Registration-directed phase 1/2 trial of irinotecan for pediatric solid tumors.

BACKGROUND: Although irinotecan hydrochloride (IRI) is a promising chemotherapeutic agent for pediatric solid tumors, its indications had been off-label in the USA, EU and Japan. Therefore, we conducted a phase 1/2 trial of IRI monotherapy in a registration-directed setting. METHODS: Children aged 2-18 years with solid tumors who were either refractory to or relapsed after standard chemotherapy were enrolled. Phase 1 was a conventional dose escalation study to determine the dose-limiting toxicity (DLT) and the recommended dose. IRI was given i.v. on days 1, 2, 3 and 8, 9, 10 in up to eight, 21 day cycles. RESULTS: The starting dose (40 mg/m2 /day) was determined to be the recommended dose because the next higher dose level (45 mg/m2 /day) resulted in two cases of DLT. Seventeen children (11 in phase 1 and six in phase 2) with a refractory solid tumor received IRI. Of the 12 patients treated with 40 mg/m2 /day, seven (58.3%) achieved a stable disease condition for >8 weeks. CONCLUSIONS: The RD of IRI in this treatment schedule was 40 mg/m2 /day. IRI did not cause tumor shrinkage but might help to stabilize refractory pediatric solid tumors. Based on the accumulating evidence from international studies of the efficacy of IRI against refractory pediatric solid tumors, the Japanese regulatory authority approved its use for this indication in 2011.

Prospective pharmacokinetic study of intravenous busulfan in hematopoietic stem cell transplantation in 25 children.

The aim of this study was to prospectively evaluate the PK and safety of ivBU in 25 Japanese children (median age six yr; range, five months-17 yr) as one of a combination of drugs in a pretransplant regimen. The patients had acute leukemia (n = 14), CML (2), JMML (5), solid tumors (2), chronic granulomatous disease (1), or metachromatic leukodystrophy (1). Five different dose schedules were used according to the patient's ABW: <9 kg (1.0 mg/kg), 9 to <16 (1.2 mg/kg), 16-23 (1.1 mg/kg), >23-34 (0.95 mg/kg), and >34 kg of BW (0.8 mg/kg). Each dose was given over two h, and sample blood was drawn at nine or 11 separate points for analysis by gas chromatography-mass spectrometry. The AUC varied from 796 to 1905 µmol min/L, and 19 of the 25 patients (76%) remained within the target range without dose adjustment. Two were diagnosed with engraftment failure. Hepatic VOD developed in four, and only one of these showed high AUC (>1500 µmol min/L). Toxicities did not correlate with the BU level. Our data showed very similar PK to those in previous studies, and these dose schedules are applicable to Japanese children.

The effect of the order of total body irradiation and chemotherapy on graft-versus-host disease.

BACKGROUND: Graft-versus-host disease (GVHD) is one of the most important complications in allogeneic hematopoietic stem cell transplantation. Intensity of conditioning regimen is one of the risk factors, which is associated with acute GVHD, and some studies have shown that alteration of the administration order from busulfan to cyclophosphamide to cyclophosphamide to busulfan could decrease cytokine levels and organ toxicity. METHODS: To investigate whether the order of total body irradiation (TBI) and chemotherapy is associated with the incidence of GVHD, we reviewed the charts of 124 consecutive hematopoietic stem cell transplantation, which was performed in Saitama Children's Medical Centre and University of Tokyo Hospital between 1995 and 2010. RESULTS: TBI performed before chemotherapy (TBI-CT) showed an increased risk for grades II to IV acute GVHD (61.6±7.8%) compared with the TBI performed after chemotherapy (CT-TBI) (42.8±7.2%) (P=0.048), whereas the incidence of grades III and IV GVHD were similar between TBI-CT and CT-TBI. Multivariate analysis showed that TBI-CT was associated with a higher risk of grades II to IV acute GVHD. However, overall survival probability of TBI-CT cohort was similar to that of CT-TBI cohort. CONCLUSIONS: Our results provided a novel risk factor for acute GVHD, which can be easily controlled by the physician.

The second therapeutic trial for children with hematological malignancies who relapsed after their first allogeneic SCT: long-term outcomes.

The impact of a second all-SCT on the long-term outcomes of children who relapse after allo-SCT has been unclear. We retrospectively analyzed the long-term outcomes of different salvage treatments for such children. Sixty-six children with hematological malignancies (40 ALL, 22 AML, three MDS, and one CML) who relapsed after a first allo-SCT received either a second allo-SCT (n = 16) or CTx and/or DLI (n = 50). The median follow-up for all children was 9.1 yr. The five-yr OS after relapse was significantly better in patients who underwent a second allo-SCT (42.9%) than in patients treated with CTx and/or DLI (11.8%) (p < 0.05). However, this advantage diminished with increasing time. The eight-yr OS for these groups of patients were 21.4% and 11.8%, respectively (p = n.s.). Among the 16 patients who received a second allo-SCT, two died more than five yr after the second allo-SCT. A second allo-SCT can therefore lead to a prolonged OS in patients who relapse after allo-SCT. However, a second allo-SCT should be selected carefully. This is because the mortality rate is still high, even when there is an extensive duration of time following the second allo-SCT.

[A phase III study of the efficacy and safety of meropenem in patients with febrile neutropenia].

Efficacy, safety and pharmacokinetics of meropenem (MEPM) were assessed when 1 g (40 mg/kg for some of the pediatric patients) t.i.d. was administered every 8hours to 101 adult and 6 pediatric patients with febrile neutropenia (FN) as diagnosed based on the Japanese guideline for FN treatment. The efficacy rate evaluated as antifebrile effect up to Day 4 of treatment was 40.0% (40/100) in adult and 66.7% (4/6) in pediatric patients. The antifebrile effect in adult patients was analyzed after stratifying them according to their neutrophil counts up to Day 4. Treatment with MEPM produced an antifebrile effect not only in patients with higher neutrophil counts (> or = 500/mm3) but also in those with lower counts (< 100/mm3), and the efficacy rate was comparable between the two groups: 38.2% in the < 100/mm3 group and 29.4 to 55.6% in the > or = 500/mm3 group. The bacteriological efficacy of MEPM evaluated as disappearance rate on Days 3 to 5 and Day 7 was both 100% (8/8 and 4/4, respectively). The time above minimal inhibitory concentration (% T > MIC) in the treatment interval was greater than 90% in 9 out of 10 patients for whom likely causative organism was isolated and identified after MEPM treatment or for whom causative organism emerging after treatment was isolated and identified. The incidence of adverse events was 93.1% in adult and 83.3% in pediatric patients. There were three deaths and one serious adverse event reported among the adult patients; however, all these cases were assessed as not related to the study medication. The incidence of adverse drug reactions was 45.5% and 66.7%, respectively. All the observed adverse drug reactions were mild or moderate in severity and none of them was severe. Adverse drug reactions which were unknown from the previous MEPM clinical studies and investigation of the results of clinical experience include 'chest discomfort', 'blood uric acid decreased', 'lymphocyte deformation', 'blood uric acid increased', 'abnormal funduscopy', 'hypesthesia' and 'hemorrhagic cystitis'. All these events were mild or moderate in severity and resolved without requiring any action or after providing symptomatic treatment. There was no unknown adverse drug reaction that resulted in treatment discontinuation. No nervous system disorders such as convulsion and impaired consciousness were reported. The results show that monotherapy of MEPM 1 g (or 40 mg/kg for some of the pediatric patients) t.i.d. every 8 hours was effective, and was also safe and well tolerated in adult and pediatric patients with FN. Therefore, MEPM monotherapy is expected to be useful as the initial treatment for Japanese patients with FN.

[Treatment outcome of non-Hodgkin lymphoma in childhood: KYCCSG NHL-89, 96].

Two consecutive treatment protocols, NHL-89 and NHL-96, for pediatric diffuse large cell lymphoma (DLC) and lymphoblastic lymphoma (LBL) were conducted between March 1989 and December 2004 by Kyushu-Yamaguchi Children's Cancer Study Group. Forty-two patients (DLC: 15, LBL: 27) and 34 patients (DLC: 8, LBL: 26) were enrolled in NHL-89 and NHL-96, respectively. DLC patients received induction therapy of high-dose methotrexate (MTX) followed by repeated administration of intermediate MTX. LBL patients received a 4-drug induction followed by intensification, consolidation with cranial radiotherapy (15 to 24Gy), and maintenance. The maintenance phase consisted of multiple drug treatment; including prednisolone, vincristine, cyclophosphamide, and 6-mercaptopurine. With a median follow-up of 150 months for NHL-89 and 90.5 months for NHL-96, the estimated event-free survival at 5 years are 76.2±6.6% and 67.7±8.0%, respectively. Both studies improved the prognosis of DLC and LBL over our previous study of NHL-858.

Cord blood transplantation from unrelated donors for children with acute lymphoblastic leukemia in Japan: the impact of methotrexate on clinical outcomes.

Cord blood transplantation (CBT) from an unrelated donor is recognized as one of the major treatment modalities in allogeneic stem cell transplantation (SCT) for children with hematologic malignancies. We analyzed the clinical outcomes of CBT for children with acute lymphoblastic leukemia (ALL) in Japan and identified the risk factors for the transplant outcomes. From 1997 to 2006, 332 children with ALL underwent CBT from unrelated donors, 270 of which had no prior transplant. Their disease statuses at transplant were first complete remission (CR) (n = 120), second CR (n = 71), and more advanced stages (n = 75). As preconditioning for SCT, total body irradiation (TBI) was given to 194 patients and, for the prophylaxis of graft-versus-host disease (GVHD), methotrexate (MTX) was given to 159 patients. The cumulative incidents of neutrophil and platelet recovery (>20 K) were 88.5% and 78.4%, respectively. The incidents of grade II-IV, III-IV acute GVHD (aGVHD), and chronic GVHD (cGVHD) were 45.6%, 20.4%, and 19.2%, respectively, and treatment-related mortality was 22.6%. The 5-year event-free survival (EFS) and overall survival (OS) at CR1, CR2, and advanced status were 47.4%, 45.5%, 15.0%, and 63.7%, 59.7%, and 20.7%, respectively. Multivariate analysis revealed that MTX with calcineurin inhibitor (CNI) was associated with decreased incidence of grade II-IV GVHD (CNI alone: hazard ratio [HR] = 1.74, 95% confidence interval [CI] = 1.06-2.83, P = .027; CNI + prednisolone (PSL), HR = 1.61, 95% CI = 1.03-2.50, P = .036), III-IV aGVHD (CNI alone: HR = 3.02, 95% CI = 1.55-5.91, P = 0.001; CNI + PSL, HR = 1.89, 95% CI = 0.93-3.83, P = .078), or cGVHD (CNI alone: HR = 1.78, 95% CI = 0.83-3.82, P = .143; CNI + PSL, HR = 2.44, 95% CI = 1.24-4.82, P = .01), compared with CNI alone or CNI + PSL. At an advanced stage of disease, GVHD prophylaxis with MTX + CNI is associated with improved OS compared with CNI alone (CNI alone: HR = 3.20, 95% CI = 1.43-7.15, P = .005; CNI + PSL, HR = 1.47, CI = 0.67-3.20, P = .332). Our retrospective study showed that CBT for children with ALL is feasible and GVHD prophylaxis with MTX + CNI is associated with significant favorable outcomes in prevention of aGVHD and cGVHD as well as survival advantage in advanced cases.

Nationwide survey of bisphosphonate therapy for children with reactivated Langerhans cell histiocytosis in Japan.

BACKGROUND: Several studies have suggested that Langerhans cell histiocytosis (LCH) is responsive to treatment with bisphosphonates (BPs). However the efficacy and safety of BPs therapy for childhood LCH is unknown. PROCEDURE: Data on children with LCH who had received BPs therapy were collected retrospectively from hospitals participating in the Japanese Pediatric Leukemia/Lymphoma Study Group. RESULTS: Twenty-one children with histologically proven LCH were identified. Of these, the case histories of 16 children who had been treated with pamidronate (PAM) for disease reactivation were analyzed in detail. The median post-PAM therapy follow-up period was 2.8 years (range: 0.9-9.3 years). The median age at commencement of PAM therapy was 9.4 years (range: 2.3-15.0 years). All children had one or more bone lesions but none had risk organ (RO) involvement. In the majority of the children, six courses of PAM were administered at a dose of 1.0 mg/kg/course at 4-week intervals. In 12 of the 16 children, all active lesions including lesions of the skin (n = 3) and soft tissues (n = 3) resolved. Of these children, eight children had no active disease for a median of 3.3 years post-PAM therapy (range: 1.8-9.3 years). Progression-free survival (PFS) was 56.3 ± 12.4% at 3 years. PFS was significantly higher in children with a first reactivation compared with children experiencing a second or subsequent reactivation. CONCLUSIONS: PAM may be an effective treatment for reactivated LCH with bone lesions. A prospective trial of the efficacy of PAM in recurrent pediatric LCH is warranted.

[Acute lymphoblastic leukemia complicated with varicella zoster virus meningoencephalitis and visceral dissemination after related bone marrow transplantation].

Meningitis or encephalitis by varicella-zoster virus (VZV) after hematopoietic stem cell transplantation (HSCT) is rarely reported. We encountered a case of meningoencephalitis with VZV re-activation 18 months after related bone marrow transplantation for recurrent acute lymphoblastic leukemia. The patient had been administered steroid and cyclosporine for chronic graft-versus-host disease. A high DNA copy number of VZV, 4.9×10(7) copies was detected in the cerebrospinal fluid. VZV also caused severe pneumonia and acute renal failure soon after the onset of meningoencephalitis. The patient was successfully treated with acyclovir, although he was left with persistent neurological sequelae. Both prompt diagnosis and early treatment of VZV reactivation are important to avoid a fatal outcome.

Outcome of 125 children with chronic myelogenous leukemia who received transplants from unrelated donors: the Japan Marrow Donor Program.

Because of a small number of patients, only a few studies have addressed the outcome of bone marrow transplantation (BMT) in children with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML), who receive graft from a volunteer-unrelated donor (VUD), especially after practical application of imatinib mesylate. The outcomes of BMT from a VUD in 125 children with Ph+ CML were retrospectively reviewed. Patients were identified through the Japan Marrow Donor Program as having undergone BMT between 1993 and 2005 and were aged 1-19 years at the time of transplant (median age, 14 years). The probabilities of 5-year overall survival (OS) and leukemia-free survival (LFS) were 59.3% and 55.5%, respectively. Multivariate analysis identified the following unfavorable survival factors: infused total nucleated cell dose<314 x 10(6) /kg (relative risk [RR]=2.43; 95% confidence interval [CI]=1.33-4.44; P=.004), advanced phase (RR=2.43; 95% CI=1.37-4.31; P=.004), and no major cytogenetic response (MCyR) at the time of BMT (RR=6.55; 95% CI=1.98-21.6; P=.002). Of the 17 patients treated with imatinib, 15 (88%) achieved MCyR at the time of BMT, and this group had an excellent 5-year OS of 81.9%. Disease phase, infused total nucleated cell dose, and cytogenetic response were independent risk factors for survival of unrelated BMT. These findings provide important information for assessing the indications for and improving outcome in unrelated BMT for the treatment of pediatric CML.

Randomized trial to compare LSA2L2-type maintenance therapy to daily 6-mercaptopurine and weekly methotrexate with vincristine and dexamethasone pulse for children with acute lymphoblastic leukemia.

BACKGROUND: A total of 201 pediatric cases of acute lymphoblastic leukemia were treated with the ALL-96 protocol by the Kyushu-Yamaguchi Children's Cancer Study Group. PROCEDURE: Risk stratification was based on white cell counts, immunophenotype, the presence of central nervous system disease at diagnosis, organomegaly, and early treatment response (day 14 bone marrow status). All of the patients were classified into standard-risk (SR) or high-risk (HR) groups and were randomly assigned to receive maintenance therapy with either LSA2L2-type or 6-mercaptopurine (6-MP)/methotrexate (MTX) with vincristine (VCR) and dexamethasone (DEX) pulse in both risk groups. RESULTS: The 7-year event-free survival (EFS) and overall survival (OS) rates in the entire study population were 72.1% (95% CI: 68.0-76.2%) and 84.8% (95% CI: 79.7-89.9%), respectively, and the EFS of the SR patients (85.3% [95% CI: 78.2-92.4%]) was significantly better than HR patients (62.4% [95% CI: 52.2-72.6%]) (P = 0.0007). CONCLUSIONS: There were no differences in the EFS between the different maintenance therapies in each risk group; however, grade IV liver toxicity occurred more often in the patients receiving 6-MP/MTX with VCR and DEX therapy than in patients receiving LSA2L2.

Hematopoietic stem cell transplantation in patients with severe congenital neutropenia: an analysis of 18 Japanese cases.

We studied the outcome of allogeneic HSCT in patients with SCN. Between 1989 and 2005, 18 patients with SCN in Japan received HSCT for reasons other than malignant transformation, i.e., because of the lack of or a partial response to treatment with r-HuG-CSF. The median age of the patients at the first HSCT was three and a half yr (range 0.2-16.7 yr). Nine patients received stem cells from an HLA-identical sibling donor and nine from an alternative donor. Twelve and six patients received myeloablative and non-myeloablative conditioning regimens, respectively. Engraftment occurred at the first HSCT in 12 patients, four patients received a second HSCT for graft failure, and two patients died. The cause of death was renal failure and graft failure at the first and second HSCT, respectively. The cumulative incidence of grade II-IV acute GVHD and TRM at the first transplantation was 11% and 5.6%, respectively. Of our patients, 16 are alive and in complete remission, with a median follow-up of six and a half yr. Our results suggest that HSCT is beneficial for patients with SCN refractory to r-HuG-CSF treatment.

[Effectiveness of remission induction with high-dose cytarabine for relapsed or refractory pediatric acute leukemia].

We conducted a multicenter postmarketing study to investigate the efficacy and safety of reinduction therapy with a high-dose cytarabine-containing regimen for pediatric patients with relapsed or refractory acute leukemia. Seven of 13 patients (53.8%) with ALL achieved complete or partial remission, and only 1 of 6 patients (16.7%) with AML achieved partial remission. The frequent non-hematologic adverse events were gastrointestinal toxicities, such as vomiting, diarrhea and abdominal pain, as well as pyrexia and headache. Infection appeared in 9 of 20 (45%) patients. There were two death during reinduction therapy. One died of invasive bronchopulmonary aspergillosis, and the other died of intracranial hemorrhage and renal failure. These results indicated that a high-dose cytarabine regimen is effective as reinduction therapy in pediatric patients with relapsed ALL, and supportive care is essential to prevent or control treatment-related adverse events, such as infection.

Rhabdomyosarcoma masquerading as acute leukemia.

Rhabdomyosarcoma (RMS) masquerading as acute leukemia (AL) is very rare. We describe three cases with RMS without any symptoms of solid tumors. Bone marrow (BM) showed approximately 95% of blast-like abnormal cells, lacking almost all of the surface antigens of myeloid- and lymphoid-lineage. The immunohistochemistry revealed positive of the cells for actin, desmin and myoglobin. It is important to examine BM samples by immunohistochemistry, when a flow cytometric analysis reveals an unusual presentation.

Anaplastic large cell lymphoma in leukemic presentation: a case report and a review of the literature.

It is extremely rare that a patient with anaplastic large cell lymphoma (ALCL) demonstrates circulating lymphoma cells. A 10-year-old Japanese boy was presented with high-grade fever and cough. The physical examination revealed marked hepatosplenomegaly with ascites and lymphadenopathy in the cervical and periauricular areas. The white cell count was 26.2x10(9)/L with 95% of abnormal lymphoid cells, which were small to medium-sized with a high nucleus/cytoplasm ratio, basophilic cytoplasm, condensed nuclear chromatins, and 1 or 2 distinct nucleoli, hemoglobin 6.4 g/dL, and platelet 0.9x10(9)/L. A flow cytometric analysis of abnormal cells in both the peripheral blood and bone marrow samples was strongly positive for CD30 on their cell membranes. Karyogram and fluorescent in situ hybridization showed abnormal cells to have a characteristic chromosomal translocation, t(2;5)(p23;q35). Reverse transcriptase-polymerase chain reaction of peripheral blood cell-derived mRNA also indicated the fusion gene product of anaplastic lymphoma kinase and nucleophosmin. Subsequently, the patient was diagnosed to have ALCL with a rare clinical feature of a peripheral leukemic presentation, and his disease revealed to be refractory to chemotherapy. On the basis of the 11 childhood cases of ALCL with leukemic presentation so far published and reviewed herein, the prognosis is very poor.

Outcome of non-T-cell-depleted HLA-haploidentical hematopoietic stem cell transplantation from family donors in children and adolescents.

Non-T-cell-depleted HLA-haploidentical hematopoietic stem cell transplantation (SCT) from family members has been reported, but its effectiveness and safety are not fully known. In this study, we examined the outcomes of 83 children and adolescents with nonmalignant (n = 11) or malignant (n = 72) disorders who underwent SCT mismatched at 2 or 3 HLA loci, either from the mother (n = 56), a noninherited maternal antigen (NIMA)-mismatched sibling (n = 14), or the father/a noninherited paternal antigen (NIPA)-mismatched sibling (n = 13). Engraftment was satisfactory. Severe (grade III-IV) acute graft-versushost disease (GVHD) was noted only in malignant disease, with an incidence of 21 of 64 evaluable patients. GVHD prophylaxis with a combination of tacrolimus and methotrexate was significantly associated with a lower risk of severe acute GVHD, compared with other types of prophylaxis (P = .04). Nine of 11 patients with nonmalignant disease and 29 of 72 patients with malignant disease were alive at a median follow-up of 26 months (range, 4-57 months). Outcomes were not significantly different among the 3 donor groups (mother versus NIMA-mismatched sibling versus father/NIPA-mismatched sibling) for the malignancy disorders. Our results indicate that non-T-cell-depleted HLA-haploidentical SCT may be feasible, with appropriate GVHD prophylaxis, for young recipients who lack immediate access to a conventional stem cell source.

Primary Ewing's sarcoma family tumors of the lung a case report and review of the literature.

Ewing's sarcoma family tumors (ESFT) have been reported to originate in a variety of sites, most commonly in the extremities. We herein report a case of a primary ESFT of the lung presenting in an 8-year-old boy. A histological examination of hematoxylin-eosin stained sections showed a homogeneous population of closely packed small neoplastic cells. The tumor cells were strongly positive for CD99/MIC2 and negative for the leukocyte common antigen, myoglobin, desmin, epithelial membrane antigen, AE1/AE3 and synaptophysin. The patient was treated with neoadjuvant chemotherapy and surgery. Nine months later, he is in good condition and chest CT scans have revealed no evidence of either local recurrence or distant metastasis. Cases of ESFT of the lung have been reported in recent years but there are still few reports of primary ESFT of the lung. To date, only eight cases of ESFT of the lung have been reported in the literature. This is the first report of an ESFT of the lung occurring in a patient under 10 years of age. The clinical course and therapeutic management of ESFT are also discussed.

Human cord blood- and bone marrow-derived CD34+ cells regenerate gastrointestinal epithelial cells.

In the present study, we aimed to clarify the capacity of human cord blood- and bone marrow-derived progenitor cells to generate gastrointestinal epithelial cells in clinical and experimental transplantation settings. First, in a clinical transplantation setting, gastrointestinal tissues derived from female pediatric or juvenile recipients of allogeneic sex-mismatched bone marrow and cord blood transplantation were examined for the presence of donor-derived epithelial cells. Gastrointestinal specimens of allogeneic recipients included Y chromosome+ cytokeratin+ epithelial cells at a frequency of 0.4-1.9%. To further determine the capacity of purified human progenitor cells, human cord blood- or bone marrow-derived CD34+ cells were transplanted into newborn NOD/SCID/beta2-microglobulin(null) mice as an experimental transplantation assay. When gastrointestinal tissues derived from recipient mice were subjected to FISH and immunofluorescence analyses, human epithelial cells were identified at a frequency of 0.24-0.58% at 3 months posttransplantation. Finally, double FISH analyses using species-specific probes revealed that human chromosome+ epithelial cells did not possess any murine chromosomes, indicating that donor-derived epithelial cells were not generated only by cell fusion. On the basis of these findings, it is concluded that purified human cord blood and bone marrow CD34+ progenitor cells can generate gastrointestinal epithelial cells across allogeneic and xenogeneic histocompatibility barriers.

CT and MR findings of brain aspergillosis.

CT and MR findings of a case of brain aspergillosis with histopathologic correlation are reported. On both CT and MR images, there were multiple lesions in the corticomedullary junction (CMJ) that appeared to disrupt the cortical sulci and that were not enhanced by intravenous contrast material. In most of these lesions, there were centrally located structures that were enhanced by intravenous contrast material and that appeared to be continuous from markedly enhanced adjacent dilated cortical vessels. Histopathologic examination of the autopsy specimen showed multiple hemorrhagic infarcts in the CMJ with remaining dilated cortical vessels that had been thrombosed by aspergillus hyphae.