Brain metastases treated with radiosurgery or hypofractionated stereotactic radiotherapy: outcomes and predictors of survival.

INTRODUCTION: To assess treatment outcome and prognostic factors associated with prolonged survival in patients with brain metastases (BM) treated with stereotactic radiosurgery (SRS) or hypofractionated stereotactic radiotherapy (HFSRT). METHODS/PATIENTS: This study retrospectively reviewed 200 patients with 324 BM treated with one fraction (15-21 Gy) or 5-10 fractions (25-40 Gy) between January 2010 and August 2016. 26.5% of patients received whole brain radiotherapy (WBRT) and 25% initial surgery. Demographics, prognostic scales, systemic and local controls, patterns of relapse and rescue, toxicity, and cause of death were analyzed. A stratified analysis by primary tumor was done. RESULTS: Median overall survival (OS) was 8 months from SRS/HFSRT. Breast cancer patients had a median OS of 17 months, followed by renal (11 months), lung (8 months), colorectal (5 months), and melanoma (4 months). The univariate analysis showed improved OS in females (p 0.004), RPA I-II (p < 0.001) initial surgery (p < 0.001), absence of extracranial disease (p 0.023), and good disease control (p 0.002). There were no differences in OS or local control between SRS and HFSRT or in patients receiving WBRT. Among 44% of brain recurrences, 11% were in field. 174 patients died, 10% from confirmed intracranial progression. CONCLUSIONS: SRS and HSFRT are equally effective and safe for the treatment of BM, with no exceptions among different primary tumors. Disease control, surgery, age, and prognostic scales correlated with OS. However, the lack of survival benefit regarding WBRT might become logical evidence for its omission in a subset of patients.

Influence of von Willebrand factor on the reactivity of human factor VIII inhibitors with factor VIII.

In order to determine the difference in reactivity of factor (F) VIII inhibitors against the FVIII/von Willebrand factor (vWF) complex and against vWF-deficient FVIII, we investigated a panel of 10 antibodies to FVIII from multitransfused individuals with severe haemophilia A and other pathologies. Immunoblotting of purified FVIII and purified thrombin-cleaved FVIII revealed that in all cases inhibitor epitopes could be localized in the heavy chain (A2 subunit) while in four cases they were also present in the light chain. One of the FVIII inhibitors remained unclassified. The effect on FVIII:C of purified IgG from inhibitor plasmas was tested against a high purity FVIII/vWF concentrate and a monoclonally purified FVIII concentrate with only trace contents of vWF, by two different functional assays. Our results suggest that for those inhibitors showing A2 plus light chain (LC) reactivity, the IgG concentration required to inhibit 50% of FVIII activity in vitro is higher for the FVIII/vWF complex than for the vWF-deficient FVIII. We conclude that there might be a protective role of vWF (at least in vitro) against FVIII inhibitors with A2 and LC subunit specificity.

Estudio epidemiológico de la hemofilia en España / Epidemiological study of hemophilia in Spain

El objetivo de este estudio epidemiológico fue la caracterización de un grupo representativo de pacientes del territorio español afectos de hemofilia con relación a su situación diagnóstica, clínica, terapéutica y a las complicaciones de la enfermedad y de su tratamiento. Se llevó a cabo por medio de un cuestionario que se envió a todos los centros de tratamiento. Resultados: fueron remitidos 825 cuestionarios evaluables, lo que corresponde aproximadamente a un tercio de la población hemofílica española. El 88 por ciento de los hemofílicos padecían hemofilia A y el 12 por ciento hemofilia B. El 36 por ciento graves (nivel inferior al 2 por ciento). La gran mayoría de pacientes estaban siguiendo un programa de tratamiento a demanda (79 por ciento). Un reducido número seguía, en el momento del registro, un tratamiento de profilaxis secundaria (17 por ciento), y tan solo un 3,4 por ciento seguía un programa de profilaxis primaria. El consumo medio de factores por paciente durante el año 1995, fue de 45.945 UI, lo que correspondería a una media de 706 Ul/kg/año. El 30 por ciento de los pacientes presentaban una o más articulaciones con algún grado de afectación. Los pacientes graves presentaban un total de 627 articulaciones afectadas de media por paciente. El 7,3 por ciento del total presentaba o habían presentado inhibidor. El 27 por ciento tenían anticuerpos anti-VIH. Los anticuerpos de la hepatitis C estaban presentes en el 61 por ciento. El antígeno HBs fue positivo en el 4 por ciento. (AU)

The orthopaedic status of severe haemophiliacs in Spain.

This paper provides an outline of the results obtained in a cross-sectional study conducted primarily with the aim of ascertaining orthopaedic complications in a group of young severe A and B haemophiliacs, the effects which these complications have on the medical resources used with these patients, and the impact of severe haemophilia on their quality of life. Its secondary aim was to link their current orthopaedic status to the type of treatment they had received prior to the study. Eleven Spanish hospitals took part in this study, monitoring 70 severe haemophiliacs (FVIII:C <2%) without inhibitors who had a mean age of 21.6 years and a median age of 22. Retrospective data collected from birth to the conclusion of the study were used and, for certain variables, data from the last 12 months. The type of treatment given had been on-demand treatment, together with prophylaxis of variable time periods, which in 32 cases (45.7%) were prolonged (>6 months). In 40 cases (57.1%) the patients underwent one or more periods of prophylaxis. Thirty-three patients (47.8%) had over 1000 days of administration of factors VIII and IX. The analysis of the total study group reveal an average of 348 bleeding episodes per patient. The findings of this study revealed that 84.3% of these patients suffer from articular complaints on the Gilbert scale, and 85.7% on the Pettersson scale. In addition, pain was reported in 16.1% of the joints, the most frequently affected being the ankle joints. Twenty-six patients (37%) had undergone orthopaedic surgery from the time of birth to the conclusion of the study. The quality of life of the severe haemophiliacs reviewed seems to have been affected. During the last 12 months, there were 216 outpatient haematological visits and 176 orthopaedic-rehabilitation visits, as well as 12 radiological explorations and two hospitalizations. During these 12 months, medical expenditure totalled $55 473 per patient per year, the most important item being factor concentrates VIII/IX ($54 119 per patient per year). The type of treatment given to these patients (on-demand and/or as secondary prophylaxis) was found to be incapable of preventing haemophilic arthropathy or guaranteeing an acceptable quality of life, although both the administration of coagulant factor concentrate to such patients and the financial resources dedicated to their treatment was very high. Consequently, a strategic change is to be considered for the prevention of haemophilic arthropathy, based on the introduction of replacement treatment involving continuous administration of factors VIII and IX in primary prophylaxis regimens from the first years of life.

Therapeutic embolization and surgical excision of haemophilic pseudotumour.

Haemophilic pseudotumour is a rare complication of haemophilia. Few cases of iliac haemophilic pseudotumour have been reported in the literature. These tumours can act as a focus for infection and cause cutaneous fistulas. When they present perforations and infections of endogenous origin their course is usually fatal. Suitable treatment has been investigated on numerous occasions, most of the literature agreeing that the only curative treatment is surgical resection. We present a case of haemophilic pseudotumour of the iliac and caecum with cutaneous fistulas, with a septic process of endogenous origin. It was treated with surgical resection after performing arterial embolization to reduce the vascularization of the pseudotumour, thereby reducing its size and the risk of bleeding complications during surgery.

Hepatitis G virus infection markers (RNA and anti-E2 antibodies) in a multicenter cohort of hemophiliacs.

BACKGROUND AND OBJECTIVE: To investigate the prevalence and evolution of hepatitis G virus (HGV) infection in hemophiliacs and to correlate evolution of HGV infection markers with immunologic parameters in those patients co-infected with HIV. DESIGN AND METHODS: HGV RNA and anti-E2 antibodies were studied in 124 patients. Serial samples were drawn every 4 months from 1992 to 1996. Lymphocyte subsets including T-helper lymphocytes, T-suppressor lymphocytes, T-cytotoxic lymphocytes, activated T-lymphocytes and natural killer cells were analyzed. RESULTS: Prevalences were 22.6% for HGV RNA and 18.5% for anti-E2. Four patients had both HGV RNA and anti E2, so the overall prevalence of HGV infection in hemophiliacs was 37.9% (11.5% in 200 controls, p<0.0001). After a median follow-up of 36.6 months 20 patients remained HGV RNA positive, whereas HGV RNA had cleared in 8, with an actuarial probability of clearance at 36 months of 34.6%. Only 2 patients developed anti-E2 antibodies. Four patients cleared anti-E2, with an actuarial probability at 36 months of 24.8%. In patients with HIV infection, both lower CD4+ lymphocyte count (p=0.01) or higher CD8+ lymphocyte count (p=0.03) showed predictive value for probability of clearing HGV-RNA. CD4+/CD8+ ratio (p=0.002) was the only variable included in the best model for HGV-RNA disappearance. INTERPRETATION AND CONCLUSIONS: A more accurate estimation of the prevalence of HGV infection can be achieved with the determination of both HGV RNA and anti-E2. Anti-E2 response can be undetectable or transitory after disappearance of HGV-RNA, giving therefore rise to the possibility of underestimating HGV prevalence with currently diagnostic methods. In HIV-positive patients, cellular immune function seems to be involved in the resolution of HGV infection, following the significant correlation found between clearance of HGV-RNA and CD4+/CD8+ lymphocyte populations.

Joint replacement for a spontaneously ankylosed hip in a haemophilic patient.

A cemented Charnley total hip prosthesis was implanted in a 48-year-old man with mild haemophilia (factor VIII 4 IU dL-1) in his right spontaneously ankylosed hip. At the time of surgery he was anti-HCV positive, anti-HIV negative, and no circulating inhibitors were encountered. The indication for surgery was long-lasting intractable low back and ipsilateral knee pain. At 4-month follow-up, relief of pain was achieved as well as correction of limb-length discrepancy, with a good result according to the Mayo Clinic hip score. Doses of 50 IU kg-1 body weight of recombinant factor VIII (Recombinate; Baxter, Glendale, California, USA) was used during the 2 weeks of admittance to the hospital. The dosage was adjusted according to the recoveries of factor VIII, with an overall factor consumption of 68 000 IU. As far as we know this is the first case reported in the literature of a person with haemophilia in whom a spontaneous hip ankylosis has been satisfactorily converted in a total hip arthroplasty with a short-term follow-up. However, a much longer follow-up is still needed to ascertain the efficacy of this surgical procedure in haemophilia.

Identification of twenty-one new mutations in the factor IX gene by SSCP analysis.

In this study we have analyzed the factor IX gene from 84 hemophilia B patients of Spanish origin. It included single-strand conformation polymorphism (SSCP) analysis of all functional regions of the gene and further sequencing of all fragments showing abnormal migration. In 76 patients (90.4%), it was possible to identify molecular alterations leading to the appearance of the disease. Twenty-one new mutations were identified, including 13 missense mutations, two nonsense mutations, three splice-site mutations, one frameshift deletion, one frameshift insertion, and one non-frameshift deletion. The approach appears to be very suitable for molecular diagnosis of hemophilia B.

von Willebrand factor contained in factor VIII concentrates of different purities supports platelet adhesion in blood samples from a heterogeneous group of patients with von Willebrand disease.

BACKGROUND AND OBJECTIVE: Plasma derived FVIII-VWF concentrates in which the VWF structure is reasonably maintained are recommended as substitutive therapy in VWD. Our aim was to assess platelet deposition and binding to subendothelial structures of VWF present in FVIII concentrates. DESIGN AND METHODS: Cryoprecipitate (CRY), intermediate-purity (IPC), or high-purity (HPC) FVIII concentrates were added in vitro to citrated blood samples from 11 patients affected by different subtypes of VWD, with the aim of normalizing VWF levels. Measurements of VWF:Ag, ristocetin cofactor (RiCof) activities, FVIII coagulant activity (FVIII:C), and platelet interaction with subendothelium under flow conditions (Baumgartner's perfusion method, computer-assisted morphometry, shear rate 1000 s-1, 10 min, 37 degrees C) were determined. Binding of VWF to the luminal surface of the perfused vessels was assessed by immunofluorescence microscopy. Paired t-test statistics were performed. RESULTS: Addition of FVIII-VWF preparations raised VWF:Ag from baseline (BSL) values of 0.3 (SD 0.2) to averages of 1.4 (SD 0.5, p < 0.001), 1.2 (SD 0.6, p < 0.001), and 0.4 (SD 0.3) IU mL-1 after CRY, IPC, and HPC, respectively. A positive labeling for VWF was observed by immunofluorescence in vessels perfused with blood containing any of the concentrates. Platelet adhesion of 13.2 (SD 7.6), 22.4 (SD 10.8), 24.8 (SD 7.8, p < 0.03), or 22.5 (SD 4.8)% was measured in BSL, CRY, IPC, or HPC tests, respectively. INTERPRETATION AND CONCLUSIONS: Our observations support the hypothesis above the mechanisms involved in the beneficial effects of commercial concentrates in von Willebrand disease: the VWF in these concentrates has functional capacity to bind to subendothelium and to support platelet adhesion.

Hemophilic synovitis of the knee and the elbow.

A prospective study from 1974 to 1996 was done to determine optimal treatment for chronic hemophilic synovitis of the knee and synovitis of the elbow. Sixty-five patients with synovitis affecting 65 knee joints and 40 patients who had synovitis of the elbow (44 elbows), despite a 3-month trial of prophylactic substitution therapy, were treated by synovectomy. Radiation synovectomies (Au-198 synoviorthesis) were done on 38 knees, open surgical synovectomy on 18, and nine had an arthroscopic procedure. Radioactive gold synoviorthesis was performed on 29 elbows, and 15 had a resection of the radial head and partial open synovectomy. Synovectomy (by any method) significantly reduced bleeding episodes, but did not halt the radiographic deterioration of the joints. It is thought that radiation synovectomy is the best choice for patients with persistent synovitis of the knee and synovitis of the elbow unresponsive to a 3-month trial of prophylactic factor replacement. If two to three consecutive synoviortheses with 3 to 6 months intervals had been ineffective, or when the radiographic score is more than two points, an open synovectomy is indicated.

Hamstring release for fixed knee flexion contracture in hemophilia.

Sixteen hamstring tenotomies and posterior capsulotomies were assessed retrospectively in 10 patients with hemophilia. The average age of the patients was 17 years (range, 16-24 years). The main indication for surgery was a fixed knee flexion contracture of 30 degrees to 45 degrees, associated with repeated hemarthroses, and failure of conservative treatment after 6 months. A posterior transverse capsulotomy and a Z shaped hamstring tenotomy were performed. The postoperative treatment consisted of repeated stretching exercises for a 6-month period. An average decrease of 25 degrees in the amount of fixed knee flexion contracture was obtained (range, 10 degrees-40 degrees). Followup for an average of 9.5 years showed 11 good, four fair, and one poor result regarding their joint scores. It is concluded that hamstring release is an effective surgical procedure for fixed knee flexion contracture in hemophilia. It seems to reduce the incidence of hemarthrosis relating to such a deformity.

Visceral leishmaniasis in haemophiliac patients with HIV: four case reports.

Visceral leishmaniasis (VL), an endemic parasitosis in Spain, is increasing as an important opportunistic infection in AIDS patients. We describe four cases of severe haemophilic patients with end-stage HIV disease who present with visceral leishmaniasis. We report the clinical course, methods of diagnosis and response to therapy. From the assessed clinical data it does not appear to be any difference with regard to VL either in other HIV risk groups or in immunocompetent groups. In contrast with previous reports, we have found that despite their immunodepressed state, positive serology for Leishmania was found in three of the four cases. A similar observation has been made in patients with VL who are immunodepressed because of other reasons. We also confirm previous reports of poor response and intolerance of antimony treatment, the deteriorating course of the disease in AIDS patients and that there is only a slight relationship between the disease and the cause of patient death. We agree with the proposition that this pathology ought to be included in the definition critera for AIDS.

The role of a 3-year period of continuous prophylactic concentrate substitution on later development of haemophilic arthropathy.

This study evaluated the effect of a period of up to 3 years of continuous prophylactic clotting factor concentrate therapy in haemophilia on the degree of arthropathy as measured 10-15 years later. Left and right elbows, knees and ankles of 115 severe and moderate haemophiliacs were evaluated clinically and radiographically after 13.9 years of follow-up, on average, after the period of prophylactic treatment. The average age at final evaluation was 15.4 years. Three groups were compared: (1) Group D, patients treated on demand only; (2) Group D+P, patients treated on demand except for a period of prophylaxis between 1978 and 1981, and (3) six patients who had had inhibitors for more than 10 years. The results were analysed by assessing the degree of change in the 'patient score', i.e. the sum of the orthopaedic scores for the six joints. No statistical differences were found among the study groups. Thus, no benefit of the earlier 3-year period of prophylaxis could be demonstrated.

Chemical synovectomy vs. radioactive synovectomy for the treatment of chronic haemophilic synovitis: a prospective short-term study.

Between January 1992 and December 1994, a prospective study was performed in two centres comparing chemical synovectomy using repeated weekly injections (range, 1-17) of Rifampicin (Group R) vs. radioactive synovectomy using 1-2 injections of Yttrium-90 (Group Y). The study was performed on 38 joints in a total of 35 haemophilic patients suffering from chronic haemophilic synovitis unresponsive to 3 months of conservative treatment (substitution therapy with the deficient coagulation factor plus a rehabilitation protocol). Group R included 18 patients with an average age of 9 years, with an average follow-up time of 25 months. In Group R, 19 joints were treated: nine knees, four elbows and six ankles. Group Y included 17 patients with an average age of 18 years, with an average follow-up time of 23 months. In Group Y, 19 joints were treated: 14 knees, two elbows and three ankles. The joints were evaluated according to the frequency of bleeding episodes and the Pettersson radiographic score. On the basis of the radiographic scale at the time of the synoviortheses, the joints were categorized as stage I (0 points), stage II (1-2 points), stage III (3-7 points), stage IV (8-10 points) and stage V (11-13 points). The overall results showed that in Group R, bleeding decreased in 12 joints, remained the same in six and worsened in one. In Group Y, bleeding decreased in 11 joints, remained the same in seven and worsened in one. In both Groups, bleeding was controlled best if joints were in stages I and II. In stages III, IV and V, synoviorthesis should not be carried out in haemophilia because it is not effective. Use of radioactive substances in persons under the age of 9 years has been discouraged in the past and therefore only Rifampicin was used in this age group. However, in patients over 9 years of age, this study showed similar decrease of bleeding in both treatment groups. Taking into account the advantages and disadvantages of both agents, we suggest the use of Rifampicin in elbows and ankles but prefer Yttrium-90 for the knees.

Haemophilia A and chronic hepatopathy caused by extrahepatic biliary atresia: two congenital diseases cured by orthotopic liver transplantation.

Since the publication of the first successful liver transplantation in a patient with severe haemophilia A by Lewis et al. in 1985, different authors have reported clinical cure of haemophilia A by orthotopic liver transplantation. In the published cases liver transplantation was performed due to end-stage chronic liver disease secondary to factor replacement therapy for haemophilia A or haemophilia B. Congenital biliary atresia is the most common cause of obstructive jaundice in the neonatal period and the most common indication for liver transplantation in childhood. In this article we report the first successful orthotopic liver transplantation performed in Spain, carried out in the youngest patient thus far described, a 5-year-old boy with haemophilia A and chronic liver disease secondary to congenital biliary atresia.