on peripheral blood smear. Bone biopsy revealed a mild, diffuse, reticular fibrosis with no collagen, and electron microscopy of the platelets showed an absence of almost all the alpha-granules. Platelet thrombospondin and fibronectin analysed by SDS-polyacrylamide gel electrophoresis and Rocket immunoelectrophoresis were absent. Follow-up of 4 years showed the same parameters with no evidence of active myeloproliferative or dysmyelopoietic disorders. Hemorrhagic diathesis was limited to ecchymoses and postprostatectomy bleeding, necessitating platelet transfusion. This led us to conclude that our patient probably had a constitutional primary alpha-granule deficiency or gray platelet syndrome. This extremely rare defect has been described in less than 10 patients, all of them very young. Our observation shows that these patients may have a long, uneventful survival.