Spectrum of clinical and genetic features of patients with inherited platelet disorder with suspected predisposition to hematological malignancies: a nationwide survey in Japan.

BACKGROUND: Inherited thrombocytopenia (IT) contains several forms of familial thrombocytopenia and some of them have propensity to hematological malignancies. The etiological and genetic features of this heterogeneous syndrome have not yet been elucidated. PATIENTS AND METHODS: We conducted a nationwide survey to collect clinical information and samples from patients with familial thrombocytopenia and/or hematological malignancies in order to obtain a comprehensive understanding of IT. RESULTS: Among the 43 pedigrees with clinical samples, RUNX1 mutations were identified in 8 pedigrees (18.6%). While MYH9 and ANKRD26 mutations were identified in 2 and 1 pedigrees, respectively, no gene mutations were detected in the remaining 32 pedigrees from a panel of previously reported pathogenetic mutations. Clinical data were comparable between FPD/AML and non-FPD/AML probands. CONCLUSIONS: Our study clarified that it is unexpectedly difficult to diagnose FPD/AML based on clinical information alone, and thus, genetic testing is strongly recommended. Our survey also identified some pedigrees with a strong family history of myelodysplastic syndromes of unknown origin. Additionally, there were 14 pedigrees in which three or more members were affected by immune thrombocytopenia (ITP), and a computer-aided simulation suggested that such a distribution almost never happens by coincidence, which implicates a genetic predisposition to ITP.

Comparable outcomes between autologous and allogeneic transplant for adult acute myeloid leukemia in first CR.

Although allogeneic hematopoietic stem cell transplantation from an HLA-matched sibling donor (MSD) is a potentially curative post-remission treatment for adults with acute myeloid leukemia (AML) in their first CR, transplant-related morbidity and mortality remains a major drawback. We retrospectively compared the outcomes of patients who underwent autologous peripheral blood stem cell transplantation (auto-PBSCT; n=375) with those who underwent allogeneic bone marrow transplantation (allo-BMT; n=521) and allo-PBSCT (n=380) from MSDs for adults with AML/CR1, in which propensity score models were used to adjust selection biases among patients, primary physicians and institutions to overcome ambiguity in the patients' background information. Both the multivariate analysis and propensity score models indicated that the leukemia-free survival rate of auto-PBSCT was not significantly different from that of allo-BMT (hazard ratio (HR), 1.23; 95% confidence interval (CI), 0.92 to 1.66; P=0.16) and allo-PBSCT (HR, 1.13; 95% CI, 0.85-1.51; P=0.40). The current results suggest that auto-PBSCT remains a promising alternative treatment for patients with AML/CR1 in the absence of an available MSD.

Complex molecular genetic abnormalities involving three or more genetic mutations are important prognostic factors for acute myeloid leukemia.

We conducted a comprehensive analysis of 28 recurrently mutated genes in acute myeloid leukemia (AML) in 271 patients with de novo AML. Co-mutations were frequently detected in the intermediate cytogenetic risk group, at an average of 2.76 co-mutations per patient. When assessing the prognostic impact of these co-mutations in the intermediate cytogenetic risk group, overall survival (OS) was found to be significantly shorter (P=0.0006) and cumulative incidence of relapse (CIR) significantly higher (P=0.0052) in patients with complex molecular genetic abnormalities (CMGAs) involving three or more mutations. This trend was marked even among patients aged ⩽65 years who were also FLT3-ITD (FMS-like tyrosine kinase 3 internal tandem duplications)-negative (OS: P=0.0010; CIR: P=0.1800). Moreover, the multivariate analysis revealed that CMGA positivity was an independent prognostic factor associated with OS (P=0.0007). In stratification based on FLT3-ITD and CEBPA status and 'simplified analysis of co-mutations' using seven genes that featured frequently in CMGAs, CMGA positivity retained its prognostic value in transplantation-aged patients of the intermediate cytogenetic risk group (OS: P=0.0002. CIR: P<0.0001). In conclusion, CMGAs in AML were found to be strong independent adverse prognostic factors and simplified co-mutation analysis to have clinical usefulness and applicability.

Clinical significance of pretransplant serum ferritin on the outcome of allogeneic hematopoietic SCT: a prospective cohort study by the Kanto Study Group for Cell Therapy.

This prospective study aimed to investigate the influence of pretransplant serum ferritin levels on the outcomes of allogeneic hematopoietic SCT (HSCT). In total, 190 patients with acute leukemia or myelodysplastic syndrome were consecutively enrolled. The patients were divided into two groups: low-ferritin group (<1000 ng/mL) and high-ferritin group (⩾1000 ng/mL). The primary end point was the cumulative incidence of infection within 100 days after HSCT, which was similar between the two groups: bloodstream infection, 35 vs 38%, P=0.65; bacterial infection, 44 vs 41%, P=0.68; and fungal infection, 6 vs 8%, P=0.71. The 1-year adjusted probability of OS of the high-ferritin group was significantly lower than that of the low-ferritin group (76 vs 63%, P=0.017). Using receiver operating characteristic curve, the threshold of pretransplant serum ferritin levels for bloodstream infection was 1400 ng/mL; the threshold for OS, EFS and non-relapse mortality was 1349 ng/mL. In conclusion, pretransplant serum ferritin levels of ⩾1000 ng/mL did not influence the incidence of infection but adversely affected OS after HSCT. A higher threshold of pretransplant serum ferritin levels may predict HSCT outcomes.

Three-dimensional surface figure measurement of high-accuracy spherical mirror with nanoprofiler using normal vector tracing method.

Processing technology using an extreme ultraviolet light source, e.g., next-generation lithography, requires next-generation high-accuracy mirrors. As it will be difficult to attain the degree of precision required by next-generation high-accuracy mirrors such as aspherical mirrors through conventional processing methods, rapid progress in nanomeasurement technologies will be needed to produce such mirrors. Because the measuring methods used for the surface figure measurement of next-generation mirrors will require high precision, we have developed a novel nanoprofiler that can measure the figures of high-accuracy mirrors without the use of a reference surface. Because the accuracy of the proposed method is not limited by the accuracy of a reference surface, the measurement of free-form mirrors is expected to be realized. By using an algorithm to process normal vectors and their coordinate values at the measurement point obtained by a nanoprofiler, our measurement method can reconstruct three-dimensional shapes. First, we measured the surface of a concave spherical mirror with a 1000-mm radius of curvature using the proposed method, and the measurement repeatability is evaluated as 0.6 nm. Sub-nanometer repeatability is realized, and an increase in the repeatability would be expected by improving the dynamic stiffness of the nanoprofiler. The uncertainty of the measurement using the present apparatus is estimated to be approximately 10 nm by numerical simulation. Further, the uncertainty of a Fizeau interferometer is also approximately 10 nm. The results obtained using the proposed method are compared with those obtained using a Fizeau interferometer. The resulting profiles are consistent within the range of each uncertainty over the middle portions of the mirror.

Effect of related donor availability on outcome of AML in the context of related and unrelated hematopoietic cell transplantation.

Although allogeneic hematopoietic cell transplantation (HCT) from a related donor is effective therapy for younger patients with AML, it remains unknown how the availability of a related donor affects the outcome when unrelated HCT is a treatment option for patients without a related donor. To address this issue, we retrospectively analyzed 605 cytogenetically non-favorable AML patients younger than 50 years for whom a related donor search was performed during first CR (CR1). The 4-year OS was 62% in 253 patients with a related donor and 59% in 352 patients without a related donor (P=0.534). Allogeneic HCT was performed during CR1 in 62% and 41% of patients with and without a related donor, respectively. Among patients transplanted in CR1, the cumulative incidence of non-relapse mortality was significantly higher in patients without a related donor (P=0.022), but there was no difference in post-transplant OS between the groups (P=0.262). These findings show the usefulness of unrelated HCT in younger patients with cytogenetically non-favorable AML who do not have a related donor. The extensive use of unrelated HCT for such patients may minimize the potential disadvantage of lacking a related donor.

One-year low-dose valacyclovir as prophylaxis for varicella zoster virus disease after allogeneic hematopoietic stem cell transplantation. A prospective study of the Japan Hematology and Oncology Clinical Study Group.

Varicella zoster virus (VZV) disease is a frequent complication after allogeneic hematopoietic stem cell transplantation (HSCT). We carried out a trial of 1-year low-dose valacyclovir (VCV) prophylaxis against VZV disease to evaluate its efficacy and safety. Patients received oral acyclovir (ACV) 1000mg/day until day 35 after HSCT. Oral VCV 500mg/day, 3 times a week, was started on day 36 and continued until 1 year after HSCT. The development of VZV disease was monitored until 2 years after HSCT. A total of 40 patients with a median age of 43 years were enrolled. VCV was well tolerated in all but 1 patient who discontinued it on day 224 because of thrombocytopenia of unknown cause. Seven patients developed VZV disease at a median of 479 days (range 145-651) after HSCT, with a cumulative incidence of 18.5%. Two patients developed breakthrough disease during VCV prophylaxis. The other 5 patients developed VZV disease after the discontinuation of VCV, and 3 of these had developed extensive chronic graft-versus-host disease. Visceral involvement and serious complications were completely eliminated. All patients responded to the therapeutic dose of VCV or ACV. One-year low-dose VCV can be safely and effectively administered for the prevention of VZV disease after allogeneic HSCT.

Extensive multiple piloleiomyoma in the submental region treated successfully by surgery and reconstruction with a submental perforator flap.

Piloleiomyoma is a benign tumour originating in the smooth muscles of the arrector pili muscle in the skin. The lesions are often sensitive to touch, cold and emotional disturbance. We present a patient with multiple piloleiomyoma (MPL) of the submentum who underwent reconstructive surgery using a submental perforator flap. The result was excellent and there were no postoperative complications. MPL of the submental region is relatively rare; to our knowledge, ours is the first report of MPL treated successfully with a submental perforator flap.

[Successful combined therapy with ATG, cyclosporin and G-CSF for both liver dysfunction and bone marrow failure in hepatitis-associated aplastic anemia].

A 28-year-old man developed cryptogenic hepatitis in January 1999, and treatment with glycyrrhizic acid improved his liver function. From June, however, pancytopenia began to develop gradually. The patient received G-CSF against leukocytopenia (WBC 1,100/microliter, neutrophils 590/microliter) and was transferred to our hospital in August 1999. A diagnosis of hepatitis-associated aplastic anemia was made on the basis of liver dysfunction (AST 156 IU/l, ALT 386 IU/l), hypoplastic bone marrow, and pancytopenia (WBC 4,400/microliter, neutrophils 3,340/microliter under G-CSF administration, Hb 9.8 g/dl, platelets 2.4 x 10(4)/microliter, reticulocytes 4.7 x 10(4)/microliter). Immediately after starting combined therapy with ATG, cyclosporin, and G-CSF, his liver function began to improve and was normalized on day 7. Pancytopenia began to ameliorate on day 9, and blood parameters on day 60 were WBC 4,200/microliter (without G-CSF administration), Hb 12.0 g/dl, platelets 9.0 x 10(4)/microliter, and reticulocytes 4.1 x 10(4)/microliter. Although the prognosis of hepatitis-associated aplastic anemia is generally poor, immunosuppressive therapy was markedly effective for both pancytopenia and hepatic dysfunction in the present case.

Sarcoidosis associated with psoriasis vulgaris.

We report a 70-year-old patient with sarcoidosis associated with psoriasis vulgaris. He had a nodule on the medial lower lid of his right eye. Oral corticosteroid for the sarcoid lesions and oral PUVA for psoriasis were employed. The cutaneous lesion disappeared within two months after starting the therapy. No relapse of sarcoidosis has been seen for eight years. The association of sarcoidosis with psoriasis has been previously reported; however, it is still unclear whether this association coincidental or meaningful.

[Successful treatment of idiopathic pure red cell aplasia with antithymocyte globulin].

An 18-year-old woman was admitted to our hospital because of severe anemia on October 16, 1999. Laboratory data included hemoglobin 3.5 g/dl, reticulocytes 2,200/microliter, WBC 3,500/microliter, and Plt 38.5 x 10(4)/microliter. Bone marrow aspiration showed a normocellular marrow with severe erythroid hypoplasia, suggesting a diagnosis of pure red cell aplasia. Methylprednisolone pulse therapy was started on October 20, but there was no response. Administration of cyclosporine A (CyA; 400-450 mg) was begun on November 1, but again there was no response. Antithymocyte globulin (ATG; 800 mg/day for 5 days, 15 mg/kg) was started from December 1 in addition to prednisolone (60 mg/day) and CyA (450 mg/day). On day 7 of ATG therapy, the reticulocyte count began to increase, and reached a peak of 32.6 x 10(4)/microliter on day 20. The patient's hemoglobin level started to increase on day 13, and reached 8.5 g/dl on day 27. A complete response has been maintained up to the time of writing, and the hemoglobin level was 11.9 g/dl on December 14, 2000. This is the first detailed Japanese case report of successful treatment of pure red cell aplasia using ATG.

[Treatment of adult acute lymphoblastic leukemia by KHALL-93--long-term outcome].

Twelve previously untreated adult patients with acute lymphoblastic leukemia were treated with a KHALL-93 regimen. The mean age was 46.9 years. Four patients (1/3) were over 60 years old, and 5 were Ph1 positive (42%). The complete remission rate was 100%. The 5-year survival was 50% (6/12). The 5-year event-free survival was 50% (6/12) in total, 71% (5/7) in Ph1 negative patients, and 63% (5/8) in patients younger than 60 years old. These results indicate that a KHALL-93 regimen is an effective therapy for adult acute lymphoblastic leukemia.

Three cases of pityriasis rubra pilaris successfully treated with cyclosporin A.

BACKGROUND: Pityriasis rubra pilaris (PRP) is reported to respond poorly to cyclosporin A (CsA). OBJECTIVE: We attempted to determine the efficacy of CsA in the treatment of classic adult-type PRP. METHODS: Three patients with classic adult-type PRP were treated with 5 mg/kg/day CsA. RESULTS: A sustained clinical response was achieved within 2-4 weeks of therapy. Relapses were noted when the CsA dose was decreased to 1.2 mg/kg/day. CONCLUSION: CsA should be considered in the treatment of classical adult-type PRP.

A case of pseudogout.

We report a 56-year-old Japanese male with a gout-like acute attack of synovitis and panniculitis in his right wrist without hyperuricemia. Calcium pyrophosphate dihydrate (CPPD) crystals were found in the synovial fluid of the affected joint. A diagnosis of pseudogout was made. The attack subsided two days after medication with 30 mg of predonisolon. Although this is a relatively common disease in elderly people, we rarely encounter such case reports in dermatological journals.

Three cases of polyarteritis nodosa cutanea and a review of the literature.

We describe three cases of polyarteritis nodosa cutanea (PNC) showing necrotizing arteritis and only cutaneous lesions without systemic symptoms or visceral involvement for eleven, six, and three years after the onset of the disease. Since it was first described, there has been continuous controversy as to whether PNC progresses to systemic PN. Some cases have been described which had begun with a cutaneous lesion and progressed to the systemic form 19 and 18 years after the onset of the disease, so we believe that long term follow-up of this disease is essential.

[X-linked sideroblastic anemia].

A 20-year-old man presented with microcytic hypochromic anemia (hemoglobin: 9.3 g/dl, MCV: 82.0 fl, MCHC: 29.5 g/dl) and dimorphism RBCs in circulating blood (RDW: 26.8%). Ringed sideroblasts accounted for 29.5% of bone marrow erythroblasts. Iron overload was also observed. Because the patient had a clear family history of anemia, he was given a diagnosis of X-linked sideroblastic anemia. The activity of delta-aminolevulinic acid synthase (ALAS) in bone marrow erythroblasts was low. However, we did not detect mutation of the gene for ALAS. The patient has responded well to a treatment regimen consisting of oral vitamin B6, Fe-chelation therapy, and phlebotomy.