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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.

Preparative regimens used prior to bone marrow transplantation (BMT) in patients with malignancies must mediate engraftment and eradicate malignant cells without producing significant extramedullary toxicities. The first agents to be tested in BMT preparative regimens, total body irradiation (TBI) and cyclophosphamide (Cy), were ineffective as single agents, but resulted in long-term disease-free survival in some leukemic patients when combined. However, Cy/TBI regimens are associated with significant acute and chronic toxicities as well as technical constraints involving the administration of radiation. Accordingly, a nonradiation-based regimen consisting of Cy and busulfan (Bu) was developed. Regimens using either a 4-day course (BuCy4) or a 2-day course (BuCy2) of Cy have been shown to have significant antileukemic effects. In general, however, BuCy regimens do not appear to result in greater antileukemic activity or lower treatment-related toxicity than Cy/TBI regimens. New preparative regimens are currently being developed to lower the incidence of disease recurrence after BMT. One such regimen consists of BuCy plus etoposide. At our institution, we are currently testing the efficacy and toxicity of regimens in which cytarabine or diaziquone are administered in combination with Bu and Cy. It is hoped that these new preparative regimens will enhance the antileukemic effects of BMT without significantly increasing treatment-related toxicity.

Invasive aspergillosis continues to be a significant cause of morbidity and mortality in patients with prolonged neutropenia. We performed a phase I trial of escalating doses of aerosolized amphotericin B given by a face mask nebulizer system with a disposable bacterial exhale filter. Five, 10, 15, and 20 mg of drug were dissolved in sterile water and inhaled over 10 to 15 minutes twice daily. Tolerance was studied in 26 patients (18 transplant recipients, and 8 leukemia patients). No side effects were observed at any dose level. Prophylactic treatment ended for 14 patients (54%) when intravenous (IV) amphotericin B was begun empirically for antifungal coverage following fevers. Eleven patients (43%) continued inhaled amphotericin B until blood counts recovered. One patient was taken off study when she developed cardiogenic pulmonary edema. No patient developed clinically suspicious or pathologically documented infection with invasive aspergillosis. Prophylactic aerosolized amphotericin B is well tolerated at 5, 10, 15, and 20 mg twice daily dosing. In addition, prophylactic aerosolized amphotericin B does not appear to sensitize patients to the subsequent use of IV amphotericin B. Although this study suggests that prophylactic inhaled amphotericin B is well tolerated and effective, a large scale controlled trial is needed.

We report a patient who underwent two allogeneic bone marrow transplants for chronic myelogenous leukemia, initially in 1984 and again after relapse in 1990, who developed an identical pulmonary syndrome at a similar interval following each transplant. The patient presented with a non-productive cough, bilateral inspiratory crackles, and multiple patchy infiltrates on chest X-ray. Pulmonary function testing revealed a restrictive abnormality but no obstructive defects. The appearance of this pulmonary disorder after each transplant coincided with the development of chronic graft-versus-host disease. In both instances, this pulmonary syndrome completely reversed with corticosteroid therapy. The patient's chest computed tomographic scan and lung biopsy specimens were consistent with the diagnosis of bronchiolitis obliterans with organizing pneumonia (BOOP). While bronchiolitis obliterans has been reported following allogeneic transplant, BOOP has not previously been reported in this setting.

Locally advanced lung cancer carries a poor prognosis, and its treatment continues to challenge medical, radiation, and surgical oncologists. While systemic chemotherapy has improved the survival of patients with small cell lung cancer (SCLC), the role and timing of thoracic radiotherapy has not been clearly defined. The roles of chemotherapy and radiotherapy appear to be reversed in the treatment of locally advanced non-small cell lung cancer (NSCLC). The routine use of thoracic radiotherapy has been shown to improve local control after surgery without affecting survival, due to a high incidence of distant metastases. This contrasts with the marginal survival benefit seen with chemotherapy in NSCLC. Nevertheless, the results of recent clinical trials in both SCLC and NSCLC are encouraging and support continued investigation. These studies and the results of recent pilot studies suggest that a closer integration of chemotherapy and radiotherapy (concomitant chemoradiotherapy) may be necessary for further improvement in outcome. This review will present the results of recent studies in systemic therapy of lung cancer and the evidence supporting concomitant chemoradiotherapeutic treatment of this disease.

Eukaryotic cells can display resistance to a wide range of natural-product chemotheraputic agents by the expression of P-glycoprotein (pgp), a putative plasma membrane transporter that is thought to mediate the efflux of these agents from cells. We have identified, in cells selected for multidrug resistance with actinomycin D, a mutant form of pgp that contains two amino acid substitutions within the putative sixth transmembrane domain. In transfection experiments, this altered pgp confers a cross-resistance phenotype that is altered significantly from that conferred by the normal protein, displaying maximal resistance to actinomycin D. These results strongly implicate the sixth transmembrane domain in the mechanism of pgp drug recognition and efflux. Moreover, they indicate a close functional homology between pgp and the cystic fibrosis transmembrane regulator in which the sixth transmembrane domain has also been shown to influence substrate specificity.

In both animal models and human studies in leukemia, residual disease on day 8 following myelosuppressive therapy is in a proliferative phase and therefore may be sensitive to the S-phase specific drug cytarabine. Based on this concept, 17 patients with refractory or relapsed leukemia or lymphoma undergoing either autologous or allogeneic bone marrow transplantation (BMT) were treated on a Phase I protocol using high doses of busulfan (16 mg/kg, days -10, -9, -8, -7) and cyclophosphamide (120 mg/kg, days -6, -5) followed by escalating doses of a 48-h continuous infusion of cytarabine (starting dose 1000 mg/m2/48 h, days -3, -2). Ten patients received autologous transplants (two with Hodgkin's disease, seven with non-Hodgkin's lymphoma, one with chronic myelogenous leukemia (CML) in blast phase). Seven received allogeneic BMT (two with refractory acute myelocytic leukemia (AML), one with refractory acute lymphoblastic leukemia (ALL) undergoing a second BMT, one with Burkitt's-type leukemia, one with ALL in fifth relapse and two with CML in accelerated/blast phase). Two of these patients received a T cell-depleted haploidentical transplant. The maximum tolerated dose of cytarabine was 1500 mg/m2/48 h; a pulmonary syndrome including dyspnea, hypoxemia, and interstitial infiltrates which responded to aggressive diuresis was the dose limiting toxicity. Of the 10 patients who received cytarabine doses of 2000 or 2500 mg/m2/48 h, five patients developed adult respiratory distress syndrome (ARDS) with three patients requiring intubation; two recovered. Of the nine patients with lymphoma, seven responded with complete tumor clearance (CTC) with two patients tumor-free 13 and 15 months post-BMT, one remained refractory and one died too early to evaluate (TETE).(ABSTRACT TRUNCATED AT 250 WORDS)

The main objectives of concomitant chemoradiotherapy are to increase local tumor control, decrease the incidence of distant metastases, and improve survival. In addition, concomitant therapy may reduce long-term cancer therapy morbidity either by reducing the need for radical surgery or by permitting the use of lower radiation doses. This article briefly summarizes the rationale for concomitant chemoradiotherapy and summarizes the most recent clinical experience for selected solid tumors. In addition, recent data that suggest additive or synergistic interaction between radiation and certain biologic response modifiers such as tumor necrosis factor and interferon are reviewed.

In an effort to better understand the preferential resistance to actinomycin D displayed by the multidrug-resistant Chinese hamster lung cell line DC-3F/ADX, we have cloned from those cells a number of cDNAs representing p-glycoprotein gene transcripts. Of the 12 clones isolated, all represent pgp1 transcripts and one, pADX165, contains a 4304-base pair insert with an open reading frame encoding a 1276-amino acid protein that is the homolog of the mouse mdr3/mdr1a gene product. A domain by domain comparison of this protein with p-glycoproteins capable of supporting multidrug resistance, i.e. human mdr1, mouse mdr1/mdr1b, and mouse mdr3/mdr1a, shows that, in addition to the ATP binding sites, the second, fourth, and eleventh transmembrane domains and the four small intracellular loops, IC-1, IC-2, IC-4, and IC-5, are highly conserved and are therefore likely to be important for the maintenance of p-glycoprotein function. Of the remaining 11 cDNA clones, 9 were found to be truncated versions of pADX165. Two others, however, pADX185 and pADX124, contained internal deletions resulting in open reading frames capable of encoding lnovel forms of p-glycoprotein. S1 nuclease and RNase protection analysis demonstrated that these cDNAs represent transcripts present in a number of different multidrug-resistant Chinese hamster lung cell lines. Hence, both are considered to be splicing variants of the hamster pgp1 gene primary transcript.

Twenty-four consecutive cementless hip arthroplasties (13 autografts and 11 allografts) have been done in which large bone grafts were used to augment major acetabular deficiencies and have been followed for a minimum of 24 months with a mean of 34 and a maximum follow-up period of 55 months. The autograft augmentations were uniformly successful. Two fixation failures occurred in the allograft group. Considering the extreme deficiency in the acetabulae encountered and the absence of sufficient autograft material in this group of patients, the use of frozen allografts (although less successful in this series) seems justified. Graft resorption as determined by direct roentgenographic measurements was less than might be expected but may be a manifestation of the short-term follow-up period. Resorption, however, was greater in the allograft group and, when marked, was associated with fixation failure.

Several new and innovative techniques have recently been introduced that purport to increase the strength of polymethyl methacrylate bone cement. One of these concepts is the use of carbon and polymer fibers to form a cement composite. Bone cement composites usually 1% fiber, are very difficult to use clinically. The composite is very sticky and viscous, which precludes effective hand packing or the use of conventional delivery systems. A new delivery system for very viscous materials is presented and examples of in vitro application are shown.

This review discusses the role of computed tomography (CT) in the evaluation of extent of plantar soft tissue infection in the diabetic foot. CT abnormalities are correlated with conventional radiography, results of preoperative aspiration cultures, intraoperative assessment, and bone, gallium, and 111In-leukocyte scan findings. Plantar soft tissue disease respects compartmental boundaries in general, with transcompartmental spread possible along musculotendinous units that normally transgress the intervening fascial septae. CT correlates well with the extent of infection as determined by other modalities, but cannot precisely predict its proximal boundary due to gradual transition between unequivocally abnormal and normal tissue. CT may be useful in establishing an appropriate level for contemplated amputation and can detect extension of superficial diabetic foot infections at an earlier stage than existing clinical methods, potentially resulting in less extensive surgical procedures.

The construct of field dependence-independence (FDI) is a bipolar characterization of cognitive style and functioning that has achieved wide interest outside the field of dental education. Since dental educators lack effective preadmission predictors of clinical grades or performance, the authors examined two tests of FDI as potential new predictors. The Embedded Figures Test (EFT) is a recognized FDI descriptor test based on the ability to identify rapidly and accurately a series of simple geometric figures "embedded" in more complex figures; such performance is characteristic of the field-independent individual. Similarly, rapid and accurate performance on the Inverted Tracing Test (ITT) (mirror tracing of simple figures) may also be characteristic of the field-independent individual. Multiple regression analyses indicated that the EFT and ITT parameters correlated more closely with clinical grades that did Dental Admission Test (DAT) predictors. The results suggest that individuals who tend to be field-independent, rather than field-dependent may hav an advantage in the dental school's clinical curriculum.

Activation of the cellular oncogene c-N-ras has been frequently observed in DNA from leukemic cells in acute myeloid leukemia (AML). Ras gene activation sufficient to mediate in vitro transformation and rodent tumorigenesis usually results from point mutations and amino acid substitutions in the 12th or 61st codons. In AML and the related myelodysplastic syndromes, amino acid substitution at the 13th codon has been observed. An activated c-N-ras gene from a 45-year-old patient with AML was isolated by transfection analysis and subjected to molecular cloning and sequence analysis. A point mutation of the 12th codon (GGT to GAT) resulting in aspartic acid substitution for glycine was observed. In other neoplasms such as colon cancer, specific ras mutations occur predominantly (e.g., K-ras, codon 12). This predominance has been of demonstrable value in analyzing large cohorts for ras activation with techniques that are rapid and economical, such as oligonucleotide hybridization. It had previously been thought that such a predominance for activation of c-N-ras at codon 13 existed in AML; however, this study in concert with others underscores the importance of 12th codon c-N-ras mutations, along with 13th and 61st codon mutations in the molecular pathogenesis of AML. Guanylate to adenylate transition mutations are commonly observed in AML and may provide insight into potential environmental leukemogens. Addressing all commonly prevalent ras activating mutations bears impact in the future design of molecular surveys of the role of ras activation in leukemogenesis.

The rabbit tibia was used as a model to study the effects of metal sensitivity reactions on the healing of fractures. Animals were injected with nickel chloride in Freund's complete adjuvant to cause sensitivity, and fractures were stabilized with 316L stainless steel intramedullary rods and followed for 16 weeks. A control group received no injections. The response was evaluated biomechanically with torsional testing at sacrifice, radiologically by examining the roentgenograms for evidence of loosening, and histologically. The results demonstrated a slight decrease in strength, a moderate increase in resorption and a significant decrease in cellularity and new bone formation in the sensitive animals as compared to control. These results are consistent with a reaction of comparatively short duration.

We studied the rate of seroconversion to positivity for antibody to hepatitis B surface antigen (anti-HBs) after immunization with hepatitis B vaccine in a group of mentally retarded institutionalized patients. Eight hundred sixty-eight individuals were screened for seromarkers of hepatitis B infection (hepatitis B surface antigen and anti-HBs), and 287 seronegative patients were vaccinated with the recommended schedule of hepatitis B virus vaccine (20 micrograms IM at 0, 1, and 6 months). Overall, 59% of patients responded to vaccination with detectable anti-HBs. We found a high correlation of lack of response with both intragluteal injection and increasing age (p less than 0.0008), although the design of the study did not allow these factors to be analyzed separately. We conclude that buttock injection and advancing age may be risk factors for poor immunogenicity of the hepatitis B vaccine in mentally retarded populations.