PubMed Health⌕ Search

Biomedical subjects

R Gonin

Publications and source records attributed to R Gonin.

At least 37 records · Page 2Linked to original sources
PubMed1997

Reliability testing of the dermatology index of disease severity (DIDS). An index for staging the severity of cutaneous inflammatory disease.

OBJECTIVES: To describe a new severity of illness index for inflammatory skin disease called the Dermatology Index of Disease Severity (DIDS), and to show its preliminary use and reliability in staging disease in patients with psoriasis and dermatitis. DESIGN: Interobserver rating study using the DIDS with as many as 10 observers independently rating the same patient at a single point in time. SETTING: Ambulatory care clinics at an academic medical center with patients from various socioeconomic backgrounds. PATIENTS: Thirty-four patients with psoriasis and 15 patients with dermatitis were included in the study. MAIN OUTCOME MEASURES: The severity of illness for each patient was rated as 1 of 5 stages: 0, no evidence of clinical disease; I, limited disease; II, mild disease; III, moderate disease; and IV, severe disease. The degree of interobserver concordance was measured by the Cohen kappa statistic. RESULTS: All 5 stages were represented in the study of patients with psoriasis. The overall kappa statistic was 0.76, which is defined as substantial interobserver concordance. The use of the instrument in dermatitis showed good consensus in staging, where the kappa statistic was 0.41. CONCLUSION: We introduce an easy and efficient instrument for staging the severity of illness in inflammatory cutaneous diseases. The reliability of the DIDS is demonstrated in patients with psoriasis and in patients with dermatitis.

Adult↗
PubMed1996

Retrovirus-mediated gene transfer of B7-1 and MHC class II converts a poorly immunogenic neuroblastoma into a highly immunogenic one.

The T cell co-stimulatory molecule B7-1 was transduced into a poorly immunogenic murine neuroblastoma cell line (Neuro-2a, N-2a) alone or in combination with MHC class II genes to test the ability of these genes to stimulate antitumor immunity. N-2a cells transduced with B7-1 exhibited reduced tumorigenicity, whereas N-2a cells overexpressing both MHC class II (syngeneic, I-Ak) and B7-1 totally abrogated tumorigenicity. Rejection of I-Ak/B7-1 cells was dependent on both CD4+ and CD8+ T cells. The ability of both vaccines to induce protection against parental N-2a was temporally dependent on the time of secondary N-2a challenge. To investigate the immunity generated by N-2a/B7-1 and N-2a/I-Ak/B7-1 vaccines, we tested the ability of these modified cells to stimulate in vitro the proliferation of syngeneic splenocytes from naive mice. A significant increase in splenocyte proliferation was observed with N-2a/I-Ak/B7-1 cells compared to N-2a cells. We also determined that vaccination with N-2a/I-Ak/B7-1 cells was able to generate cytotoxic T cell responses to unmodified N-2a cells. The introduction of B7-1 and I-Ak into N-2a was able to convert a poorly immunogenic tumor to a highly immunogenic one; however, mice bearing large established unmodified tumors had little response to vaccination with N-2a/I-Ak/B7-1 cells. Our results emphasize the importance of tumor immunogenicity in the treatment of established tumors with MHC class II/B7-1 tumor cell vaccines.

Animals↗
PubMed1996

A phase II study of weekly oral methotrexate and zidovudine (AZT) in advanced adenocarcinoma of the pancreas and hepatocellular carcinoma.

From January 1992 through May 1993, 31 patients with adenocarcinoma of the pancreas or hepatocellular carcinoma were treated with weekly oral methotrexate (7.5 mg/M2 every 6 hours for 6 doses) and continuous oral AZT (200 mg four times daily). Patients were treated for a total of 6 months or until disease progression. The median age was 66 (range 44-79) and the median KPS was 80. No patient had received prior chemotherapy. Hematologic toxicity was severe with 50% of patients developing hemoglobins less than 8 gm/dl and 70% with granulocyte counts less than 1000 per mm3. One patient achieved a radiographic complete remission and 2 had stable disease. Two-thirds of patients progressed within 2 months of beginning therapy. The combination of methotrexate and AZT is an inactive regimen in pancreatic and hepatocellular carcinoma and is associated with considerable toxicity.

Adenocarcinoma↗
PubMed1996

Establishing equivalence between scaled measures of quality of life.

In this paper, methodologies which have been used in the pharmaceutical industry to demonstrate the equivalence of drug preparations, are applied to the measurement of quality of life (QOL). This approach is feasible when the generated data are measured on the same scale. Data from the quality of life instruments are transformed into interval scales by means of an appropriate scaling procedure. It is demonstrated that equivalence of QOL instruments is linked by a linear relationship between the QOL instruments Functional Assessment of Cancer Therapy (FACT) and the Functional Living Index-Cancer (FLIC). The linear relationship is derived using orthogonal least squares regression which takes into account that both measures are subject to error.

Activities of Daily Living↗
PubMed1996

Discordance in the histopathologic diagnosis of melanoma and melanocytic nevi between expert pathologists.

The reliability of a diagnostic test depends on the reproducibility of the result. Many clinical diagnostic tests can be quantified with established ranges and standard deviations. Other tests are more subjective, such as those that depend on analysis of a visual image with an increased possibility of variance in the result. To study this variance, the authors analyzed the performance of expert pathologists in the interpretation of cutaneous melanocytic tumors. A panel of expert pathologists was convened to review anatomic pathology specimens from melanocytic tumors. Each pathologist submitted five specimens, from which 37 were selected for review. Only one slide was used for each case. All specimens were interpreted by each pathologist without consultation with each other. In addition to standard diagnostic terms, each specimen was designated as benign, malignant, or indeterminate. Statistical analysis was used to determine the degree of concordance. The combined kappa statistic for the eight observers and three possible outcomes (benign, malignant, or indeterminate) was 0.50. A kappa statistic of this magnitude, is defined as being moderate. In 62% of the specimens, there was unanimous agreement or only one discordant designation. Thirty-eight percent had two or more discordant interpretations. No single pathologist had a disproportionate number of discordant designations. This study mimics the consultation practice of anatomic pathology and shows the variability and discordance in diagnostic language and designation of biological behavior. The results suggest the criteria for the diagnosis of melanomas and melanocytic nevi need to be refined and more consistently applied.

Analysis of Variance↗
PubMed1996

Predicting the risk of bacteremia in childen with fever and neutropenia.

PURPOSE: We sought to identify factors assessable at the time of admission for fever and neutropenia that predict bacteremia in children with cancer. PATIENTS AND METHODS: One hundred fifteen consecutive episodes of fever and absolute neutrophil count (ANC) less than 500/microliter in 72 children with cancer were studied prospectively to determine the risk of bacteremia using data assessable at the time of presentation. After exploratory analysis identified admission temperature and absolute monocyte count (AMoC) as the strongest predictive factors, recursive partitioning was used to determine cutpoints for these variables that resulted in discrimination between episodes associated with a lower or higher risk of bacteremia. RESULTS: There were 24 episodes of bacteremia (21% of episodes). Episodes were grouped using the cutpoints for AMoC and temperature: 17% were classified as low risk for bacteremia (AMoC > or = 100/microliter), 65% as intermediate risk (AMoC < 100/microliter and temperature < 39.0 degrees C), and 18% as high risk (AMoC < 100/microliter and temperature > or = 39.0 degrees C). No episodes classified as low risk were associated with bacteremia; 19% of intermediate-risk and 48% of high-risk episodes were associated with bacteremia. The odds ratio of bacteremia for the high-risk versus the intermediate-risk group is 4.4 (95% confidence interval, 1.6 to 12.9). The risk classification was validated using data from 57 different episodes of fever and neutropenia treated in the same hospital. CONCLUSION: Three levels of risk for bacteremia are defined using the AMoC and temperature at the time of admission for fever and neutropenia. Trials now should be conducted to test whether these factors may be used to assign some children to less intensive or outpatient antibiotic therapy at the time of presentation with fever and neutropenia.

Adolescent↗
PubMed1996

Positron emission tomography evaluation of residual radiographic abnormalities in postchemotherapy germ cell tumor patients.

PURPOSE: This study was performed to assess the ability of positron emission tomography (PET) to differentiate residual radiographic abnormalities in postchemotherapy nonseminomatous germ cell tumor (GCT) patients. MATERIALS AND METHODS: Thirty patients with nonseminomatous GCT were evaluated with PET scans before surgical resection of a residual mass or masses. Standardized uptake values (SUV) were calculated for the region of maximal 2-fluoro-2-deoxyglucose (FDG) uptake and compared with histologic findings. RESULTS: Eleven patients had necrosis/fibrosis in the resected specimen, 15 had teratoma, and four viable GCT. The median SUV for the necrosis/fibrosis group was 2.86, teratoma 3.07, and viable GCT 8.81. A significant association between SUV and histology was found when comparing viable GCT versus necrosis/fibrosis plus teratoma (P = .004). Patients with an SUV greater than 5 were 75 times more likely to have viable cancer than teratoma or necrosis/fibrosis (odds ratio; 95% confidence interval, 3.66 to 1,536). PET did not differentiate necrosis/fibrosis from teratoma. However, PET was able to differentiate viable GCT from residual necrosis/fibrosis or teratoma. CONCLUSION: PET-FDG imaging can be useful for detection of residual viable carcinoma following chemotherapy in nonseminomatous GCT patients with residual masses. It may be a valuable adjunct in the determination of which patients should undergo postchemotherapy resection.

Adolescent↗
PubMed1996

Histologic evaluation of preauricular and postauricular human skin after high-energy, short-pulse carbon dioxide laser.

BACKGROUND: Despite its growing use in dermatalogic surgery, the effects of high-energy, short-pulse carbon dioxide laser on human skin have not been well documented. OBJECTIVES: To study the histologic effects of this high-energy, short-pulse CO2 laser on human skin and to compare these changes with the effects of standard chemexfoliation procedures. OBSERVATIONS: Twenty-four hours after laser administration, there was extensive epidermal necrosis and coagulative change in the superficial papillary dermis. With increasing doses of laser energy, there was a statistically significant increase in the depth of dermal wounding (P<.001 for days 1 and 3, F-test). Reepithelialization occurred in most specimens by day 3. By day 90, most specimens showed a subepidermal dermal repair zone consisting of compact new collagen fibers overlying collagen with evidence of solar elastosis. CONCLUSION: This high-energy, short-pulse CO2 laser produces morphologic changes similar to those seen with medium-depth chemical peels. This laser can ablate skin precisely and bloodlessly with little interference in the wound healing process, suggesting that it may serve as an alternative treatment for photoaged skin.

Analysis of Variance↗
PubMed1996

Minimizing graft rejection in allogeneic T cell-depleted bone marrow transplantation.

Between October 1991 and May 1994, 42 patients were treated with cyclophosphamide, thiotepa, and total body irradiation followed by an allogeneic transplantation of marrow depleted of T cells with soybean agglutinin and E-rosetting. Patients included in this study had acute myelogenous leukemia (13), chronic myelogenous leukemia (12), acute lymphocytic leukemia (nine), Hodgkin's disease or non-Hodgkin's lymphoma (four), multiple myeloma (three), or myelodysplastic syndrome (one). The mean age was 34 (range 8 to 51 years). Nineteen patients had a matched sibling donor and 18 received marrow from 6/6 matched unrelated donors while five received transplants from unrelated donors disparate at one DR locus (5/6 match). Time to granulocyte engraftment (AGC > or = 500/mm3) occurred at a mean of 16.5 days for related and 11.4 days for unrelated transplant recipients, and was related to the increased use of G-CSF in the unrelated population. There was no correlation with number of mononuclear cells, T cells, or CD34-positive cells infused, the rate of engraftment or the incidence of transplant complications. Multivariate analysis determined that G-CSF administration and a diagnosis other than ALL were the only factors associated with a faster rate of engraftment. Patients receiving unrelated donor transplants, those with ALL, or those who had a low T cell number infused (< or = 8.0 x 10(3) cells/kg) experienced delayed hospital discharge. The regimen resulted in excellent rates of engraftment (95.2%) with only one failure to engraft and one graft rejection. The incidence of grade III-IV acute graft-versus-host disease was 0% with sibling and 26.1% with unrelated donors. There were no cases of veno-occlusive disease. Fifty percent of patients are alive with a mean follow-up of 26.4 months. We conclude that this regimen is well tolerated and results in excellent engraftment with a low incidence of severe graft-versus-host disease and few therapy-related toxicities.

Adolescent↗
PubMed1995

Interferon-inducible protein 10 and macrophage inflammatory protein-1 alpha inhibit growth factor stimulation of Raf-1 kinase activity and protein synthesis in a human growth factor-dependent hematopoietic cell line.

Stimulatory cytokines, including granulocyte-macrophage colony-stimulating factor (GM-CSF) and steel factor (SLF), act in a synergistic manner to stimulate the growth of hematopoietic progenitor cells, an effect also demonstrated for the growth factor-dependent human hematopoietic cell line MO7e. While little is known about the mechanisms responsible for mediating synergistic interactions of cytokines, Raf-1, a component of the MAP kinase signaling pathway, is thought to play a role in the stimulatory response evoked by several cytokines, including SLF and GM-CSF. Interferon-inducible protein-10 (IP-10) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) are members of the chemokine family of suppressive cytokines. Prior exposure of hematopoietic cells to chemokines, including IP-10 and MIP-1 alpha, inhibits the synergistic action of growth factors on stimulating cell proliferation. We report that treatment of MO7e cells with the combination of GM-CSF and SLF directly stimulates statistically significant synergistic increases in the phosphorylation and activation of Raf-1 kinase, and in cellular protein synthesis levels. Pretreatment of MO7e cells with IP-10 or MIP-1 alpha blocked synergistic growth factor action, resulting in statistically significant suppression of cell proliferation, protein synthesis, and Raf-1 phosphorylation and activation. IP-10 and MIP-1 alpha treatment also evoked significant increases in intracellular cAMP levels. Pretreatment of cells with agents which serve to raise intracellular cAMP levels, or with cAMP analogs inhibited the synergistic actions of GM-CSF and SLF in a manner similar to IP-10 and MIP-1 alpha. In addition, treatment of cells with a potent inhibitor of cAMP-dependent protein kinase A blocked the suppressive action of MIP-1 alpha and IP-10 on Raf-1 kinase activity and on MO7e cell proliferation. The ability of IP-10 and MIP-1 alpha to antagonize the synergistic action of GM-CSF and SLF appears to involve inactivation of Raf-1 and the down-regulation of protein synthesis. Our findings suggest that both MIP-1 alpha and IP-10 mediate their suppressive effects in MO7e cells by stimulating increases in cellular cAMP levels and activating protein kinase A, a mechanism we believe to be unique to these chemokines and not one applied to all growth suppressive members of the chemokine superfamily (for example, interleukin 8 and platelet factor 4).

Cell Line↗
PubMed1995

A phase II trial of subcutaneously administered recombinant human interleukin-2 in patients with relapsed/refractory thymoma.

The thymus is the site of T-cell maturation and contains T-cell precursors that differentiate into cytolytic T lymphocytes (CTLs) in vitro in the presence of interleukin-2 (IL-2). Malignant thymoma is often associated with a lymphocytic infiltration of these precursors. The antitumor effects of IL-2 are mediated in part by activated CTLs. Based on these considerations and anecdotal reports of its anti-tumor activity in thymoma, we conducted a Phase II trial of IL-2 in 14 patients with thymoma. IL-2 was administered s.c. at a dose of 12 x 10(6) IU/m2/day for 5 days for 4 weeks followed by a 2-week rest period. Patients were evaluated for response after each 6-week cycle, and those tolerating therapy with no disease progression were eligible for a maximum of 4 cycles. All patients had failed prior standard chemotherapy and 12 had received prior radiotherapy. All 14 patients were evaluable for toxicity and response. The median number of cycles received was two. One patient was removed from study during cycle 1 because of severe bronchospasm. Five patients required dose reductions for grade 3 toxicity (anorexia, nausea, hyperbilirubinemia, elevated SGPT, and skin desquamation, one patient each). Two patients developed new symptoms of myasthenia gravis while in the study and were removed (one for progressive disease, one for steroid requirement). There were no objective responses. The one patient who required steroids for newly diagnosed myasthenia gravis had a minor response. We conclude that subcutaneously administered IL-2, although it has acceptable toxicity, has no significant clinical activity in previously treated patients with advanced thymoma.

Adult↗
PubMed1995

Cisplatin plus etoposide with and without ifosfamide in extensive small-cell lung cancer: a Hoosier Oncology Group study.

PURPOSE: To determine whether the addition of ifosfamide to cisplatin plus etoposide improves the response rate, time to disease progression, or overall survival in previously untreated patients with extensive-stage small-cell carcinoma of the lung (SCLC). PATIENTS AND METHODS: Patients with extensive SCLC with a Karnofsky performance score (KPS) > or = 50 and adequate renal function and bone marrow reserve were eligible. Patients with CNS metastases were eligible and received concurrent whole-brain radiotherapy. Patients were randomized to receive cisplatin (20 mg/m2) plus etoposide (100 mg/m2) (VP) both given intravenously (i.v.) on days 1 to 4 or cisplatin (20 mg/m2), ifosfamide (1.2 g/m2), and etoposide (75 mg/m2) (VIP) all given i.v. on days 1 to 4. Cycles were repeated every 3 weeks for four cycles. RESULTS: From May 1989 through March 1993, 171 patients were randomized (84 to VP and 87 to VIP). The median follow-up duration is 26 months. All patients were assessable for survival; 163 were fully assessable for response and 162 for toxicity. Myelosuppression was greater with VIP. Objective responses were observed in 55 of 82 (67%) and 59 of 81 (73%) assessable patients treated with VP and VIP, respectively (difference not significant). The difference in the median time to progression was statistically different (P = .039). The median survival times on VP and VIP were 7.3 months and 9.0 months, respectively (P = .045 for survival curves by stratified log-rank test) with 2-year survival rates of 5% versus 13%, respectively. CONCLUSION: VIP combination chemotherapy is associated with an improved time to progression and overall survival over VP therapy in patients with extensive SCLC.

Adult↗
PubMed1995

Late relapse of testicular cancer.

PURPOSE: This study analyzed a large group of patients with testicular germ cell cancer in complete remission, who relapsed more than 2 years after completion of treatment. PATIENTS AND METHODS: A review of all patients treated at Indiana University Medical Center from 1979 through 1992 for late relapse was conducted. Eighty-one patients were treated for late relapse of testicular cancer. Forty-seven patients relapsed more than 5 years after successful management of their initial disease. RESULTS: At initial diagnosis, 35 patients had clinical stage I, 18 stage II, and 28 stage III disease. Twenty-three of 35 stage I, all 18 stage II, and all 28 stage III patients were treated by chemotherapy before their late relapse. The median follow-up duration of patients post-management of late relapse was 4.8 years. Twenty-one patients (25.9%) are continuously disease-free. Nineteen of these 21 patients had surgical resection of carcinoma or teratoma as a component of their therapy. Of sixty-five patients treated for late relapse by chemotherapy, 17 (26.2%) had a complete response, but only two have been continuously disease-free with chemotherapy alone. These two never received prior chemotherapy. CONCLUSION: Late relapse of testis cancer is more common than previously thought. Surgery is the preferred mode of therapy. Chemotherapy has only modest success in this entity, in contrast to the excellent results in de novo germ cell tumors. Patients treated for testicular germ cell cancer need annual follow-up evaluations throughout their life due to the possibility of late relapse.

Adolescent↗
PubMed1995

Phase II study of daily oral etoposide plus ifosfamide plus cisplatin for previously treated recurrent small-cell lung cancer: a Hoosier Oncology Group Trial.

PURPOSE: The study was undertaken to determine the activity and toxicity of oral etoposide (VP-16), ifosfamide, and cisplatin combination chemotherapy for previously treated, recurrent small-cell lung cancer (SCLC). PATIENTS AND METHODS: In this phase II trial, 46 patients were enrolled to receive oral VP-16, 37.5 mg/m2/d for 21 days, ifosfamide 1.2 g/m2/d for 4 days, and cisplatin 20 mg/m2/d for 4 days, with courses repeated every 28 days. Response, survival, and toxicity data were then noted. RESULTS: Forty-two of 46 patients were assessable for response, survival, and toxicity. Thirty-six of 42 patients had received prior cisplatin plus VP-16. The first 22 patients received oral VP-16 for 21 days, but the subsequent 20 patients received oral VP-16 for 14 days after an interim analysis showed marked myelosuppression. Twenty-three of 42 patients (55%) had an objective response, with six complete responses (CRs; 14%), and 17 partial responses (PRs; 40%). The median progression-free survival time was 20 weeks (range, 2 to 66) and the overall median survival duration was 29 weeks (range, 1 to 76). Myelosuppression was significant, with six treatment-related deaths, four as a result of sepsis. CONCLUSION: The combination of oral VP-16, ifosfamide, and cisplatin is an active regimen in the treatment of recurrent SCLC. However, hematologic toxicity was severe in this pretreated patient population.

Administration, Oral↗
PubMed1995

Phase III trial of thoracic irradiation with or without cisplatin for locally advanced unresectable non-small-cell lung cancer: a Hoosier Oncology Group protocol.

PURPOSE: Here we report the results of a phase III study, to evaluate whether the addition of cisplatin to radiation therapy (XRT) would improve progression-free survival or overall survival for patients with locally advanced unresectable non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Two hundred forty patients with biopsy-proven unresectable NSCLC without distant metastases or lower-stage medically inoperable patients were randomized to one of two treatment arms. Arm A consisted of thoracic XRT alone, 60 to 65 Gy total tumor dose in daily fractions of 1.80 to 2.00 Gy; and arm B consisted of identical XRT with the addition of cisplatin 70 mg/m2 every 3 weeks for three cycles beginning on the first day of irradiation. RESULTS: Two hundred fifteen patients were eligible and assessable. The overall response rate was 50% on the combination arm versus 38% on the XRT-alone arm (P = .076). The median progression-free survival time was 23 versus 22 weeks, respectively (P = .0537). The median survival time was 43 weeks on the combination arm versus 46 weeks on the XRT arm (Poverall = .3469). The 1-, 2-, and 5-year survival rates were 43%, 18%, and 5% on the combination arm versus 45% 13%, and 2% on the XRT arm, respectively. CONCLUSION: Cisplatin, administered every 3 weeks, does not significantly improve response rate, progression-free survival, or overall survival when added to thoracic XRT for locally advanced unresectable NSCLC.

Adult↗
PubMed1995

Distinct patterns of minimal residual disease associated with graft-versus-host disease after allogeneic bone marrow transplantation for chronic myelogenous leukemia.

PURPOSE: Allogeneic bone marrow transplantation (BMT) has been shown to provide effective therapy for chronic myelogenous leukemia (CML), but previous reports have also demonstrated the persistence of bcr-abl-positive cells for months to years after BMT in the majority of patients. To evaluate the biologic significance of persistent bcr-abl-positive cells, we examined the relationship between clinical parameters known to affect the risk of relapse and the ability to detect bcr-abl-positive cells post-BMT. PATIENTS AND METHODS: We analyzed 480 samples from 92 patients at two transplant centers for the presence of bcr-abl-positive cells by polymerase chain reaction (PCR). Two different BMT preparative regimens and protocols for prevention of graft-versus-host disease (GVHD) were used. One center used cyclophosphamide plus total-body irradiation (CY/TBI) and T-cell-depleted marrow; the second center used busulfan plus cyclophosphamide (Bu/CY) and untreated marrow with cyclosporine and methotrexate (Csp/MTX) as GVHD prophylaxis. RESULTS: We first determined the percent of patients at each center with > or = one PCR-positive (PCR+) result at defined intervals post-BMT. Between 0 and 6 months post-BMT, the majority of patients (80% to 83%) in both populations had PCR-detectable bcr-abl-positive cells. Between 6 and 24 months post-BMT, 80% to 88% of patients who received T-cell-depleted marrow remained PCR+, as compared with 26% to 30% of patients who received unmodified marrow. After 24 months post-BMT, the percentage of PCR+ patients was not significantly different in the two populations. This pattern of detection of bcr-abl-positive cells post-BMT followed the development of chronic GVHD in patients who received unmodified marrow. All patients were also divided into three groups based on post-BMT PCR results as follows: (1) persistent PCR+ (n = 29), (2) intermittent PCR-negative ([PCR-] n = 40), and (3) persistent PCR- (n = 23). These three groups were found to have a low, intermediate, and high probability of maintaining remission and disease-free survival, respectively (P = .0001). Intermittent or persistent PCR- results, which reflect levels of minimal residual disease < or = the limit of detection by PCR, were clearly associated with both acute (P = .004) and chronic (P = .000005) GVHD. Nevertheless, 44% of patients without GVHD also had intermittent or persistent PCR- assays. CONCLUSION: The persistence of PCR-detectable bcr-abl-positive cells early post-BMT in more than 80% of patients suggests that neither BMT preparative regimen effectively eradicates CML cells in most patients. Subsequently, acute and/or chronic GVHD are associated with a decreased ability to detect residual bcr-abl-positive cells, which suggests that immunologic mechanisms mediated by donor cells are important for inducing long-term remissions after BMT. The demonstration that 44% of patients without GVHD had either low or undetectable levels of residual leukemia suggests the presence of mechanisms capable of suppression or eradication of CML independent of GVHD.

Acute Disease↗
PubMed1995

Phase I study of high-dose ifosfamide, carboplatin and etoposide with autologous hematopoietic stem cell support.

More effective high-dose combination regimens are needed which have broad cytotoxic activity, steep dose-response relations and non-overlapping non-hematologic toxicities (to allow administration of full doses of each agent). This study was designed to define the dose-limiting toxicities and maximum tolerated doses of ifosfamide, carboplatin and etoposide (ICE) with hematopoietic stem cell support. Ifosfamide and carboplatin were initially fixed at 75% and 80% of the single agent maximum tolerated doses, respectively, and etoposide added to the combination. After the dose-limiting toxicity of etoposide was reached, its dose was fixed and ifosfamide and carboplatin were individually dose escalated as tolerated. All agents were given by 96h continuous infusion (days -7 to -3). Autologous marrow, with or without peripheral blood progenitor cells, was reinfused on day 0. Forty eight adults with advanced malignancies were enrolled in cohorts of three to five patients. At the maximum tolerated doses of ifosfamide 16 g/m2, carboplatin 1.8 g/m2 and etoposide 1.2 g/m2, renal toxicity precluded further dose escalation. Two patients died of organ (renal, CNS) toxicity (4%). Renal toxicity was particularly prominent in patients with prior cisplatin exposure. An early chemotherapy-stopping rule was developed, supported by pharmacologic analysis, which resulted in immediate discontinuation of ifosfamide and carboplatin if the serum creatinine, monitored twice daily during chemotherapy, exceeded 1.5 mg/dl and was > 0.5 mg/dl above baseline. High-dose ICE is well tolerated if serum creatinines are carefully monitored during chemotherapy administration. The early chemotherapy-stopping rule may enhance safety of the regimen but requires validation by addition correlation with pharmacokinetic data for each of the chemotherapeutic agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗