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J Krischer

Publications and source records attributed to J Krischer.

At least 55 records · Page 3Linked to original sources
PubMed1994

Islet cell antibodies predict insulin-dependent diabetes in United States school age children as powerfully as in unaffected relatives.

Islet cell antibodies (ICA) in the sera of nondiabetic relatives of patients with insulin-dependent diabetes (IDD) are predictive of the disease, a finding that permits the design of intervention strategies to prevent it. However, 85% or more of patients with new onset IDD have no affected relative. We therefore screened 9,696 schoolchildren between the ages of 5 and 18 yr (mean age 10.7 yr) in Pasco County, Florida for ICA in three surveys during 1984/5, 1987/8, and 1990/1 and have followed them prospectively. Approximately 4,000 of these children have been followed for nearly 8 yr. ICA titers > or = 10 Juvenile Diabetes Foundation units on replicate tests were detected in 57 of the children (0.59%). 10 children have developed diabetes so far, and all had ICA detected beforehand. The likelihood of developing IDD among the ICA-positive children was compared with 2,959 age-matched nondiabetic first degree relatives of IDD probands who were screened for ICA by our laboratory during the same time period and also followed prospectively. Of 103 (3.5%) ICA-positive relatives, 31 have developed IDD. Life table analysis reveals no statistically significant differences in the probability of developing IDD between the ICA-positive schoolchildren and ICA-positive first degree relatives (P = 0.3). The estimated risk of developing IDD by 7 yr in the ICA-positive schoolchildren was 45% (95% confidence interval 15-74%) compared with 43% (confidence interval 22-63%) in the relatives. We conclude that ICA appear to be as predictive of IDD in low-risk schoolchildren as they are in high-risk relatives. These data suggest that it is feasible to predict IDD by screening a general population of schoolchildren for ICA and that those found to be positive could be considered, in addition to relatives, for intervention protocols to prevent the disease.

Adolescent↗
PubMed1993

Ifosfamide with mesna uroprotection and etoposide in recurrent, refractory acute leukemia in childhood. A Pediatric Oncology Group Study.

BACKGROUND: Ifosfamide has previously been shown to be active as a single agent and in combination with doxorubicin, etoposide, and teniposide in pediatric solid tumors and adult acute leukemia. The authors performed a dose-escalation trial of ifosfamide with a fixed dosage of etoposide, with mesna uroprotection, in children with multiply recurrent acute leukemia. METHODS: Chemotherapy was administered daily for 5 days. Etoposide 100 mg/m2 was followed by ifosfamide at an initial dosage of 1.6 g/m2. The ifosfamide was escalated in 20% increments to the maximum tolerated dosage in cohorts of three patients. Mesna 400 mg/m2 was given immediately before the ifosfamide and then at 3 and 6 hours after ifosfamide in the initial patients. Subsequent patients were treated with mesna 400 mg/m2 just before ifosfamide, and then every 2 hours to a total dosage equal to the ifosfamide dosage. RESULTS: Forty-four heavily pretreated patients were entered on study. Forty were evaluable for toxicity and 36 for response as well. The maximum tolerated dosage of ifosfamide was 4.0 g/m2/d for 5 days (20 g/m2/course). Overall, 10 patients achieved complete remission, and 3 achieved partial remission. Remissions were brief, although four patients went on to bone marrow transplant while in remission. One patient is still alive. CONCLUSIONS: The combination of etoposide and ifosfamide with mesna uroprotection showed promising activity in children with multiply recurrent acute leukemia.

Acute Disease↗
PubMed1993

Insulin increases the Na(+)-K(+)-ATPase alpha 2-subunit in the surface of rat skeletal muscle: morphological evidence.

The cellular localization of the alpha 2-subunit of the Na(+)-K(+)-ATPase was defined by immunoelectron microscopy, and the effect of insulin on the amount of alpha 2-immunoreactive subunits on the cell surface was quantitated. Two protocols were used for tissue fixation and immunolocalization. Protocol 1 was characterized by fixation with 2% paraformaldehyde, use of a monoclonal antibody, and detection with 3-nm-diameter gold-labeled Fab fragments or 10-nm gold-labeled immunoglobulin G. Protocol 2 was characterized by fixation with 4% paraformaldehyde plus 0.1% glutaraldehyde, use of a polyclonal antibody, and detection with 10-nm gold-labeled protein A. In control muscle, the alpha 2-subunit of the Na(+)-K(+)-ATPase was present at the plasma membrane and in intracellular tubular and vesicular structures located in subsarcolemmal and triadic regions. Acute insulin stimulation increased the number of immunolabeled alpha 2-subunits in the plasma membrane after both fixation protocols. The gain in the plasma membrane ranged from 1.5- to 3.7-fold and was significant at the level of P < 0.005. These results provide morphological quantitative evidence that the alpha 2-subunit of the Na(+)-K(+)-ATPase is present both at the plasma membrane and intracellularly in mammalian skeletal muscle and that insulin acutely increases its abundance in the muscle surface.

Animals↗
PubMed1993

Endocytosis is inhibited in hepatocytes from diabetic rats.

The consequences of type I diabetes on cellular endocytosis were investigated by comparing [125I]insulin, [125I]alpha 2-macroglobulin, and Lucifer yellow uptake in hepatocytes freshly isolated from control and STZ-induced diabetic rats. In addition to the previously described reversible inhibition of ligand-induced internalization of the insulin receptor, we report a decrease in the constitutive receptor-mediated endocytosis of alpha 2-macroglobulin and a near abolition of fluid-phase endocytosis of Lucifer yellow in cells from diabetic animals. Despite decreased receptor autophosphorylation and internalization, the ligand-induced surface redistribution of the insulin receptor was normal in the diabetic cell population. By contrast, the insulin receptor association with clathrin-coated pits was impaired in diabetic cells as a result of a decreased concentration of these specialized invaginations on the nonvillous cell surface. The morphology and diameter of clathrin-coated pits were similar in both conditions under study. These results demonstrate a general impairment of endocytosis in hypoinsulinemic diabetes: receptor-mediated endocytosis was less affected than fluid-phase endocytosis. Impaired endocytosis of specific ligands or other macromolecules could be an important mechanism underlying the accumulation of extracellular matrix or even blood cholesterol removal in diabetes.

Animals↗
PubMed1992

Evaluation of CHIP (iproplatin) in recurrent pediatric malignant solid tumors. A phase II study (Pediatric Oncology Group).

CHIP (325 mg/M2), a second generation cisplatin derivative, was administered intravenously every 3 weeks to 85 pediatric patients with recurrent sarcomas (19), osteosarcomas (20), neuroblastoma (23), germ cell tumors (10), and other malignant tumors (7). Thirty-eight of them had been previously exposed to cisplatin. Partial remissions were only observed in 3 of 23 (13% SE = 7%) patients having neuroblastoma. Severe thrombocytopenia (65%) and neutropenia (35%) were the dose limiting factors.

Adolescent↗
PubMed1992

A study of toxicity and comparative therapeutic efficacy of vindesine-prednisone vs. vincristine-prednisone in children with acute lymphoblastic leukemia in relapse. A Pediatric Oncology Group study.

Vindesine (des-acetyl Vinblastine) is a synthetic derivative of vinblastine, and was produced with the hope that it would have less neurotoxicity and hematopoietic toxicity than other vinca alkaloids. Phase I and II studies also demonstrated significant activity in lymphoid malignancies, especially Acute Lymphoblastic Leukemia (ALL). The present study was designed to compare therapeutic effectiveness of twice weekly vindesine (2 mg/M2/dose) plus Prednisone (60 mg/M2/dose) (Treatment 1) to weekly Vincristine (2 mg/M2/dose) plus Prednisone (60 mg/M2/day) (Treatment 2). All patients were less than 21 years of age, and had documented bone marrow relapse (blast count > 25%). In 39 patients presumed sensitive to vincristine, there were 11 complete responses out of 20 patients (55%) randomized to receive vindesine/prednisone and 7 complete responses out of 19 patients (37%) treated with Vincristine/Prednisone. In 37 patients resistant to vincristine, there were 7 complete responses (19%). Vindesine was more toxic than Vincristine. Major toxicities of vindesine included paraesthesias, peripheral neuropathy and ileus. Vindesine hematological toxicity appeared greater, but such toxicity is hard to assess in patients with bone marrow disease. In this study, vindesine and vincristine had similar efficacy, but vindesine use was associated with more toxicity.

Adolescent↗
PubMed1991

Hyperfractionated radiation therapy in brain stem tumors. Results of treatment at the 7020 cGy dose level of Pediatric Oncology Group study #8495.

Between May 1986 and February 1988, 57 patients were accrued to the second dose level of a Phase I/II Pediatric Oncology Group (POG) study exploring the use of hyperfractionated radiation therapy (HRT) in children with high-risk brain stem tumors. Local fields were treated with fraction sizes of 117 cGy given twice daily, with a minimum interfraction interval of 6 hours, to a total dose of 7020 cGy in 60 fractions over 6 weeks. Information regarding clinical status during HRT was available for 55 patients (44 [80%] improved, 6 remained stable, and 5 deteriorated). Results of initial and follow-up computed tomography (CT) scan and/or magnetic resonance imaging (MRI) were available for review for 52 patients. One patient had a complete response (CR) to treatment, 3 had a partial response (PR) (more than 50% response), and 40 remained stable, for a total response rate (CR + PR + stable) of 77%. Median time to disease progression was 6 months. Median survival time was 10 months. Survival rate was 39.6% (standard error [SE] = 6.6%) at 1 year and 23% (SE = 5.8%) at 2 years. Complications of treatment included an enhanced skin reaction in six patients and otitis media and/or externa in nine. One patient bled into tumor shortly after completion of HRT, and three had intralesional necrosis. Five patients continued taking steroids for protracted periods in the face of improved clinical and/or radiologic findings. Complications related to the use of steroids included opportunistic infections, impaired glucose tolerance, hypertension, osteoporosis, and significant mood changes. In no patient was there evidence of any late injury attributable to HRT. When compared with results of treatment with HRT at a lower dose level (6600 cGy), there appears to be a trend toward improved survival at 7020 cGy despite a less favorable patient population at the higher dose level. A second dose escalation to 7560 cGy in 60 fractions over 6 weeks has been implemented as planned.

Adolescent↗
PubMed1991

Toxicity trials of amsacrine (AMSA) and etoposide +/- azacitidine (AZ) in childhood acute non-lymphocytic leukemia (ANLL): a pilot study.

Recurrent or induction therapy-resistant ANLL carries a grave prognosis. The combination of AMSA at 100 mg/M2 daily for 5 days and etoposide at 200 mg/M2 daily for the first 3 days of therapy was given to 40 patients with refractory ANLL. An additional 17 patients received those two agents plus azacitidine at a dosage of 250 mg/M2 on days 4 and 5. All three drugs were given as one-hour infusions. All patients had normal electrolyte determinations daily and were on cardiac monitors during the period of drug administration. No arrhythmias were detected in 522 doses of AMSA. Toxicities observed were primarily related to myelosuppression. Forty-nine of the 57 patients required hospitalization for suspected or proven infection. Nausea/vomiting and mucositis were the next most commonly occurring toxicities. Responses were seen in 22 patients.

Adolescent↗
PubMed1991

Phase II study of 13-cis-retinoic acid in pediatric patients with acute nonlymphocytic leukemia--a Pediatric Oncology Group study.

Forty-one patients with refractory acute non-lymphocytic leukemia (ANLL) in relapse were treated with 13-cis-retinoic acid (cRA) as salvage therapy. The cRA was given as a single oral dose of 100 mg/m2/day for 4 weeks. One patient achieved a complete remission and two patients achieved a partial remission with reduction of the bone marrow blast count from 40 to 20% after the first course. We recommend further study of cRA in combination with other agents in the treatment of ANLL in children.

Adolescent↗
PubMed1991

A comparison of induction and maintenance therapy for acute nonlymphocytic leukemia in childhood: results of a Pediatric Oncology Group study.

Two hundred fifty-six children with previously untreated acute nonlymphocytic leukemia (ANLL) were evaluated on a Pediatric Oncology Group (POG) phase III randomized trial of both induction and continuation chemotherapies. Induction therapy compared vincristine, cytarabine, and dexamethasone (VADx) with daunorubicin, cytarabine, and thioguanine (DAT). The complete remission (CR) rate using DAT was superior (82% v 61%, P = .02). Postremission therapy consisted of either "standard" two-cycle therapy or a more intensive four-cycle regimen given for 2 years. Overall, there was no difference in outcome for patients randomized to either continuation regimen. The overall complete continuous remission rate (CCR) for the "best" induction/continuation therapy combination at 2 years was .50 (SE = .06), at 3 years was .35 (.04), and at 4 years was .34 (.05). Analysis of selected clinical and laboratory parameters demonstrated differences in induction responses favoring DAT induction but did not impact eventual disease-free survival. There were two subgroups of patients who responded better to four-cycle continuation therapy. These were patients with French-American-British (FAB) M1/M2 (2-year CCR was .20 v .44, P = .01) and patients older than 10 years at diagnosis (.32 v .62, P = .004).

Agranulocytosis↗
PubMed1991

High-dose cytarabine for intensification of early therapy of childhood acute myeloid leukemia: a Pediatric Oncology Group study.

In June 1984, the Pediatric Oncology Group (POG) initiated a pilot study (8498) using high-dose cytarabine (HdA; 3 g/m2) for intensification of early therapy in childhood acute myelogenous leukemia (AML) (group I). Remission induction therapy consisted of two courses of daunorubicin, cytarabine (Ara-C), and thioguanine (DAT). Postremission therapy consisted of four sequential courses, each consisting of (1) four doses of HdA (HdA4) followed by asparaginase (L-Asp), (2) etoposide (VP) plus azacytidine (Az), (3) prednisone, vincristine, methotrexate, and mercaptopurine (POMP), and (4) Ara-C daily for 5 days by continuous infusion. Six doses of intrathecal Ara-C were given for CNS prophylaxis. In December 1986, the protocol was amended (group II) to substitute six doses of HdA (HdA6) for the second DAT (two + five) induction course; postinduction, a single course of HdA6 was given instead of four HdA/L-Asp courses, and the remainder of the therapy was unchanged. One hundred forty group I patients and 145 group II patients were assessable. The two groups were similar with regard to clinical prognostic groups. No significant differences were noted in the two groups with regard to remission induction (85% [SE = 2%] in each group), induction deaths (6.5% v 7.0%), or deaths in remission (one in each group). Cerebellar toxicity was reported in three patients in group II (with HdA6) but none in group I (HdA4). At present, patients who received HdA6 (group II) had higher event-free survival than patients in group I (EFS at 3 years, 34% [SE = 11%] v 29% [SE = 4%]), and disease-free survival (DFS at 3 years, 42% [SE = 14%] v 34% [SE = 4%]), but the differences were not statistically significant. In both groups, children less than 2 years and those with WBCs less than 100,000/microL had significantly better outcome (EFS of 55% [SE = 10%] and 36% [SE = 5%] at 3 years, respectively) than children greater than or equal to 2 years and those with WBCs greater than or equal to 100,000/microL (EFS of 27% [SE = 5%] and 20% [SE = 9%] at 3 years, respectively.

Adolescent↗
PubMed1990

Toxicity of high-dose cytosine arabinoside in the treatment of advanced childhood tumors resistant to conventional therapy. A Pediatric Oncology Group study.

Experience with high-dose cytosine arabinoside (HDAC) in pediatric solid tumors is limited. Sixteen children with solid tumors resistant to conventional therapies were registered in a pilot Pediatric Oncology Group (POG) study that required the administration of HDAC at 3 g/m2 every 12 hours for four doses. There were four cases of rhabdomyosarcoma, two cases of fibrosarcoma, four cases of neuroblastoma, and one case each of germ cell tumor, Wilm's tumor, retinoblastoma, hepatocellular carcinoma, Ewing's sarcoma, and Burkitt's lymphoma. All eligible patients had advanced diseases and had previously received extensive chemotherapy. Thirteen patients received one course of HDAC and three patients received two courses of HDAC. Due to prior treatments, patients had less than normal marrow reserves. Short-term toxicity included nausea, vomiting, suppression of hemopoiesis, drug fever, and increased blood urea nitrogen (BUN), creatinine, and liver enzymes. All evaluable patients recovered from their toxicities. There were no drug-related deaths. None of the patients had neurologic problems, including the only patient with prior irradiation to the skull. With the above schedule, HDAC appears to have manageable toxicity.

Child↗
PubMed1990

A prospective study of the development of diabetes in relatives of patients with insulin-dependent diabetes.

BACKGROUND: The presence of cytoplasmic islet-cell autoantibodies has been recognized as a risk factor for the development of diabetes mellitus in relatives of patients with insulin-dependent diabetes mellitus (IDDM), but the magnitude of the risk is unknown, as is the influence of other factors, such as age, sex, and race. METHODS: From 1979 through 1989, we studied 4015 initially nondiabetic relatives of 1590 probands with IDDM to determine the risk of IDDM according to the presence and titer of autoantibodies, as well as other factors. RESULTS: Of the 4015 nondiabetic relatives, 125 (3.1 percent) had islet-cell antibodies in their initial serum samples, and 40 contracted IDDM. Islet-cell antibodies were most frequent (4.3 percent) in relatives who were under 20 years of age (P = 0.001) and in those (4.8 percent) from families with more than one affected member (a multiplex pedigree) (P = 0.003). Independent risk factors for the development of diabetes in the relatives included age of less than 10 years at the time of the initial study (P = 0.001), membership in a multiplex pedigree (P = 0.02), and a positive test for islet-cell antibodies in the initial serum sample (P = 0.0001). Twenty-seven of the relatives in whom diabetes developed (67.5 percent) had positive tests for islet-cell antibodies before the diagnosis of IDDM, giving a relative risk of IDDM of 68 (95 percent confidence interval, 34 to 134) for antibody-positive relatives. Islet-cell-antibody titers of 20 Juvenile Diabetes Foundation units or higher were associated with an increasing risk of diabetes. CONCLUSIONS: Nondiabetic relatives of probands with IDDM who are in the first two decades of life, are members of multiplex pedigrees, and have increased titers of islet-cell antibodies are the most likely to contract IDDM themselves.

Adolescent↗
PubMed1990

Phase I trial of indicine-N-oxide in children with leukemia and solid tumors: a Pediatric Oncology Group study.

A phase I trial of indicine-N-oxide was carried out in 12 children with solid tumors and in 16 with leukemia. Doses of 5, 6, and 7.5 g/m2 were given parenterally as a 15-min infusion every 3 weeks. The maximum tolerated dose in patients with solid tumors was 7.5 g/m2 and the dose-limiting toxicity was myelosuppression. In leukemia, the maximum tolerated dose was 6.0 g/m2 and hepatotoxicity was dose-limiting. Half of the children with leukemia showed elevations in transaminase levels and one child died of massive hepatic necrosis. This hepatotoxicity limits the use of indicine-N-oxide in children with leukemia. Antineoplastic activity was limited to a transient reduction in the numbers of circulating leukemic cells.

Adolescent↗