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J B Perkins

Publications and source records attributed to J B Perkins.

At least 19 recordsLinked to original sources
PubMed1998

Defining the role of novel high-dose chemotherapy regimens for the treatment of high-risk breast cancer.

We have explored several novel high-dose combinations in an attempt to increase antitumor activity while decreasing treatment-related toxicity. From October 1989 through June 1997, we performed phase I/II dose-escalation trials exploring novel high-dose regimens including ifosfamide/carboplatin/etoposide, mitoxantrone/thiotepa, and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ)/mitoxantrone/thiotepa. We have also evaluated busulfan/cyclophosphamide and cyclophosphamide/thiotepa/carboplatin in phase II trials. Three hundred ninety-three patients have been treated in these trials and followed for a minimum of 3 months. Event-free survival (including relapses and treatment-related mortality; +/-SE) at 3 years by stage and chemosensitivity is as follows: stage II, four to nine positive nodes (n=16), 52%+/-17%; stage II, greater than nine nodes (n=30), 46%+/-11%; stage III (n=59), 50%+/-8%; inflammatory stage III (n=15), 27%+/-17%; stage IV, anthracycline responsive (n=69), 19%+/-5%; stage IV, anthracycline refractory but responsive to salvage therapy with ifosfamide, carboplatin, and etoposide or paclitaxel (n=53), 12%+/-6%; stage IV, refractory (n=128), 5%+/-2%; and stage IV, not evaluable for response (n=23), 10%+/-8%. Treatment-related mortality was 4% for both phase I and II studies involving stage II breast cancer patients, 5% for stage III breast cancer, 15% for inflammatory breast cancer, and 18% for all stage IV breast cancers, responsive and refractory. We conclude that high-dose therapy for the treatment of high-risk early stage breast cancer or metastatic breast cancer results in durable remissions. Chemosensitivity to induction regimens remains the most important prognostic indicator, although long-term survival has been seen even in patients with highly refractory disease. Further studies are necessary to define optimal high-dose strategies based on stage and chemosensitivity of disease.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

High-dose chemotherapy and autologous peripheral blood stem cell transplantation in patients with multiple myeloma and renal insufficiency.

Six patients with multiple myeloma and chronic renal insufficiency (serum creatinine >3.0 mg/dl), including four on dialysis, received high-dose busulfan and cyclophosphamide (BUCY) followed by autologous peripheral stem cell transplantation. Peripheral blood stem cells were collected after priming with cyclophosphamide, etoposide and G-CSF. Patterns of engraftment and toxicities were not apparently different from those seen in myeloma patients with normal renal function. There was one toxicity-related death, resulting from a massive spontaneous subdural hematoma. One patient died of disease progression 6 months after transplant, while the remaining four patients are alive and free of myeloma progression 6 to 39 months after high-dose therapy. Two of these patients have remained in complete remission for 28 and 39 months. Our experience suggests that high-dose therapy with BUCY and autologous peripheral blood stem cell rescue is feasible in patients with multiple myeloma and renal failure.

Adult↗
PubMed1997

A sampling and analytical method for the simultaneous determination of multiple organonitrogen pesticides in air.

An air sampling and analytical method was developed for organonitrogen pesticides using a combined filter and XAD-2 sorbent sampler and high performance liquid chromatography-ultraviolet detection. The method was evaluated for 14 organonitrogen pesticides by National Institute for Occupational Safety and Health evaluation guidelines and procedures. Evaluation experiments addressed limits of detection and quantitation, analytical recovery, sampler capacity, sample stability, and precision and bias over a range of 12 to 240 micrograms per sample. Samples were stable when stored for up to 30 days under either ambient or refrigerated conditions. Based on the finding of this work, 10 of the 14 compounds studied (aldicarb, captan, carbaryl, carbofuran, chlorpropham, diuron, formetanate, methiocarb, oxamyl, propham) can be successfully determined simultaneously using one method with an accuracy of better than +/- 25% of the true value with 95% confidence. Two other compounds (carbendazim/benomyl, methomyl) can be measured with the same accuracy over a more limited concentration range. The remaining two compounds (propoxur, thiobencarb) may meet this criterion, but additional samples would need to be included in the data analysis. With the current data, these two compounds can be determined with an accuracy of better than +/- 27% of the true value with 95% confidence.

Agricultural Workers' Diseases↗
PubMed1997

Nephrotoxicity of high-dose ifosfamide/carboplatin/etoposide in adults undergoing autologous stem cell transplantation.

The objective of this study was to evaluate nephrotoxicity in adult patients treated with high-dose ifosfamide, carboplatin, and etoposide followed by autologous stem cell transplantation. We conducted a retrospective analysis of clinical and laboratory data from 131 patients with various malignancies who received treatment with escalating doses of ifosfamide, carboplatin, and etoposide followed by autologous stem cell transplantation as part of a phase I/II therapeutic trial. Abnormalities in glomerular filtration were evaluated by measuring peak creatinine levels and tubular dysfunction by the lowest recorded serum levels of potassium, magnesium, and bicarbonate, at different time periods after administration of ifosfamide, carboplatin, and etoposide, and after autologous stem cell transplantation. For the entire group of 131 patients, peak creatinine levels were > 1.5 mg/dL but < 3.0 mg/dL in 37% and levels were > 3.0 mg/dL in 11% at some time during their hospital stay. At the time of discharge, creatinine levels were 1.6 mg/dL to 3.0 mg/dL in 25% of patients and were > 3 mg/dL in 5%. Immediately after high-dose therapy, peak creatinine levels were significantly higher in patients receiving higher doses of ifosfamide compared to those receiving lower doses (P < 0.00001) and those receiving intermediate doses (P < 0.005). There was a dramatic decrease in serum bicarbonate, potassium, and magnesium levels immediately after chemotherapy, and they remained significantly decreased throughout the patient's hospital stay, despite massive replacement efforts (P ranging between < 0.008 and < 0.001). This is the largest adult population study documenting the incidence and severity of ifosfamide/carboplatin/etoposide-associated acute nephrotoxicity. Renal dysfunction was dose related and reversible in the majority of patients.

Adolescent↗
PubMed1996

Cloning, sequencing, and characterization of the Bacillus subtilis biotin biosynthetic operon.

A 10-kb region of the Bacillus subtilis genome that contains genes involved in biotin-biosynthesis was cloned and sequenced. DNA sequence analysis indicated that B. subtilis contains homologs of the Escherichia coli and Bacillus sphaericus bioA, bioB, bioD, and bioF genes. These four genes and a homolog of the B. sphaericus bioW gene are arranged in a single operon in the order bioWAFDR and are followed by two additional genes, bioI and orf2. bioI and orf2 show no similarity to any other known biotin biosynthetic genes. The bioI gene encodes a protein with similarity to cytochrome P-450s and was able to complement mutations in either bioC or bioH of E. coli. Mutations in bioI caused B. subtilis to grow poorly in the absence of biotin. The bradytroph phenotype of bioI mutants was overcome by pimelic acid, suggesting that the product of bioI functions at a step prior to pimelic acid synthesis. The B. subtilis bio operon is preceded by a putative vegetative promoter sequence and contains just downstream a region of dyad symmetry with homology to the bio regulatory region of B. sphaericus. Analysis of a bioW-lacZ translational fusion indicated that expression of the biotin operon is regulated by biotin and the B. subtilis birA gene.

Bacillus subtilis↗
PubMed1996

Cloning and characterization of the metE gene encoding S-adenosylmethionine synthetase from Bacillus subtilis.

The metE gene, encoding S-adenosylmethionine synthetase (EC 2.5.1.6) from Bacillus subtilis, was cloned in two steps by normal and inverse PCR. The DNA sequence of the metE gene contains an open reading frame which encodes a 400-amino-acid sequence that is homologous to other known S-adenosylmethionine synthetases. The cloned gene complements the metE1 mutation and integrates at or near the chromosomal site of metE1. Expression of S-adenosylmethionine synthetase is reduced by only a factor of about 2 by exogenous methioinine. Overproduction of S-adenosylmethionine synthetase from a strong constitutive promoter leads to methionine auxotrophy in B. subtilis, suggesting that S-adenosylmethionine is a corepressor of methionine biosynthesis in B. subtilis, as others have already shown for Escherichia coli.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1996

Identification and characterization of transcripts from the biotin biosynthetic operon of Bacillus subtilis.

Northern (RNA) blot analysis of the Bacillus subtilis biotin operon, bioWAFDBIorf2, detected at least two steady-state polycistronic transcripts initiated from a putative vegetative (Pbio) promoter that precedes the operon, i.e., a full-length 7.2-kb transcript covering the entire operon and a more abundant 5.1-kb transcript covering just the first five genes of the operon. Biotin and the B. subtilis birA gene product regulated synthesis of the transcripts. Moreover, replacing the putative Pbio promoter and regulatory sequence with a constitutive SP01 phage promoter resulted in higher-level constitutive synthesis. Removal of a rho-independent terminator-like sequence located between the fifth (bioB) and sixth (bioI) genes prevented accumulation of the 5.1-kb transcript, suggesting that the putative terminator functions to limit expression of bioI, which is thought to be involved in an early step in biotin synthesis.

Bacillus subtilis↗
PubMed1996

Clinical significance of bone marrow metastases as detected using the polymerase chain reaction in patients with breast cancer undergoing high-dose chemotherapy and autologous bone marrow transplantation.

PURPOSE: The present study evaluates the clinical significance of detection of cytokeratin 19 (K19) in the bone marrow of patients with breast cancer undergoing high-dose chemotherapy (HDCT) and autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: We studied retrospectively cryopreserved bone marrow aspirates from 83 patients with high-risk stage II, III, and IV breast cancer obtained before bone marrow harvest but after induction chemotherapy. All samples were histologically negative for metastases. Polymerase chain reaction (PCR) for K19 was performed according to methods described previously and results were correlated with the probability of relapse following HDCT and ABMT. RESULTS: The incidence of occult metastases as defined by PCR for K19 message was 52% for 19 stage II, 57% for 14 stage III, and 82% for 50 stage IV patients (two-tailed P = .0075, chi 2 test). The probability of relapse at 3 years after ABMT was 32% and 94% for K19-positive stage II/III and stage IV patients, respectively, versus 10% and 14% for K19-negative stage II/III and stage IV patients, respectively. The difference was significant for stage IV patients (two-tailed P = .0002). CONCLUSION: It has been shown that PCR is a highly sensitive method to detect K19 message in the bone marrow. The incidence of K19 positivity in bone marrow increases significantly with advancing stage. In patients with breast cancer, especially metastatic breast cancer, undergoing HDCT and ABMT, the presence of K19 is associated with a poor prognosis.

Adult↗
PubMed1996

Analysis of dose-response relationships in the setting of high-dose ifosfamide, carboplatin, and etoposide and autologous hematopoietic stem cell transplantation: implications for the treatment of patients with advanced breast cancer.

Dose intensity appears to play a role in the treatment of breast cancer. Although many reports have been published regarding dose intensity using nonmyeloablative doses, little data have been presented in the setting of high-dose chemotherapy and autologous hematopoietic stem cell transplantation. The results of a retrospective review of a phase I/II trial evaluating the effect of escalating doses of ifosfamide/carboplatin/etoposide on survival of patients with locally advanced and metastatic breast cancer are discussed here. Patients were divided by ifosfamide dose: low dose (6,000 to 14,400 mg/m2) and high dose (17,100 to 24,000 mg/m2). Three-year event-free survival was no different between the two dose groups in patients with locally advanced disease (71% [low] v 56% [high]). In patients with metastatic disease, however, although the difference did not meet statistical significance, there did appear to be a trend toward improved survival with increased dose intensity (8% [low] v 25% [high]). Our results show that dose intensity may be important in inflammatory and metastatic breast cancer. This trend was seen in both anthracycline-responsive and -refractory patients. While further study of dose intensity in this setting is warranted, dose-intensive high-dose therapy with autologous hematopoietic stem cell transplantation can be considered for patients with advanced breast cancer.

Adenocarcinoma↗
PubMed1996

Phase I-II study of high-dose busulfan and cyclophosphamide followed by autologous peripheral blood stem cell transplantation for hematological malignancies: toxicities and hematopoietic recovery.

In a phase I-II study, we evaluated toxicities, tolerability, pace of engraftment, and tumor responses to high-dose bulsulfan and cyclophosphamide followed by autologous peripheral blood stem cell transplantation in patients with hematological malignancies. We treated 51 patients with various hematological malignancies involving the bone marrow with busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) followed by reinfusion of autologous peripheral blood stem cells. Stem cells were previously collected during hematopoietic recovery after cyclophosphamide (100 mg/kg) and etoposide (600 mg/m2) followed by G-CSF (5 micrograms/kg/day). Neutrophil recovery (>0.5 x 10(9)/I) was rapid in the majority of patients (median 10 days after transplant, range 7-91 days), resulting in a low number of days with severe neutropenia (median 7 days, range 5-85 days) and with fever (median 5 days, range 1-13 days). Platelet recovery, however, was delayed in 60% of patients. There was one acute transplant-related death (2%). Four patients died of late, presumed infections, pulmonary complications (interstitial pneumonia). Tumor responses were documented in a significant proportion of these patients with high-risk hematological malignancies. We conclude that peripheral blood stem cell transplantation results in rapid recovery of neutrophils but variable recovery of platelets after high-dose busulfan and cyclophosphamide, when stem cells are harvested following priming with cyclophosphamide/etoposide and G-CSF. The regimen is well-tolerated with limited non-hematological toxicities and transplant-related mortality. While significant tumor responses were documented in this trial, the ultimate efficacy of the regimen needs to be further defined.

Adult↗
PubMed1995

Maximum-tolerated doses of ifosfamide, carboplatin, and etoposide given over 6 days followed by autologous stem-cell rescue: toxicity profile.

PURPOSE: A phase I dose-escalation study of ifosfamide, carboplatin, and etoposide (ICE) with autologous stem-cell rescue (ASCR) was conducted to determine the maximum-tolerated dose (MTD) of ICE given over 6 days. PATIENTS AND METHODS: One hundred fifty-four patients with a variety of poor-prognosis malignancies received escalating doses of ifosfamide 6,000 to 24,000 mg/m2, carboplatin 1,200 to 2,100 mg/m2, and etoposide 1,800 to 3,000 mg/m2 divided over 6 days. Mesna was administered in a dose equal to ifosfamide. ASCR was performed 48 hours after the completion of ICE. The source of stem cells was bone marrow (BM) in patients without BM micrometastases and peripheral-blood stem cells (PBSC) in patients with BM micrometastases. Patients were evaluated for hematologic and nonhematologic toxicities, as well as response to therapy. RESULTS: The MTD of the ICE regimen is 20,100 mg/m2 of ifosfamide, 1,800 mg/m2 of carboplatin, and 3,000 mg/m2 of etoposide. The dose-limiting toxicities of ICE were CNS toxicity and acute renal failure. Additionally, reversible elevations of serum creatinine levels were noted in 29% of patients treated at the upper dose levels. Forty-six patients were treated at the MTD. Severe, reversible mucositis and enteritis were the major nonhematologic toxicities seen at the MTD (78% and 33%, respectively). The overall mortality rate was 8% for all dose levels (4% at the MTD). At the MTD, the median times to an absolute neutrophil count > or = 0.5 x 10(9)/L, to a platelet count > or = 20 x 10(9)/L, and to discharge were 18, 22, and 24 days, respectively. The overall response rate was 40% for 77 patients with assessable disease at the time of treatment. CONCLUSION: ICE is well tolerated, with acceptable hematopoietic side effects and predictable organ toxicity.

Acute Disease↗
PubMed1995

Ifosfamide/carboplatin/etoposide chemotherapy for metastatic breast cancer with or without autologous hematopoietic stem cell transplantation: evaluation of dose-response relationships.

We conducted a phase I/II trial to investigate the activity of ifosfamide/carboplatin/etoposide given over 2 or 3 days (mini-ICE) to patients with anthracycline-refractory or recurrent metastatic breast cancer. In a companion phase I/II dose-escalation study, those patients with responsive or stable disease following either anthracycline-based chemotherapy or mini-ICE and with adequate organ function were then considered eligible for treatment with a 6-day ICE regimen (maxi-ICE) followed by autologous hematopoietic stem cell transplantation. Our results showed that the ICE regimen has activity against anthracycline-refractory metastatic breast cancer. A dose-response relationship was not apparent with the mini-ICE regimen; however, among patients receiving maxi-ICE, a dose-response relationship was suggested in those patients responding to anthracycline-based chemotherapy.

Antibiotics, Antineoplastic↗
PubMed1994

High-dose ifosfamide/carboplatin/etoposide: maximum tolerable doses, toxicities, and hematopoietic recovery after autologous stem cell reinfusion.

We treated 115 patients in a phase I/II dose-escalation study of ifosfamide/carboplatin/etoposide (ICE) followed by autologous stem cell rescue. Patients treated had a variety of diagnoses, including breast cancer (high-risk stage II disease with eight or more positive nodes, stage III disease, and responsive metastatic disease), non-Hodgkin's lymphoma, Hodgkin's disease, acute leukemia in first remission, and various solid tumors that were responsive to induction therapy. Patients received autologous bone marrow stem cells or peripheral blood stem cells primed by one of several methods. The maximum tolerated dose of ICE was determined to be ifosfamide 20,100 mg/m2, carboplatin 1,800 mg/m2, and etoposide 3,000 mg/m2 when administered as a 6-day regimen. The dose-limiting toxicities included acute renal failure, severe central nervous system toxicity, and "leaky capillary syndrome" with hypoalbuminemia, profound fluid overload, and pulmonary insufficiency. Analysis of hematologic recovery based on stem cell source and influence of hematopoietic growth factor administration was undertaken. Hematopoietic growth factor use significantly reduced neutrophil engraftment time for patients receiving bone marrow stem cells, with evidence of earlier recovery times for patients receiving granulocyte colony-stimulating factor compared with granulocyte-macrophage colony-stimulating factor. Neutrophil recovery times varied based on the source of stem cells used, with the earliest engraftment times seen for patients receiving peripheral blood stem cells primed with cyclophosphamide and granulocyte colony-stimulating factor. Platelet recovery times were not statistically different for any of the subsets. In conclusion, the maximum tolerated dose of ICE has been defined, and the source of stem cells and the use of hematopoietic growth factors influence hematopoietic recovery.

Adolescent↗
PubMed1993

Optimizing high-dose therapy using pharmacokinetic principles.

The oncologic literature of the past decade contains numerous articles supporting the concept of "dose intensity." The hypothesis that greater intensity of effective drug therapy can result in higher cure rates is supported by the results obtained in bone marrow transplantation for leukemia, lymphoma, and, possibly, breast carcinoma. Stem cell infusion overcomes the first level of the dose-limiting toxicities, ie, bone marrow suppression. This predictable toxicity develops in all patients. Second organ toxicities, such as renal, hepatic, or cardiopulmonary toxicity, occur in a less predictable manner. This variation in individual patient tolerance may be related to wide variations in drug concentration between patients while receiving the same dose. This interpatient variability has been well described for many oncologic agents, but is not unique to oncologic therapy. Important but incompletely defined relationships of importance to high-dose therapy include (1) the relationship of drug dose to concentration within patient groups and for the individual patient and (2) the relationship of drug concentration, or other related parameter such as area under the concentration versus time curve, to toxicity and outcome. Assuming such relationships can be defined, the value of using improved methods to select drug doses for an individual patient to achieve therapeutic goals needs to be explored. The purpose is to optimize therapy. In the bone marrow transplantation setting, the ideal is to provide the greatest drug exposure without undo risk of life-threatening second organ toxicity. To solve these problems, we need models that predict and allow us to control therapy in a much more precise manner than is currently possible. This review examines the concept of dose intensity, defines this concept in terms of plasma drug concentrations, and reviews methods that can aid the control of therapy in the individual patient. The potential importance of this methodology to the individual patient is discussed.

Antineoplastic Agents↗
PubMed1993

Two novel high-dose treatment regimens for metastatic breast cancer--ifosfamide, carboplatin, plus etoposide and mitoxantrone plus thiotepa: outcomes and toxicities.

This report describes the results of two phase I/II dose escalation trials for the treatment of metastatic breast cancer. Successive groups of patients with metastatic breast cancer responsive to induction therapy following standard doses of chemotherapy were treated with escalating doses of ifosfamide (6,000 to 24,000 mg/m2), carboplatin (1,200 to 2,100 mg/m2), and etoposide (1,800 to 3,000 mg/m2) followed by autologous stem cell rescue. The maximum tolerated doses of these drugs were defined as ifosfamide 20,100 mg/m2, carboplatin 1,800 mg/m2, and etoposide 3,000 mg/m2. Major nonhematologic toxicity consisted of mucositis and enteritis, and the dose-limiting toxicities were central nervous system toxicity and acute renal failure. The overall treatment-related mortality rate was 4%. The event-free survival rate at 500 days for these patients was 31%. Patients with metastatic breast cancer refractory to all standard dose therapy were treated with escalating doses of mitoxantrone (45 to 105 mg/m2) and thiotepa (900 to 1,350 mg/m2) followed by autologous stem cell rescue. The maximum tolerated doses of these drugs were defined as mitoxantrone 90 mg/m2 and thiotepa 1,200 mg/m2 with mucositis and enteritis as the major nonhematologic toxicities and delayed myelosuppression as the dose-limiting toxicity. Twelve percent of the patients remain event free at 500 days and the treatment-related mortality rate for this group of heavily pretreated patients was 17%. These data suggest that patients with metastatic breast cancer may benefit from high-dose therapy and that treatment-related toxicity is tolerable.

Adult↗