Minimally Invasive Diagnosis of Secondary Intracranial Lymphoma.

Diffuse large B cell lymphomas (DLBCL) are an aggressive group of non-Hodgkin lymphoid malignancies which have diverse presentation and can have high mortality. Central nervous system relapse is rare but has poor survival. We present the diagnosis of primary mandibular DLBCL and a unique minimally invasive diagnosis of secondary intracranial recurrence. This case highlights the manifold radiological contributions to the diagnosis and management of lymphoma.

Supplemental vitamin K improves the stability of anticoagulation in a patient with low tissue stores of vitamin K secondary to coeliac disease.

Maintenance of a patient's international normalised ratio (INR) within the appropriate target range remains a challenge in clinical practice. The effects of concurrent medication, alcohol and compliance on stable control are well documented. Recent evidence also shows that supplemental vitamin K in patients with low body stores improves the stability of INR in these patients. Here, the case of a 57-year-old with coeliac disease requiring warfarin for a metallic mitral valve, who had poor INR stability resulting in thrombotic and bleeding complications, is described. Her vitamin K body stores were extremely low. Supplementation of vitamin K (100 µg daily) resulted in improvement in anticoagulation stability (mean (SD) 3.41 (1.68) vs 4.68 (3.34)). The percentage time spent within target INR range doubled following vitamin K supplementation. This case illustrates a relatively new approach to managing patients with highly unstable INR levels and provides extra understanding of factors influencing INR stability.

Allogeneic bone marrow transplantation with matched unrelated donors for patients with hematologic malignancies using a preparative regimen of high-dose cyclophosphamide and fractionated total body irradiation.

Allogeneic bone marrow transplantation (BMT) from an HLA-identical sibling donor is effective therapy for patients with bone marrow failure states and those with hematologic malignancies. However, only a minority of them will have an HLA-identical sibling donor; unrelated donors, matched or partially mismatched, have been used successfully for patients lacking a related donor. Even though results with allogeneic transplants using unrelated donors are encouraging, the incidence of complications including graft-versus-host disease (GVHD) and graft rejection or late graft failure is increased compared to identical sibling transplants. The combination of cyclophosphamide and total body irradiation (TBI) has been used as an effective preparative regimen for allogeneic transplants, however, the total dosage and dosing schedule of both the cyclophosphamide and TBI has varied significantly among studies. To decrease the rate of graft rejection and late graft failure with volunteer donors, we evaluated a preparative regimen of high-dose cyclophosphamide (200 mg/kg over 4 consecutive days, days -8, -7, -6, -5) followed by fractionated TBI (1400 cGy administered in eight fractions over 4 days, days -4, -3, -2, -1). GVHD prophylaxis included FK506 and methotrexate. From July 1993 to January 1996, 43 adult patients, median age 38 years (range 18-58 years), were treated with this preparative regimen. Seventeen patients had low-risk disease and 26 had high-risk disease. Thirty-one donor/recipient pairs were matched for HLA-A, -B, and -DR by serology and molecular typing. Seven additional pairs were minor mismatched at the HLA-A or HLA-B loci. Four other donor/recipient pairs were HLA-A,-B, and -DR identical by serology but allele mismatched at either DRB1 or DQB. Forty patients were evaluable for myeloid engraftment. Engraftment occurred in all 40 patients at a median of 19 days. There were no cases of graft rejection or late graft failure. Nephrotoxicity was the primary adverse event with 26 patients (60%) experiencing a doubling of their creatinine. Hepatic veno-occlusive disease occurred in seven patients, six of whom had high-risk disease. All patients who had relapsed or refractory disease prior to BMT achieved a complete remission following BMT. Six patients transplanted for high-risk disease relapsed a median of 377 days post-BMT. None of the patients with low-risk disease have relapsed following transplant; the Kaplan-Meier survival for those patients with low-risk disease is 62% and 37% for those patients transplanted with high-risk disease (P = 0.0129). The median Karnofsky performance status is 100% (range 70-100%). Therefore, a preparative regimen of high-dose cyclophosphamide and fractionated TBI is an acceptable regimen for patients receiving an allograft from unrelated donors.

1-Desamino-8-arginine-vasopressin corrects the hemostatic defects in type 2B von Willebrand's disease.

DDAVP is effective treatment in most types of von Willebrand's disease; however, in type 2B von Willebrand's disease the use of DDAVP has been contraindicated due to DDAVP-induced thrombocytopenia. Several reports have confirmed the thrombocytopenic effects of DDAVP and the presence of circulating platelet aggregates in type 2B von Willebrand's disease. We have infused three type 2B patients with DDAVP. The three patients had different mutations of their vWf. All three patients had a missense mutation which resulted in a single amino acid substitution in the disulfide loop of the A1 domain. Administration of 20 micrograms of DDAVP resulted in significant elevations of factor VIII, vWf antigen, and ristocetin cofactor levels. In contrast to other studies, DDAVP did not induce or enhance thrombocytopenia in these three patients. When blood was obtained by fingerstick and diluted into sodium oxalate (Unopette) or EDTA (Microvette), the platelet counts did not change over 4 hr. In contrast, blood collected directly into evacuated tubes containing sodium citrate, lithium heparin, or EDTA consistently demonstrated varying degrees of thrombocytopenia and platelet clumping. We also observed a shortening of the pre-infusion bleeding time over the 4 hr period. All three patients have been studied twice and each has shown consistent results. DDAVP appears to be a useful form of treatment in type 2B vWd.

Endogenous platelet fibrinogen: its modulation after surface expression is related to size-selective access to and conformational changes in the bound fibrinogen.

Platelet stimulation results in the release of endogenous platelet fibrinogen which binds to the platelet surface. Previous studies have demonstrated that plasma fibrinogen bound to activated platelets becomes inaccessible to a variety of probes. We have studied endogenous platelet fibrinogen binding to activated platelets by employing an immunopurified polyclonal anti-fibrinogen antibody and F26, a monoclonal anti-fibrinogen antibody, which recognizes fibrinogen only when it is bound to a surface. Employing the Ig or F(ab')2 of the poly- or monoclonal antibody we found a marked decrease of fibrinogen accessibility 30-60 min after platelet activation. In contrast, platelet-bound fibrinogen remains accessible to the Fab fragment of F26 at a constant level for 30 min and increases at 60 min. The reduction of the polyclonal Fab fragment binding at 30 and 60 min is similar to the F26 Ig. These results indicate that the decreased accessibility of bound fibrinogen is related to two mechanisms; (1) that the access route to fibrinogen in size selective for the antibody probes and only small antibody probes, e.g. Fab fragments, can gain access to fibrinogen and (2) fibrinogen undergoes a conformational change(s) after binding which exposes at least one neo-epitope in the D domain of fibrinogen and which may decrease or mask the reactivity of other fibrinogen domains. Only the F26 Fab probe has full access to and identifies fibrinogen present on the platelet surface 60 min after stimulation.

Platelet activation and alpha granule secretion in type IIB von Willebrand's disease.

Type IIB von Willebrand disease is characterized by enhanced ristocetin-induced platelet aggregation, spontaneous platelet aggregation, thrombocytopenia and the absence of the largest plasma von Willebrand factor (vWf) multimers. The absence of the largest plasma vWf multimers is related to their enhanced binding to platelets. The abnormal affinity of the IIB von Willebrand factor to platelets results in thrombocytopenia, but the mechanism is not known. We have studied the platelets from three patients with type IIB von Willebrand disease and have found evidence of platelet activation and alpha granule secretion as defined by increased amounts of von Willebrand factor, fibrinogen and the alpha granule protein PADGEM/GMP-140 on the surface of these platelets. The degree of thrombocytopenia appears to be directly related to the number of platelets with fibrinogen bound to the surface. PADGEM/GMP-140, an alpha granule membrane protein, fuses with the platelet plasma membrane after activation and is a site on platelets which binds to neutrophils or monocytes. This alpha granule protein may play an additional role in platelet clearance and thrombocytopenia in type IIB von Willebrand disease. This may, in part, explain the absence of thromboembolic phenomena despite the presence of activated platelets in patients with type IIB von Willebrand disease.

Endogenous platelet fibrinogen surface expression on activated platelets.

Intracellular platelet fibrinogen surface expression was studied in arabinogalactan-purified, resting, and thrombin-stimulated platelets. Platelet fibrinogen is derived from endocytosis of plasma fibrinogen by megakaryocytes. Like a variety of other adhesive proteins, it is stored in the platelet alpha-granule. Platelet fibrinogen surface expression was studied by using the antigen-binding fragments of a murine monoclonal antibody to platelet fibrinogen, F26, and an immunopurified polyclonal antifibrinogen antibody. Studies correlating platelet fibrinogen surface expression with the presence of the glycoprotein IIb-IIIa (GPIIb-IIIa) complex showed that in the presence of ethylene glycol tetraacetic acid (EGTA) at 37 degrees C, neither the GPIIb-IIIa complex nor platelet fibrinogen was expressed on the surface of thrombin-activated platelets. Similar experiments performed in the presence of EGTA and calcium showed proportional expression of the GPIIb-IIIa complex and platelet fibrinogen. The addition of Arg-Gly-Asp-Ser-containing peptides, the pentadecapeptide of the fibrinogen gamma-chain carboxy terminus, or the monoclonal antibody 10E5, when directed against the GPIIb-IIIa complex before thrombin activation, inhibited 65% to 94% of the platelet fibrinogen expression, as determined with the polyclonal and monoclonal antigen-binding fragments. When these same inhibitory agents were added immediately after or 5 minutes after thrombin, the amount of inhibition decreased significantly. Similar studies with a washed platelet system revealed that when the inhibitors of platelet fibrinogen expression were added before thrombin stimulation, the degree of inhibition observed was only 24% to 38%. This suggests that the major portion of platelet fibrinogen expression involves the release of platelet fibrinogen and its subsequent binding to GPIIb-IIIa. This binding may occur within the open canalicular system or on the platelet surface; in either case, wherever the site of released platelet fibrinogen binding occurs, it can be markedly inhibited by the RGD-containing peptides and the gamma-chain fibrinogen peptides. Approximately 10% to 30% of platelet fibrinogen may be expressed prebound to a platelet receptor, or else it is released and binds to a platelet receptor other than the GPIIb-IIIa complex.