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.

Management of hemophilia in Spain.

Results are presented of a nation-wide inquiry into the management of hemophilia in Spain. It is calculated that there are 1,172 hemophilic patients in the country. A survey has been made of the therapeutic materials (prepared commercially or by hospitals) used in 1974 and their availability in the various hospitals of the Social Security Service. It is estimated that an average of 10,708 units of deficient factor were used per patient in this year. The number of patients on home therapy is 1.2% of the total. All cost of hemophilia treatment is covered by the Social Security. Comments are made on progress during the last five years.

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.

Identification of a new haemophilia BM case produced by a mutation located at the carboxy terminal cleavage site of activation peptide.

We describe a novel point mutation due to C----G transversion at nucleotide 20518 in the exon VI of factor IX gene, resulting in the substitution of glycine (GGG) for arginine (CGG) at position 180 in the polypeptide. This point mutation was found in a patient with a haemophilia BM variant. We designated the altered factor IX produced by this new mutation as factor IXMadrid. This mutation blocks the cleavage site involved in the release of the activation peptide at Arg180-Val181. It also abolishes the Aval site (CTCGGG) in exon VI, which can be directly detected with the enzymatic DNA amplification technique (PCR) and offers the possibility of direct analysis in carrier and prenatal diagnosis in kindreds with this mutation.

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.

Factor IXMadrid 2: a deletion/insertion in factor IX gene which abolishes the sequence of the donor junction at the exon IV-intron d splice site.

DNA from a patient with severe hemophilia B was evaluated by RFLP analysis, producing results which suggested the existence of a partial deletion within the factor IX gene. The deletion was further localized and characterized by PCR amplification and sequencing. The altered allele has a 4,442-bp deletion which removes both the donor splice site located at the 5' end of intron d and the two last coding nucleotides located at the 3' end of exon IV in the normal factor IX gene; this fragment has been replaced by a 47-bp sequence from the normal factor IX gene, although this fragment has been inserted in inverted orientation. Two homologous sequences have been discovered at the ends of the deleted DNA fragment.

Joint debridement for haemophilic arthropathy of the knee.

Joint debridement was performed for advanced haemophilic arthropathy of the knee in eleven patients. Follow up was for an average of 5.4 years and the results were evaluated retrospectively by the Hospital for Special Surgery disability score sheet. The clinical results were excellent in four, good in five and fair in two. Debridement should be considered in the young haemophiliac to avoid, or delay, total knee arthroplasty. The operation may give the patient years of life without pain and it appears to slow the development of radiographic changes.

[Pathogenesis of peripheral cytopenias in hemophiliac patients]. / Observaciones sobre la patogenia de las citopenias periféricas en pacientes hemofílicos.

The frequent occurrence of peripheral cytopenias is a common clinical fact in patients with HIV-1 infection, and its pathogenetic mechanism is not clear, although several hypotheses have been proposed. Such cytopenias are frequently observed in haemophilic patients, in whom the immunologic alteration induced by continuous antigenic stimulants derived from plasma concentrate therapy has been postulated as an additional causative factor. One-hundred and forty five haemophiliacs treated with commercial antihaemophilic concentrates were studied. The patients were divided into three therapeutic groups according to the mean number of units of therapeutic factor VIII administered per Kg every year in the four years prior to the study (group I: less than 500 U; group II: between 501 and 1500 U; group III: more than 1500 U). The occurrence of cytopenias in the patients was co-ordinated with the presence or absence of HIV infection and the therapeutic group. The statistical studies showed clear correlation between peripheral cytopenias and presence of anti-HIV markers, regardless of the amount of concentrates perceived (except for the total neutrophil count).

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.

Septic arthritis in HIV positive haemophiliacs. Four cases and a literature review.

Septic arthritis is rare in haemophiliacs. Four new cases who were also HIV positive are reported. In three, the knee was involved, and in the fourth the elbow. The organism was streptococcus pneumoniae and staphylococcus aureus in one patient each, and salmonella in two. Although all the patients were human immunodeficiency virus (HIV) positive at the time of diagnosis, only two patients developed autoimmune deficiency syndrome (AIDS) after their septic arthritis. These two died later due to AIDS complications. Treatment was conservative in all cases with antibiotic therapy and prompt rehabilitation. The results were fair in two and good in two. Therefore nonoperative management is advocated before surgical drainage is considered. It seems likely that a positive HIV status is related to the appearance of septic arthritis in haemophiliacs.

[Intra-articular methylprednisolone therapy in chronic hemophilic synovitis of the knee]. / Terapia con metilprednisolona intraarticular en la sinovitis crónica hemofílica de rodilla.

This prospective study evaluates the effectiveness of intraarticular methylprednisolone (IAMP) (80 mg) in 10 knees of 10 hemophilic patients with chronic synovitis. This treatment was prescribed because the lack of sensitivity to substitutive therapy with the deficient coagulation factor during 2 months. The patients average age was 25 years (range, 18 to 30) and the minimum follow up was 1 year. The patients were radiographically and ultrasonographically (US) evaluated before starting any kind of treatment and periodically until finishing the follow up. The results one year after the injection were excellent in 4 cases, good in 3 cases, fair in 2 cases and poor in 1 case. Correlation between results and previous radiographic status of the knee has not been found. A close correlation between clinical features and US examination findings was demonstrated. This study has demonstrated that IAMP is an useful procedure for medically treating the chronic hemophilic synovitis of the knee, even with radiographic signs of arthropathy. IAMP must be born in mind before applying other methods more aggressive. US is very useful for diagnosing and following up the effects of IAMP on this condition.

Hematological abnormalities in hemophilic patients with human immunodeficiency virus infection.

Hematological abnormalities are common in patients with AIDS or AIDS-related complex. We studied cytological characteristics in peripheral blood and bone marrow samples of 33 hemophilic patients with HIV Infection and in six HIV negatives. The HIV-positive patients presented leukopenia (60.6%), thrombocytopenia (69.9%), and anemia (57.5%). Bone marrow showed abnormalities of maturation in one or more cell lines similar to those described in other HIV-infected groups of patients. These findings were more prominent in megakaryocytes and granulocytic series. Lymphocytosis, plasmocytosis, and increased hemophagocytosis were also common. These alterations do not appear in HIV-negative patients and seem related to a direct effect of HIV on bone marrow cells or to alterations in T-cell regulatory functions.

Hemostatic effect of normal platelet transfusion in severe von Willebrand disease patients.

Platelet von Willebrand factor (vWF) has been suggested to play an important role in the hemostatic process. Clinical and experimental data indicate that bleeding time (BT) and platelet-vessel wall interaction cannot be normalized unless the defect of platelet vWF is also corrected. We have examined the effect of normal platelet concentrate transfusion 1 hour after cryoprecipitate infusion in five type III von Willebrand disease (vWD) patients. The cryoprecipitate infusion attained normal circulating levels of ristocetin cofactor, vWF antigen, and factor VIII activity. In two patients, cryoprecipitate infusion did not modify the BT (greater than 30 minutes), whereas in the remaining three patients BT was only partially corrected (from greater than 30 to 12, 18, and 21 minutes). However, the immediate platelet transfusion completely corrected the BT in four cases, and in one case it shortened the BT to 8.30 minutes (n = 3 to 8 minutes). In the perfusion study, cryoprecipitate infusion only resulted in a slight increase in platelet deposition (surface coverage range: 2.4% to 11.3%), whereas the platelet concentrate transfusion elicited a more marked improvement (range: 8.2% to 26.4%; P less than .02 v post-cryoprecipitate). These results suggest an important in vivo role of the platelet vWF in supporting platelet-vessel wall interaction. They also give support to the occasional addition of normal platelet transfusion to the cryoprecipitate infusion for the control of serious bleeding episodes resistant to cryoprecipitate in severe vWD patients.