Acute bleeding after allogeneic bone marrow transplantation: association with graft versus host disease and effect on survival.

BACKGROUND: Hemorrhagic complications are frequently implicated clinically for the high morbidity and mortality of acute graft versus host disease (GVHD), however, only few reports characterize the incidence and timing of bleeding in relation to GVHD, and essentially no study has quantified the effect of bleeding on survival of allogeneic patients with GVHD. This study examines the association of bleeding with acute GVHD and the effect of both complications on survival. METHODS: A total of 463 allogeneic patients transplanted at the Johns Hopkins Hospital, were included in the study. Bleeding evaluation was based on daily scores of intensity and blood transfusions. All bleeding sites were recorded. GVHD staging was defined by the extent of rash, serum bilirubin, diarrhea, and confirmatory histology. RESULTS: The incidence of GVHD was 27.4%, bleeding occurred in 40.2%. The incidence of bleeding was higher in patients with GVHD as compared with non-GVHD, and correlated with GVHD severity. The higher bleeding incidence in GVHD was due to gastrointestinal hemorrhage, hemorrhagic cystitis, and pulmonary hemorrhage. While the majority of bleeding (51/75) in non-GVHD patients initiated within 30 days after bone marrow transplantation (BMT), only 32.3% (21/65) of the bleeding in the GVHD group initiated within 30 days, and the risk for bleeding continued until day 100. Bleeding was a late event compared to GVHD, however, most bleeding episodes were associated with active GVHD. Both GVHD and bleeding were individually associated with reduced survival, with profound additive adverse effect: median survival in 221 nonbleeding non-GVHD was >83.2 months, GVHD nonbleeding (39 patients) had median of 10.6 months, bleeding non-GVHD (99 patients) had median of 4.3 months, and median survival of the GVHD bleeding group (85 patients) was 3.2 months. CONCLUSIONS: Our results support an association of bleeding with acute GVHD, suggesting that GVHD is a risk factor for bleeding after BMT. The occurrence of bleeding clearly identified poor outcome subgroup within GVHD, suggesting further evaluation for clinical application of bleeding in the assessment of GVHD severity.

PI polymorphism in Israel: report on six Jewish population groups.

A total of 1148 Israeli Jews was typed for PI and divided by areas of origin into six groups: Eastern Europe (n = 236), Central Europe (n = 156), Rumania (n = 158), Bulgaria (n = 215), North Africa (n = 229), and Middle East (n = 154). Frequencies of PI*M1 (0.74-0.77) in Jews of European countries were higher than 0.68 in Jews of N. Africa and 0.62 in Jews of the Middle East. PI*M2 frequencies were correspondingly lower in European Jews: 0.11-0.14 vs 0.19 and 0.20 in non-European Jews. PI*M3 frequency range was 0.07-0.11 in European Jews and was highest in Middle Eastern Jews (0.17). PI*Z was found in one MZ individual. PI*S was low (less than 0.01) except in Sephardi Jews of Bulgaria and N. Africa (0.016 and 0.015). A rare variant, PI*Elemberg, was observed in five individuals from different countries of origin. The present results are in accord with those of a previous study on some Israeli Jewish groups and on some other Middle Eastern groups.

Generalized granuloma annulare post autologous bone marrow transplantation in a Hodgkin's disease patient.

A case of generalized granuloma annulare is described in a patient with Hodgkin's disease 3 weeks after autologous bone marrow transplantation (BMT). This is, to our knowledge, the first report of generalized granuloma annulare post-BMT. Immunological pathogenesis is suggested and the association with delayed-type hypersensitivity reaction is discussed.

Acute bleeding and thrombocytopenia after bone marrow transplantation.

The relationship between hemorrhage and low platelet count was first established in patients with acute leukemia, and has been widely applied to thrombocytopenic patients, including BMT patients. Yet, the role of thrombocytopenia in bleeding post BMT has not been systematically studied. We evaluated the risk of bleeding and outcome associated with thrombocytopenia in BMT patients who had prophylactic platelet transfusions at a trigger of 20 x 10(9)/l. Thrombocytopenia was investigated in 321 patients with moderate or severe bleeding (BLD), and in a matched comparison group of 287 patients who did not bleed (NBLD). Profound thrombocytopenia (< or = 10 x 10(9)/l) was found in 8.6% of the BLD patients during the week before the bleeding onset, significantly more frequent than in NBLD patients (2.1% to 4%, P < 0.02), during weeks 2 to 6 post BMT (the period when 75% of the bleeding initiated). On the first day of bleeding, platelet counts < or = 10 x 10(9)/l were found in 13.5%, 11-20 x 10(9)/l in 20.4%, and > 20 x 10(9)/l in 66.1% of all episodes. Overall survival in BLD patients was not associated with the severity of thrombocytopenia before bleeding onset. Severity of thrombocytopenia was significantly associated with reduced survival in NBLD patients. We concluded that bleeding post BMT was significantly associated with thrombocytopenia, but the attributable risk of bleeding from profound thrombocytopenia was not large. Thrombocytopenia may be an important clinical sign in NBLD patients, and should be further explored in relation to acute toxicities other than bleeding.

Meningiomas involving the optic nerve: technical aspects and outcomes for a series of 50 patients.

OBJECTIVE: Surgical strategies and results for 50 patients with meningiomas involving the optic nerves are discussed and evaluated. Factors affecting the degree of resection and patient outcomes are presented. We emphasize our surgical techniques for resection of these tumors and we discuss the advantages of different approaches, depending on the relationship of the tumor to the optic nerves. METHODS: Data for 50 patients with meningiomas involving the optic nerves who were surgically treated between 1991 and 2002 were reviewed, by using patient files, operative notes, and pre- and postoperative imaging and ophthalmological examination findings. RESULTS: Thirty-one female patients and 19 male patients, with a mean age of 53 years, were treated. Thirty-one patients (62%) underwent complete tumor removal (Simpson Grade 1 or 2), and 19 patients underwent subtotal removal (Grade 4). Factors affecting the grade of resection were tumor size (P = 0.01), location (P = 0.007), and internal carotid artery encasement (P = 0.019). Patients who underwent Grade 1 or 2 resection exhibited a mean tumor size of 3.0 cm, and patients who underwent Grade 4 resection exhibited a mean tumor size of 4.1 cm. Only three patients had residual tumor on the optic nerve; all others had tumor in the cavernous sinus or at the orbital apex or exhibited vascular involvement. Visual outcomes were influenced predominantly by tumor size, preoperative visual function, and optic nerve encasement. CONCLUSION: Meningiomas that involve the optic nerves require special considerations and surgical techniques. Early decompression of the optic nerve within the bony canal allows identification and separation of the tumor from the nerve, permitting removal of the tumor from this area with minimal manipulation of the optic nerve.

Lateral approach to anterolateral tumors at the foramen magnum: factors determining surgical procedure.

OBJECTIVE: We discuss and evaluate surgical strategies and results in 42 patients with a variety of tumors involving the anterior and anterolateral foramen magnum and present factors affecting the degree of resection and patient outcomes. We describe our surgical techniques for resection of these tumors via the lateral approach, including consideration for occipital condylar resection and vertebral artery management. METHODS: A retrospective analysis was performed of 42 surgically treated patients with tumors involving the anterior and anterolateral foramen magnum. Patients received treatment between 1991 and 2002; patients' files, operative notes, and pre- and postoperative imaging studies were used for the analysis. RESULTS: The female-to-male ratio was 28:14. Mean patient age was 47 years. Pathological entities comprised 18 meningiomas, 12 chordomas, 3 glomus tumors, 3 schwannomas, and 6 miscellaneous tumors. We mobilized the vertebral artery at the dural entry point in all patients with meningiomas. The vertebral artery was mobilized at the C1 transverse foramen for the majority of extradural tumors. Partial condyle resection was performed in eight meningiomas and five extradural tumors. Complete condyle resection was required in 12 cases, including 9 chordomas, 2 carcinomas, and 1 bone-invading pituitary adenoma. Thirteen patients required occipitocervical fusion after tumor resection. CONCLUSION: In anterior or anterolaterally located foramen magnum tumors, we think the extreme lateral or far lateral approach affords significant advantages. Vertebral artery mobilization and occipital condyle resection may be needed depending on the extent and location of the foramen magnum tumor and its specific pathological characteristics. Tumor invading the occipital condyle or significant condylar resection may cause occipitocervical instability and require fusion.

Familial ovarian carcinoma: a problem in genetic counselling.

Ovarian papillary adenocarcinoma is reported in two families. In one family, this tumor was detected in four females, of whom two had had mammary cancer below the development of the ovarian tumor. In the second family, a mother and daughter died of ovarian adenocarcinoma. The mode of inheritance in both families fits the pattern of autosomal dominant transmission of a single gene. Both are Jewish families from Germany, presently residing in Israel. The two families are presented as examples illustrating the difficult question of genetic counselling in families with recurrent cases of ovarian carcinoma. The difficulty arises because this tumor is relatively frequent but is usually observed in isolated cases without systematic follow-up in the patients' families. Only a few cases, where more than one person in a family is affected, have been selectively reported in the literature.

A rare adenosine deaminase allele (ADA6) in an Arab moslem village in Israel.

The rare allele ADA6, was detected in seven members of an Arab Moslem family from northern Israel. All had the electrophoretic pattern of heterozygotes ADA6--1. This phenotype was formerly described in a small German family. The individuals examined in this study are a small branch of a much larger family only part of which lives in Israel. The origin of the family was traced back to a tribe which migrated to Jordan in the XVIII th century from the Kingdom of Hegaz in the northern part of the Arabian peninsula.

Protease inhibitor subtypes in some population groups from Israel.

Results of protease inhibitor (PI) subtyping on polyacrylamide gel isoelectrofocusing of 599 Israeli non-Jews and 1,393 Israeli Jews are recorded. A discriminant analysis (DS) was performed on frequency data of the 5 PI alleles (M1, M2, M3, S and Z) with data of Europeans, Israeli non-Jews and Israeli Jews. A higher percentage of correct classification was obtained when Jews were treated as a separate population group rather than when distributed in their areas of origin. This suggests a greater resemblance, in the PI system, of the studied Jewish groups to each other than of the European Jews to Europeans and of the studied mediterranean Jews to Middle Eastern non-Jews. A cluster analysis disclosed distance relationships in a similar direction. PI allele distribution, in the studied Jewish samples, has the following characteristics: Jews share with Middle Eastern non-Jews an absence of PIZ, which is present in Europeans. Mediterranean Jews have higher frequencies than Ashkenazi Jews, of PIS alleles, which are absent in Middle Eastern non-Jews. European Jews are closer to the Europeans than Middle Eastern Jews in their PIM allele frequencies. An original common gene pool of Jews with Middle Eastern non-Jews is postulated, of which the Sephardic (Spanish) and Middle Eastern Jews differ, now, in having PIS, and European Jews differ in having slightly lower PIM3 and PIM2 and higher PIM1 frequencies. A possibility of admixture and selection, affecting different alleles in different Jewish communities at different times, is suggested to have contributed to the present-day deviations from the supposed original gene pool.

Gc subtypes in some population groups from Israel. Comparison between world population groups and between Jews and non-Jews of the same areas.

Results of Gc subtyping on 1,222 Israelis, Arabs and Jews, are summarized and their gene frequencies are analyzed in comparison with available data on Gc subtypes in non-Jews. A discriminant and a cluster analysis demonstrated that in their Gc subtype frequencies European and non-European Jews resemble the populations of the areas where they lived before immigrating to Israel. A possible explanation for this resemblance, which is seen in some and not seen in other genetic markers in Jews, is suggested here to be connected with the function of Gc as a vitamin D-binding protein.

A new rare PGD variant, PGD Mediterranean.

The authors report a rare slow PGD variant observed in seven individuals in different Israeli population groups.

Genetic blood markers in Arab Druze of Israel.

A sample of 153 individuals from a Druze village, in northern Israel, was typed for the following genetic markers--ABO, MNSs, Rh, P, Kell, and Duffy in the blood groups AcP, AK, ADA, EsD, GL01, ICD, LDH, G6PD, PGM 1 & 2, PHI, PGD and peptidases A, B, C, and D in the red cell enzymes and for the serum proteins Hp and GC subtypes. Rare variants were observed in the following systems: PGD, a new slow variant, PGM, type 8-1; Pep A, types 2-1 and 3-1, Pep B, type 2-1; Pep D, types 3-1 and 3-3; and type GC, 2-V. Significant deviations from Hardy-Weinberg expectations were observed for MNSs and Duffy because of increased homozygosity, which was also observed in three other systems. Gene frequencies compared well with those of Arab Druze and Moslems in Lebanon and of Israeli Moslems in most of the systems, except for the lower frequencies of blood group B, the NS chromosome, the cde haplotype, and the AcPA allele in the present sample. A considerably lower frequency of the Fy allele was found in the Druze compared with Arab Moslems. It may be due to the Druze having been less exposed to inflow of African genes, to their being highlanders, and, therefore, less exposed to Plasmodium vivax malaria, or to both of the above.

Serum haptoglobin types and leukemia.

Haptoglobin types were determined on 211 patients with leukemia of the four most common types: acute lymphatic (ALL), chronic lymphatic (CLL), acute myeloid (AML), and chronic myeloid leukemia (CML). Frequency distributions of the three common Hp types in patients differed significantly from the control population. A significant increase in the relative incidence of Hp 1-1 was observed in patients with ALL, AML, and CML, but not with CLL. A similar trend was consistent in the data from previously published studies for the same three types of leukemia but not for CLL. Our results and the analysis of data from previous studies, suggest an association of Hp type with some leukemias, which is expressed in a consistent elevation of Hp 1-1 type among leukemia patients with ALL, AML, and CML.

Gc subtypes in the Middle East: report on an Arab Moslem population from Israel.

Gc subtypes were determined by isoelectrofocusing and immunofixation on 342 blood samples from an Arab Moslem population in Israel. Observed allele frequencies were: Gc1F 0.2120, Gc1S 0.6023, and Gc2 0.1857. Those are similar to formerly reported frequency data for other Middle Eastern populations. A discriminant analysis, performed on data from 35 populations, resulted in a satisfactory classification of population groups related through geographic and racial origin.

Acute bleeding complications in patients after bone marrow transplantation.

Acute bleeding is a frequent complication that commonly associates with increased morbidity after bone marrow transplantation. Except for diffuse alveolar hemorrhage and cerebral hemorrhage, bleeding is infrequently recorded as a direct cause of death. Yet outcome analyses showed that bleeding from any reviewed site was associated with reduced survival. Reduced survival was correlated with bleeding intensity and the number of bleeding sites. These data point to the need to monitor all manifestations of bleeding, as bleeding may identify patients at risk for bone marrow transplantation toxicity. Until recently, prophylactic platelet transfusions were commonly given at a trigger of 20 x 10(9)/L. Whereas bleeding is more likely to occur when platelet counts drop to low levels, most bleeding episodes were recorded with platelet counts greater than 20 x 10(9)/L, suggesting causes other than profound thrombocytopenia in the pathogenesis of bleeding. Given that a trigger of 10 x 10(9)/L has become accepted for prophylactic platelet transfusions, care should be taken to ensure that parameters other than the incidence of bleeding have not been adversely affected.

Inheritance of PiM subtypes. A study of 151 families with a total of 242 children and of 142 mother-child pairs.

Pi phenotypes were classified by isoelectric focusing in sera of 151 families with a total of 242 children and in sera of 142 mother-child pairs. The six common subtypes of PiM are genetically determined by three alleles named PiM1, PiM2, and PiM3. No exceptions to the postulated mode of inheritance have been found. The possibility of further heterogeneity of the intermediate variant PiM3 is discussed.

Genetic studies on the Gc subtypes.

Gc subtypes were determined by immunofixation isoelectric focusing. In a family study involving 93 families with a total of 176 children, a three-allele model with six genotypes was confirmed. The distribution of Gc subtypes was studied in three populations from Europe and in a sample of Druzes from Northern Israel. Three new variant Gc types were observed.

Bulgarian Jews in Israel: genetic blood markers. Red-cell antigens, serum proteins and red-cell isozymes.

Two hundred and sixteen unrelated Bulgarian Jews were typed for the following genetic systems: ABO, MNS, Rh, Kell and Duffy of the blood groups; ADA, AK1, ACP1, ESD, GLO, PGD, PGM1 and PGM2 of the red-cell enzymes, and for the serum proteins HP, GC and PI. A comparison of observed gene frequencies with those of two other Sephardi Jewish groups, from Libya and Morocco, disclosed significant heterogeneity in several systems. This was mostly due to Moroccan Jews differing from Bulgarian or from both the Libyan and Bulgarian Jews. A comparison of gene frequencies in Bulgarian Jews with those in Oriental Jews from Iraq and in Ashkenazi Jews from Poland disclosed a similarity between the three groups in Rh, ADA, GLO, PGM1 and HP. The frequencies for the above systems in the three groups were closer to those of Middle Easterners than to those of Europeans. A different pattern was observed for GC and PI, in which Bulgarian resembled Polish Jews and differed significantly from Iraqi Jews. This probably reflects an outcome of convergent adaptive processes.

Serum protein polymorphisms in Arab Moslems and Druze of Israel: BF, F13B, AHSG, GC, PLG, PI, and TF.

We report results of typing two population samples, Israeli Arab Moslems and Arab Druze, for seven serum protein genetic variants. Data are presented in comparison with results for the same markers in a sample of Jordanian Arabs. In Israeli Moslems gene frequencies for BF (n = 169) were BF*S = 0.6361, BF*F = 0.3343, BF*S07 = 0.0296, and BF*1 = 0, and for TF (n = 90) the gene frequencies were: TF*C1 = 0.7167, TF*C2 = 0.2611, and TF*C3 = 0.0222. Allele frequencies for AHSG in Israeli Moslems (n = 155) and Druze (n = 192) were AHSG*1 = 0.9129 and 0.8750 and AHSG*2 = 0.0806 and 0.1250, respectively. Gene frequencies for PLG in Moslems (n = 149) and Druze (n = 190) were PLG*A = 0.4597 and 0.5288 and PLG*B = 0.5101 and 0.4188, respectively. The typing of Israeli Arab Druze (n = 194) for F13B resulted in F13B*1 = 0.8454, F13B*2 = 0.0387, F13B*3 = 0.0979, and F13B*4 = 0.0180. Results on the same population for PI (n = 192) were PI*M1 = 0.7839, PI*M2 = 0.1276, PI*M3 = 0.0781, PI*M4 = 0.0026, and PI*M5 = 0.0026. Observed rare alleles in various systems indicate gene flow from Europe, Africa, and Asia into the Middle East. The results on Arab populations were considered in relation to available population data in the three adjacent continents. The emerging gene frequency profile for Arabs seems to fit with the central geographic and climatic position of the Middle East.