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Biomedical subjects

M D Krailo

Publications and source records attributed to M D Krailo.

At least 55 records · Page 3Linked to original sources
PubMed1992

The CCSG prospective study of venous access devices: an analysis of insertions and causes for removal.

This is an interval analysis of the 2-year prospective multicenter Childrens Cancer Study Group study of 1,141 chronic venous access devices in 1,019 children with cancer. Device type was external catheter (EC) 72%, totally implantable (TID) 28%, and did not differ for diagnosis or age except more double-lumen devices in bone marrow transplant protocols (77%) and more TIDs in children less than 1 year old (17.7%). Insertion characteristics evaluated in 1,078 (95%) were: operating room placement 99%; general anesthesia 98%; cutdown 67%; percutaneous 33%; atrial position 50%, caval position 50%; and perioperative antibiotics 48%. Vein entry was the external jugular 33%, internal jugular 22%, subclavian 35%, cephalic 7%, and saphenous 3%. Insertion was difficult or very difficult in only 10% and operative complications occurred in only 0.7%. Degree of difficulty bore no relationship to device type or patient age. The reasons for removal in 736 devices (67%) were due to complications in 39%, of which infections were the most frequent. There was some variance between centers ranging from 8.5% to 31% for infection; 2.8% to 24% for dislodgment; and 0% to 13% for occlusion. ECs had a higher risk of dislodgment; elective removals were more frequent in TIDs; there was no difference in infection as a cause for removal between ECs and TIDs. Dislodgment was associated with the shortest distance of the cuff to the skin exit (mean, 4 cm): less than or equal to 2 cm, 49%; greater than 2 cm, 28% (P = .009) and occurred most frequently in the younger patient (18.9%, 0 to 1 years; 0.5%, greater than 8 years.

Adolescent↗
PubMed1992

Phase II trial of indicine N-oxide in relapsed acute leukemia of childhood. A report from the Childrens Cancer Study Group.

We treated 31 children with acute lymphoblastic leukemia (ALL), 14 children with acute nonlymphoblastic leukemia (ANLL) in relapse, and 1 child with chronic myelogenous leukemia (CML) in blast crisis (CALLA negative) with indicine N-oxide in a Phase II study. The efficacy and toxicity of the drug were assessed at two dose levels: 2,000 mg/m2/day for 5 consecutive days (14 patients) and 2,500 mg/m2/day for 5 consecutive days (17 patients). One patient with ALL at each dose level achieved a complete response (CR) lasting 6 months and 1 month, respectively. The patient with CML achieved a partial response lasting 4 months. None of the patients with ANLL achieved a CR. Hepatotoxicity was mild (grade 1 or 2) in 63% and moderate (grade 3) in 9% of mild (grade 1 or 2) in 63% and moderate (grade 3) in 9% of patients; 3 patients (9%) experienced severe hepatotoxicity. Although indicine N-oxide has some antileukemic activity in ALL and is safe at the doses used in this study, the antileukemic activity is significantly less at these two doses than at greater than or equal to 3,000 mg/m2/days for 5 consecutive days. Unfortunately, when the higher doses are administered to children, they are associated with an unacceptably high incidence of severe, irreversible hepatotoxicity.

Acute Disease↗
PubMed1992

Lack of significant activity of 2'-deoxycoformycin alone or in combination with adenine arabinoside in relapsed childhood acute lymphoblastic leukemia. A randomized phase II trial from the Childrens Cancer Study Group.

Forty-nine children with recurrent acute lymphoblastic leukemia (ALL) were entered into a randomized Phase II trial evaluating 2'-deoxycoformycin (dCF) alone or in combination with adenine arabinoside (ara-A). 2'-Deoxycoformycin is an inhibitor of adenosine deaminase (ADA), an enzyme found in relatively high amounts in malignant lymphoid cells. Ara-A inhibits DNA polymerase and DNA synthesis. Because its efficacy in vivo as an anticancer agent is limited by its rapid inactivation by ADA, ara-A was combined with dCF to produce cytoreductive levels of ara-A. Twenty-four patients were assigned to receive dCF alone and 25 to receive the combination. No patient responded to dCF alone, and one patient developed a complete remission after treatment with the combination. The toxicity of dCF alone was minimal, except for one patient who became obtunded on day 5 following the first cycle of therapy. In contrast, five patients developed severe toxicity with the combination, including renal failure (three patients), hepatic failure (three patients), and neurologic toxicity (two patients). These results indicate that, at the doses and schedule used in this study, the combination of dCF and ara-A has significant toxicity and minimal activity against recurrent ALL in children.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Pharmacology and phase I trial of high-dose oral leucovorin plus 5-fluorouracil in children with refractory cancer: a report from the Children's Cancer Study Group.

Because of the synergy seen in adult trials when 5-fluorouracil is combined with leucovorin, we initiated a Phase I trial of this combination in children's refractory cancer. Leucovorin, an equal mixture of the (6R,S)-diastereoisomers, was administered p.o. for 6 consecutive days as 4 equal doses at 0, 1, 2, and 3 h totaling 500 mg/m2/day. 5-Fluorouracil was given daily on days 2 to 6 as an i.v. bolus immediately following the last dose of leucovorin. The leucovorin dose was held constant while the 5-fluorouracil dose was escalated in cohorts of patients from 300 mg/m2/day to its maximally tolerated dose. Thirty-five patients (19 with acute leukemia and 16 with solid tumors) were evaluable for toxicity. The maximally tolerated dose of FUra was 450 mg/m2/day for 5 treatments for patients with solid tumors and 650 mg/m2/day for 5 treatments for the children with leukemia. The dose-limiting toxicities were myelosuppression and stomatitis. Other side effects included transient, mild elevations of serum transaminases, mild nausea, vomiting, and diarrhea. The pharmacokinetics of high-dose p.o. leucovorin was studied in 23 children. There was considerable interpatient variability in the plasma concentrations of total bioactive folates (TBAF), (6S)-leucovorin, and (6S)-5-methyltetrahydrofolic acid. The maximum plasma concentration (Cmax) of TBAF was 821 +/- 97 (SE) nM, occurring at a median of 8 h; the Cmax of (6S)-leucovorin was 77 +/- 11 nM, occurring at 4 h. The TBAF concentration fell to 146 +/- 42 nM by 24 h. (6S)-5-Methyltetrahydrofolic acid accounted for 90 +/- 7% of the TBAF at the Cmax. The plasma concentration of (6R)-leucovorin, the unnatural isomer, was equal to that of TBAF. Thus, p.o. leucovorin reduced the 5-fold excess of (6R)-leucovorin over TBAF seen after i.v. doses. The relative amounts of the three major plasma species were approximately the same as in adults, even though the Cmax of each compound was lower.

Administration, Oral↗
PubMed1991

Results of treatment of malignant germ cell tumors in 93 children: a report from the Childrens Cancer Study Group.

We report treatment results in 93 children entered on study from 1978 to 1984 with malignant germ cell tumors (MGCTs), excluding dysgerminoma and tumors of the testis or brain. The estimated 4-year survival and event-free survival (EFS) for all 93 patients were 54% and 49%, respectively. For 30 children with ovarian tumors, the estimated 4-year survival was 67% and EFS was 63%. For 63 children with nongonadal tumors, survival and EFS were 48% and 42%, respectively. The comparison of EFS between ovarian and nongonadal tumors was significant at P = .03. The treatment plan included a second-look surgical procedure after 18 weeks of chemotherapy. Over half of 36 patients evaluated as having a residual mass present immediately before second-look surgery had no malignant tumor after review of surgical specimens. Age greater than 11 years at diagnosis, incomplete removal of tumor at first surgery, and more than one structure or organ involved at diagnosis increased the risk for adverse event. The histologic subtype of the primary tumor was not related to outcome. Diagnosis was verified by independent pathologic review, and treatment was uniform. Seventeen percent of all registered patients (21 of 127) were excluded because of ineligible pathologic diagnoses; sixty percent (13 of 21) were immature teratomas.

Adolescent↗
PubMed1991

Effective treatment of unresectable or metastatic hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy: a report from the Childrens Cancer Study Group.

The Childrens Cancer Study Group (CCSG) undertook a study (CCG-823F) to test the feasibility of administering continuous infusion doxorubicin (CI DOX) and cisplatin (CDDP) in patients with unresectable or incompletely resected hepatoblastoma (HB) or hepatocellular carcinoma (HCC). Chemotherapy consisted of CI DOX 20 mg/m2/d for days 1 to 4 and CDDP 100 mg/m2 on day 1 followed by a 21-day rest period. Second-look surgery was performed after the administration of four chemotherapy courses. Forty-seven (47) assessable patients were entered on study, 33 with HB and 14 with HCC; of these, 34 (26 HB and eight HCC) completed the initial four courses of chemotherapy. Of the 26 HB patients, 25 were evaluated as responding to chemotherapy before the scheduled second-look procedure and were considered surgically resectable at that time. Surgery was performed on 22 patients; three patients refused the second-look surgery. Nine patients had no evidence of residual malignant disease, seven underwent surgical resection of remaining tumor, four were left with microscopic residual disease, one had a partial resection with gross tumor left behind, and one remained unresectable. Nine HCC patients completed four chemotherapy courses. Eight patients achieved a partial remission and second-look surgery was attempted on seven. Only two had all malignant disease removed at the second procedure. Data from 225 courses of chemotherapy were evaluated for toxicity. Neutropenia (absolute granulocyte count less than 500/mL) was observed in 68 courses, and five of these episodes were associated with sepsis. Severe mucositis was documented in 21 courses, and hypomagnesemia (magnesium less than 1.2 mg) was noted in 30 patients. Two patients developed decreased left ventricular shortening fraction, which resolved when chemotherapy was discontinued. In summary, CI DOX plus CDDP is a well-tolerated and effective regimen in inducing surgical resectability in HB patients who are unresectable at diagnosis and significantly improves survival for this group of patients to 66.6%.

Adolescent↗
PubMed1990

Carboplatin in childhood brain tumors. A Children's Cancer Study Group Phase II trial.

Between October 1985 and March 1988, Children's Cancer Study Group institutions entered 95 patients with recurrent brain tumors into a Phase II trial of carboplatin 560 mg/m2 every 4 weeks. Complete or partial responses were observed for one of 19 evaluable children with brainstem glioma, two of 14 with ependymoma, six of 19 with medulloblastoma or central nervous system primitive neuroectodermal tumor (PNET), and none of 15 with high-grade astrocytoma. Of 33 children with medulloblastoma, ependymoma, or central nervous system PNET, five of 12 with no prior cisplatin exposure had responses, and two of 21 with prior cisplatin exposure had responses (P = 0.03). Thirty-four percent of patients had absolute neutrophil count nadirs less than 500/microliters, and 37% had platelet count nadirs less than 25,000/microliters. Sixteen percent had moderate to severe otoxicity, 10% had nausea and vomiting, and none had nephrotoxicity.

Adolescent↗
PubMed1990

Plasma pharmacokinetics and cerebrospinal fluid concentrations of idarubicin and idarubicinol in pediatric leukemia patients: a Childrens Cancer Study Group report.

Idarubicin (4-demethoxydaunomycin) is an anthracycline analogue with striking in vitro and in vivo activity against murine leukemias. Based on activity in adults with acute lymphoblastic leukemia, the Childrens Cancer Study Group initiated studies to evaluate idarubicin in children with leukemia in second or subsequent relapses. As part of those studies, we have characterized the plasma pharmacokinetics of idarubicin and the major circulating metabolite idarubicinol in 21 patients. Idarubicin plasma elimination was described by a three-compartment open model following i.v. infusion (10-15 mg/m2) on a schedule of weekly for 3 weeks and on a schedule of daily for 3 days every 3 weeks (total dose, 30-45 mg/m2). There was substantial variability in idarubicin elimination among patients, but no indication of dose-dependent or of schedule-dependent changes in pharmacokinetic parameters. The mean terminal half-life, total body clearance, and steady state volume of distribution were 17.6 h, 679 ml/min/m2, and 562 l/m2, respectively. Idarubicinol elimination was prolonged compared to that of the parent drug with a terminal half-life of 56.8 h. This metabolite clearly accumulated in plasma during the 3 days of treatment on the schedule of daily for 3 days. Urinary recoveries (48 h) of idarubicin and idarubicinol after a single dose of idarubicin were 2.4 and 10.1%, respectively. Idarubicin was detected in 2 of 21 cerebrospinal fluid samples obtained 18-30 h after administration. In marked contrast, idarubicinol was detected in 20 of those 21 samples. Concentrations in the 20 samples varied from 0.22-1.05 ng/ml with a mean value of 0.51 ng/ml.

Adolescent↗
PubMed1990

A phase II study of diaziquone in children with recurrent or progressive solid tumors. Report from the Childrens Cancer Study Group.

Seventy-two children with recurrent, progressive, or metastatic lymphomas and other solid tumors, exclusive of primary central nervous system (CNS) tumors, were treated with aziridinylbenzoquinone (AZQ, diaziquone) at 9 mg/m2/day by 30-min intravenous infusion for 5 days every 3 weeks. Fifty-four patients were evaluable for response. Three partial responses occurred, two in patients with recurrent Hodgkin's disease and one in a patient with intraocular retinoblastoma. Sufficient numbers of patients with osteosarcoma, neuroblastoma, and Wilms' tumor were evaluable to demonstrate inactivity of this dosing regimen in these tumor types. Numbers of evaluable patients for other tumor types were insufficient to conclusively demonstrate inactivity. Myelosuppression, which was profound and prolonged, was observed. As administered in this study, AZQ has marginal activity and severe myelotoxicity in children with solid tumors.

Adolescent↗
PubMed1988

Phase I/II study of bisantrene in childhood cancer: a report from the Childrens Cancer Study Group.

A phase I/II study of bisantrene using a 3-week schedule was undertaken in 171 children with refractory leukemias and solid tumors. The doses ranged from 190 to 430 mg/m2. The maximum tolerated dose for children with solid tumors and acute leukemias was 280 mg/m2 and 360 mg/m2 every 3 weeks, respectively. The dose limiting toxicities were hepatic and hematologic. One patient with ALL achieved a complete remission and partial responses were observed in three patients with soft-tissue sarcomas. The data indicate that bisantrene, at the doses and schedule used in this study, has limited antitumor activity in pretreated children with cancer.

Adolescent↗
PubMed1987

Use of unequal allocation in survival trials.

In some two-treatment clinical survival trials, a large imbalance in the allocation of patients to treatments will result in approximately the same power for the logrank test as equal allocation. This fact can be used in some trials to reduce significantly the number of patients allocated to a potentially inferior treatment.

Biometry↗
PubMed1987

Chronic effects of fractionated renal irradiation on the pharmacokinetics of intravenous methotrexate.

the chronic effects of renal irradiation on the pharmacology of methotrexate was studied in a rat model. Unanesthetized rats received 2 doses of bilateral fractionated kidney irradiation (16.2 Gy or 19.8 Gy in 9 fractions). Alterations in renal function were first seen at 3 months in the 19.8 Gy group and 12 months in the 16.2 Gy groups. Life table analysis showed a shift in the survival curve of about 3 months between the 2 radiation doses. The pharmacokinetics of i.v. methotrexate showed an increase in the area under the plasma curve beginning at 9 months in the 19.8 Gy group and at 15 months in the 16.2 Gy group. The volume of distribution of methotrexate was smaller in the irradiated rats than in unirradiated controls. Multiple linear regression models showed significant correlations between parameters of methotrexate clearance and certain renal function tests. Nevertheless, no set of renal function tests consistently predicted alteration in methotrexate clearance in the 2 radiation groups. Furthermore, time after irradiation remained a highly significant variable indicating that renal irradiation causes time dependent change in methotrexate pharmacokinetics that can not be accounted for by the usual tests of renal function.

Animals↗
PubMed1987

The effects of moderate physical activity on menstrual cycle patterns in adolescence: implications for breast cancer prevention.

Girls who engage in strenuous physical activity are often amenorrheic and have recently been reported to be at a reduced risk of breast cancer. To determine whether moderate amounts of exercise affect menstrual cycle patterns and ovulatory frequency in young postmenarcheal girls, the menstrual cycles and physical activity patterns of 168 high school girls were monitored for a 6 month period. Anovulatory cycles were associated with later age at menarche, fewer elapsed years since menarche and greater levels of energy expended per week in physical activity. After adjusting for age at menarche and years since menarche, there was a significant dose-related trend in the risk of anovular menstrual cycles associated with increasing levels of physical activity (1-sided P = 0.03). Major determinants of average cycle length were weekly average energy expenditure (less than or equal to 750 kcal wk-1 associated with cycles that were on average 2.4 days longer), age at menarche (an increase of 0.7 days per year of age) and race (Asians having cycles about 1.9 days longer than Caucasians). Because a major determinant of breast cancer risk may be the cumulative number of ovulatory cycles, these data suggest that regular participation in moderate physical activity, by reducing the frequency of ovulatory cycles in adolescence, may provide an opportunity for the primary prevention of breast cancer.

Adolescent↗
PubMed1986

Serum beta-2 microglobulin levels in homosexual men with AIDS and with persistent, generalized lymphadenopathy.

In order to investigate the nature of the immune disorders associated with the acquired immune deficiency syndrome (AIDS) and the AIDS-related condition of persistent, generalized lymphadenopathy (PGL), serum beta-2 microglobulin (beta 2-M) levels were determined in patients with AIDS and PGL and in asymptomatic homosexual and heterosexual controls. Sixteen of 20 (80%) patients with AIDS exhibited elevated beta 2-M levels. In contrast, 20 of 44 (45%) patients with PGL, 4 of 20 (20%) asymptomatic homosexuals, and only 3 of 46 (7%) heterosexuals had increased serum beta 2-M levels (P less than 0.001). When considering mean levels of beta 2-M, only the asymptomatic control individuals had normal values. AIDS patients had significantly higher mean beta 2-M levels when compared to all other groups (P less than 0.05). The mean level for PGL patients was greater than that in the homosexual and heterosexual controls (P less than 0.05). No relationship was found between presence of antibody to human T-lymphotropic retrovirus (HTLV-III) and beta 2-M levels in the patients with AIDS or PGL. The authors conclude that beta 2-M is elevated in patients with AIDS and PGL, suggesting an increased turnover of a certain subpopulation of lymphocytes in these patients. Beta 2-M levels also appear to parallel disease activity, as well as immune dysfunction, with the greatest elevation occurring in patients with AIDS, followed by those with PGL, and asymptomatic homosexuals. Beta 2-M levels may be a useful confirmatory marker in AIDS and its related disorders.

Acquired Immunodeficiency Syndrome↗
PubMed1986

Comparison of metoclopramide and metoclopramide plus dexamethasone for complete protection from cisplatinum-induced emesis.

Metoclopramide was compared to a metoclopramide plus dexamethasone combination in patients receiving high-dose cisplatinum. Metoclopramide 2 mg/kg intravenously was given every 2 hours for 4 doses during two consecutive chemotherapy cycles. A randomized double-blind crossover was used with placebo or dexamethasone 20 mg given intravenously before the first metoclopramide dose. Thirty-six patients completed both study arms. There was no difference in mean vomiting episodes (1.92 for metoclopramide versus 1.33 for the combination, p = 0.20). However complete protection (no vomiting episodes) was achieved in 56% receiving the combination but only 36% receiving metoclopramide alone (p less than 0.08). No significant difference in toxicity or patient preference was noted. Late nausea or vomiting lasting 2 to 7 days appeared in 26% of cycles and was associated with but not completely explained by a greater number of acute vomiting episodes. Combination antiemetic therapy can achieve a higher incidence of complete protection from cisplatinum-induced vomiting. However, late nausea and vomiting may require modification of present regimens.

Adult↗
PubMed1985

Do regular ovulatory cycles increase breast cancer risk?

The "estrogen window hypothesis" of the etiology of breast cancer proposes that unopposed estrogen stimulation is the most favorable state for tumor induction and that normal postovulation progesterone secretion reduces susceptibility. The authors believe that epidemiologic and experimental studies suggest rather that the opposite is true, i.e., that breast cancer risk is directly related to the cumulative number of regular ovulatory cycles. Unlike the endometrium, breast tissue mitotic activity is enhanced in the luteal phase of the menstrual cycle. Regular vigorous physical activity is one method of reducing the frequency of ovulatory cycles, and such exercise could markedly reduce a woman's lifetime risk of developing breast cancer.

Adolescent↗
PubMed1984

Age at natural menopause and breast cancer risk: the effect of errors in recall.

Many case-control studies of breast cancer have reported estimates of relative risk of approximately 1.9 for menopause after 54 years of age when compared with menopause before 45 years of age. These estimates may be biased towards unity because of errors in recall of a woman's age at menopause. This paper investigates the magnitude of error associated with self-classification of women into categories of age at menopause by using personal interview and medical record data of 67 control women from a case-control study of breast cancer conducted in two retirement communities near Los Angeles in 1977-1978. These estimates of "misclassification" error are combined with various sets of "true" relative risks to yield "observable" relative risks. It is demonstrated that the relative risks associated with various age at menopause groups are likely to range from 1-3.4 rather than 1-1.9 as has been reported in the literature.

Adult↗