The requirement of platelets for experimental murine pulmonary metastases, as well as the ability of tumor cells to aggregate platelets was first recognized by Gasic and co-workers, twentyfive years ago (1). This stimulated a considerable interest in the mechanism of tumor-induced platelet aggregation, as well as attempts to inhibit experimental metastases with anti-platelet agents since it was assumed that the ability of tumor cells to aggregate platelets correlated with tumormetastasis. The literature on the use of anti-platelet agents to inhibit in vivo metastases is controversial. Indeed our own laboratory expended considerable effort in elucidating 3 different mechanisms of tumor-induced platelet aggregation (2). However, sensitive agents employed in vitro to inhibit aggregation had no effect when employed in vivo on pulmonary metastases of the very same syngeneic tumors (3). We therefore found it necessary to confirm Gasic's original observations. W e found that anti-murine platelet antibody markedly inhibited the number and volume of metastases of 3

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Primary effusion lymphoma (PEL) is a recently described rare type of non-Hodgkin's lymphoma occurring almost exclusively in HIV infected people. Human herpesvirus 8 (HHV-8), has been linked with PEL, and a causative relationship has been suggested. In the vast majority of PEL cases Epstein-Barr virus (EBV) has been found in the tumour cells. We describe here an elderly human immune deficiency (HIV) seronegative man with intractable chest pain and pleural effusion. The diagnosis of malignant lymphoma was suggested cytologically and confirmed histologically following pleural biopsy. No lymphadenopathy or organ involvement with lymphoma was found. Systemic chemotherapy with a modified CHOP regimen with G-CSF support gradually led to the resolution of the chest pain and ultimately resulted in a complete clinical remission (CCR). The presence of HHV-8 was demonstrated by PCR using paraffin-embedded tissue samples from the involved pleura, whereas EBV-associated genetic material was absent. The patient remained in CCR for 18 months and died of an unrelated cause (cerebrovascular event). Only 11 other cases with clinical and virological features similar to those of our patient have been reported in the literature. Analysis of these rare cases suggests HIV-negative EBV-negative PEL to be a distinct clinical entity with epidemiological features resembling classical KS and supports an EBV-independent role for HHV-8 in the pathogenesis of PEL.

Many patients with chronic lymphocytic leukemia (CLL) develop progressive treatment-resistant disease. Rituximab (RTX), a monoclonal antibody targeting CD20 on B lymphocytes and widely used in other indolent B-cell neoplasms is less efficacious in CLL, possibly because of associated complement deficiencies. Initial in vitro and in vivo observations support the central role of complement in rituximab-mediated loss of CD20(+) cells in CLL. In an open trial conducted in outpatient hematology clinics in Israel and Greece, we examined whether providing complement by concurrent administration of fresh frozen plasma (FFP) would enhance the effect of RTX in CLL. Five patients with severe treatment-resistant CLL were included in the trial. All had been previously treated with fludarabine, and three also failed treatment with RTX. Each patient was treated with two units of FFP followed with RTX 375 mg/m(2) as a single agent, repeated every 1-2 weeks as needed. A rapid and dramatic clinical and laboratory response was achieved in all patients. Lymphocyte counts dropped markedly followed by shrinkage of lymph nodes and spleen and improvement of the anemia and thrombocytopenia. This could be maintained over 8 months (median) with additional cycles if necessary. Treatment was well tolerated in all cases. In conclusion, adding FFP to RTX may provide a useful therapeutic option in patients with advanced CLL resistant to treatment. Further studies are needed to confirm and study the efficacy of the FFP/RTX combination in advanced CLL, establish the mechanisms, and possibly extend its use to other B-cell-dependent pathologies, such as treatment-refractory autoimmune diseases.

Thrombin has been shown to activate tumor-cell adhesion to platelets, fibronectin and von Willebrand factor 2-to 3-fold in vitro, and enhance metastasis 10-to 156-fold in vivo. We therefore elected to determine whether thrombin binds to tumor cells and whether thrombin-treated tumor cells enhance their adhesion to endothelial cells, the first barrier to tumor invasion and metastasis. Thrombin-treated human and hamster melanoma cells enhanced their adhesion to bovine aortic endothelial cells 2. I -to 2.3-fold, respectively. Similar results were obtained with bovine capillary endothelial cells. Thrombin activation of tumor cells was rapid, reaching its peak 15 rnin after thrombin activation: and transient, declining to baseline levels by 60 min. '"1-thrombin bound to both SK-Mel-28 and HM-29 cells in a saturation-dependent manner, was inhibitable by unlabelled thrombin, and could be 90% washed away with buffer following 30 min of incubation. Electron microscopy of tumor cells bound to fibronectin-coated millipore filters revealed adhesion of naive as well as thrombin- We have recently reported that thrombin-treated tumor cells enhance their adhesion to naive platelets, fibronectin and von Willebrand factor 2-to 3-fold in vitro; and enhance experimental pulmonary metastasis 10-to 156-fold in vivo (Nierodzik et al., 1992). Similar results were obtained with thrombin-activated platelets in vitro and thrombin injected intravenously with tumor cells (Nierodzik et al., 1991). Because the effect of thrombin on in vivo metastasis was considerably greater than its effect on tumor-cell adhesion to platelets and adhesive ligands, we considered the possibility that thrombintreated tumor cells might also enhance their adhesiveness to endothelial cells, an important host barrier against tumor-cell invasion. This proved to be indeed the case.The present report documents saturation binding of thrombin to tumor cells, enhanced adhesion of cells from 2 different thrombin-treated melanoma lines (HM29 and SK Me1 28) to bovine aortic and capillary endothelial cells, as well as the transient adhesive effect of thrombin treatment (peaking at 15 min and disappearing at 60 min). MATERIAL AND METHODS Tumor-cell linesSK Me1 28 is a human melanoma cell line obtained from the ATCC (Rockville, MD). HM-29 is a hamster melanoma, kindly supplied by Dr. J-C. Bystryn of New York University Medical School. Both were grown in RPMI (GTBCO, Grand Island, NY) supplemented with 1% penicillin-streptomycin, 2% glutamine, 1% non-essential amino acids and 10% FCS (GIBCO) in 50-ml plastic tissue-culture flasks. Cells were harvested at subconfluence with Trypsin-EDTA or EDTA alone. Monoclonal antibodiesAnti-pl (AIAS) was a gift from Dr. M. Hemler, DanaFarber Cancer Institute, Boston, MA. Anti-a3P1 (PB15) was a gift from Dr. W.G. Carter. Anti-qP, (LM609) was a gift from Dr. Cheresh, Scripps Clinic, La Jolla, CA. Anti433 (LK-2 against platelet GPIIIa) was prepared in our laboratory. Rat anti-a5 (PlE5) was a gift from Dr. C. Damsky, UCSF, San Francisco, CA, and a...

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Our findings showing the potential of LGLL cells for cytokine release in vitro suggests that these cells may play a major role in the immune disturbances observed in large granular lymphocytic leukemia accompanied by autoimmunity features.

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