Chieko Watanabe

Analysis of the circumstances at the end of life in children with cancer: Symptoms, suffering and acceptance

Abstract Background : In an effort to improve the quality of life of children with cancer, this study analyzes the signs and symptoms at the end of life in such children. It is hoped that these data will contribute to the development of appropriate programs to address the challenges faced by these children.

Clinical relevance of in vitro chemoresistance in childhood acute myeloid leukemia

To determine the clinical relevance of in vitro drug chemoresistance in childhood acute myeloid leukemia, we used an MTT assay to test leukemic cells from 132 newly diagnosed children. Patients were diagnosed according to the French–American–British (FAB) classification as follows: M0 (n = 12), M1 (n = 16), M2 (n = 53), M4 (n = 17), M5 (n = 19) and M7 (n = 15). The results revealed that, compared to leukemic cells from complete-responders (n = 107), those from non-responders who failed induction therapy (n = 17) were 1.4 to 5.0 times more resistant in vitro to cytarabine (P = 0.005), melphalan (P = 0.003), etoposide (P = 0.011), L-asparaginase (P = 0.017), aclarubicin (P = 0.026) and dexamethasone (P = 0.039). For seven other drugs tested, the median lethal dose of 70% and leukemic cell survival of non-responders were higher than those of complete-responders, but the difference was not statistically significant. We sought correlations between FAB subtypes and in vitro drug resistance. Leukemias of the FAB M4 and M5 subtype were more sensitive to L-asparaginase (P = 0.01, P = 0.0036) than those of the FAB M2 subtype. FAB M5 leukemia was more sensitive to etoposide than were the FAB M2, M4 and M7 subtypes (P = 0.001, P = 0.034, P = 0.023, respectively). By contrast, FAB M5 leukemia was significantly more resistant to prednisolone and dexamethasone than were the FAB M0, M1, M2, M4 and M7 subtypes. We sought correlations between in vitro drug resistance and long-term clinical outcome, but found no associations in this case. These results suggest that in vitro resistance to cytarabine, melphalan, etoposide, L-asparaginase, aclarubicin and dexamethasone might represent factors that can predict response to the early course of therapy. Selecting an appropriate anti-cancer drug according to the FAB classification together with drug sensitivity testing may contribute to improved prognoses in childhood acute myeloid leukemia.

Analysis of the circumstances at the end of life in children with cancer: A single institution's experience in Japan

Abstract Background : With the aim of improving the quality of life of children with cancer, this study presents an analysis of one hospitals experience with terminal care.

Successful unrelated bone marrow transplantation for a patient with chronic granulomatous disease and associated resistant pneumonitis and Aspergillus osteomyelitis

We describe the successful treatment of a 20-year-old patient with chronic granulomatous disease (CGD), by unrelated bone marrow transplantation (UBMT). The patient is relatively old compared to other CGD patients treated with BMT. He had had repeated serious infections from early childhood and was diagnosed as CGD, gp91-phox deficiency. Prolonged antibiotic-resistant pneumonitis worsened when the patient was 18 years old. In addition, he suffered Aspergillus osteomyelitis and acute renal failure due to amphotericin B. He received 94 granulocyte transfusions from 94 adult donors and the infections gradually improved. In September 1998, at 20 years of age, he underwent UBMT from an HLA 6 antigen-matched male donor, with CY and TBI conditioning. He received MTX and CsA as prophylaxis against GVHD. No serious complications occurred and rapid engraftment was achieved. Acute GVHD (grade 2, at day 19) and chronic GVHD (limited, at day 192) occurred. However, both were easily controlled. The patient is alive and well with no late rejection 26 months after UBMT. Bone Marrow Transplantation (2001) 28, 83–87.

In vitro efficacy of l‐asparaginase in childhood acute myeloid leukaemia

Summary.  To explore the potential efficacy of l‐asparaginase treatment in acute myeloid leukaemia (AML) patients, we studied the in vitro resistance of French–American–British (FAB) subtypes of childhood AML to l‐asparaginase using a methyl–thiazol–tetrazolium assay. We tested leukaemic cells obtained from 177 common acute lymphoblastic leukaemia (cALL) and 228 AML children at diagnosis. The median 70% lethal dose of l‐asparaginase (LD70asp) (U/ml) was 0·46 in the cALL and 6·70 in the AML samples. The median LD70asp among each FAB subtype of AML was 0·76 (M0), 0·46 (M1), 10·00 (M2), 10·00 (M3), 1·18 (M4), 1·35 (M5) and 10·00 (M7). Type M3 samples had the highest LD70asp. The LD70asp of the M2 samples was significantly higher than that of the M1, M4 and M5 samples. When the LD70asp values were classified as low (0·016–0·159), intermediate (0·16–1·59) or high (1·6–10·00), the frequency of low, intermediate or high LD70asp among the M1 samples were similar to those among the cALL samples. In conclusion, cells from AML types M1, M4 and M5 were relatively sensitive to l‐asparaginase, and M1 cells were as sensitive as those of cALL, suggesting that l‐asparaginase treatment may be effective for these subtypes of AML.

Two Groups of Philadelphia Chromosome—Positive Childhood Acute Lymphoblastic Leukemia Classified by Pretreatment Multidrug Sensitivity or Resistance in In Vitro Testing

The development of effective chemotherapy is imperative for children with Philadelphia chromosome—positive (Ph) acute lymphoblastic leukemia (ALL) because of the poor prognosis of this condition. Initial cellular drug resistance is thought to be an important cause of induction failure and early relapse.We carried out in vitro tests using a methyl-thiazol-tetrazolium assay on bone marrow samples from 274 children with newly diagnosed ALL. Sixteen children (5.8%) had Ph-positive results of cytogenetic analysis. We examined in vitro drug resistance to 14 agents and found that leukemic cells in Ph ALL were significantly more resistant than were cells in non-Ph ALL to melphalan, bleomycin, etoposide, mitoxantrone, L-asparaginase, and vinblastine. With the prednisolone, L-asparaginase, and vincristine (PAV) combination of drugs, 10 of the 16 Ph patients with ALL (62.5%) showed relative resistance (RR) (sensitivity to only 1 or to none of the 3 drugs) at initiation of treatment.These 10 patients experienced significantly poorer event-free survival (EFS) than did the 6 patients with supersensitivity (SS) (defined as sensitivity to all 3 or to 2 of the 3 drugs,P = .019). Leukemic cells from RR patients were found to be multiresistant to 12 drugs with 2.0- to 58.4-fold RR compared with cells from SS patients. This PAV sensitivity delineates initially sensitive and resistant groups. Of these, the SS subgroup of Ph ALL patients may be curable with chemotherapy and stem cell transplantation. For EFS improvement in the RR group, it may be necessary to use a new chemotherapy approach from initiation.

Distinctive Multidrug Sensitivity and Outcome of Acute Erythroblastic and Megakaryoblastic Leukemia in Children With Down Syndrome

We assessed the in vitro chemosensitivity of acute erythroblastic and megakaryoblastic leukemia cells from children with Down syndrome (DS) compared to non-DS children. We conducted in vitro tests using the MTT assay of bone marrow samples from 12 children with DS and 16 children without DS. Patients were newly diagnosed based on the morphology and expression of platelet-specific antigens. Induction failure occurred more frequently in the non-DS group (n = 4) than in the DS group (n = 0, P = .053). Children with DS had a superior event-free survival (EFS) probability of 0.750 at 4 years, compared to an EFS probability of 0.375 for non-DS children (P = .049). Blast cells from DS patients were significantly more sensitive to daunorubicin, melphalan, mitoxantrone, 4-hydroperoxy-cyclophosphamide, vincristine, etoposide, bleomycin, and pirarubicin than those from non-DS patients. Four of the 16 non-DS patients were found to have acquired an extra chromosome 21 in their leukemia cells; blasts from these patients also tended to have greater chemosensitivity than those from patients without an extra chromosome 21. Blast cells from DS patients are markedly sensitive to various drugs. These results suggest that the fragility of blast cells derived from DS patients may be related to an increased susceptibility to apoptosis.

Congenital anaplastic astrocytoma differentiated into pilocytic astrocytoma: an autopsy case.

We report an autopsy case of congenital astrocytoma and its histopathological changes during 5 years of the patients development from birth to death. At birth, a right exophthalmic tumor was observed, and MRI revealed that the tumor occupied the right orbital space and had also affected the suprasellar diencephalic structures. The right orbital tumor, which was enucleated at 2 months of age, was a highly cellular tumor with moderate pleomorphism resembling anaplastic astrocytoma. On the other hand, at autopsy, a brain tumor was found in the right diencephalic region with features of pilocytic astrocytoma, accompanied by leptomeningeal dissemination. A biopsy specimen, which was obtained from the chiasmatic part of the tumor at 4 months of age, showed an intermediate appearance between the orbital tumor and the brain tumor obtained at autopsy. Immunohistochemical examination confirmed that all three phases of the tumors showed an astrocytic lineage, and the Ki‐67 labeling index decreased rapidly after 2 months of age. We believe that this congenital anaplastic astrocytoma differentiated into a pilocytic astrocytoma during the 5 years of the patients development. The transformation of the congenital astrocytoma from anaplastic to pilocytic forms can be attributed to the nature of the tumor, namely postmitotic neoplastic cells are characterized by their ability to undergo self‐differentiation, along with the organotropism of the developing brain.

A rare case of childhood precursor B-cell lymphoblastic lymphoma in the mandible

Precursor B-cell lymphoblastic lymphoma (B-LBL) is uncommon nd rarely presents as a primary solitary bone tumor. Precuror B-cell neoplasms usually originate in bone marrow as B-cell cute lymphoblastic leukemia and, in advanced stages, can produce estructive bone lesions. Several cases are reported in the literature escribing B-LBL manifesting as a solitary bone tumor [1,2]. Howver B-LBL with oral cavity involvement is extremely rare. Here we resent the case of a childhood B-LBL in the mandible.