Biomedical subjects

T Leong

Publications and source records attributed to T Leong.

At least 19 recordsLinked to original sources

PubMed2001

Novel DNA sequence variants in the hHR21 DNA repair gene in radiosensitive cancer patients.

PURPOSE: Radiation therapy is an important treatment modality for oncology patients. DNA sequence variants have so far been identified in only a few genes in radiosensitive cancer patients. Patients known to be clinically radiosensitive were tested for mutation of a gene involved in DNA double-strand break repair and sister chromatid cohesion--hHR21. METHODS AND MATERIALS: Clinically radiation-sensitive patients were accrued to the study after giving informed consent. Blood samples were obtained and lymphoblastoid cell lines established. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to amplify the hHR21 gene, and the DNA product was sequenced to identify any genetic abnormalities. Northern blot analysis, cell survival, and growth assays were performed on control cells and cells with hHR21 variants, and a restriction digest assay was developed to screen for carriers of a detected gene variant. RESULTS: The DNA sequence of the hHR21 gene was determined in 19 radiation-sensitive cancer patients. In 6 of the 19 patients, a thymidine (T) to cytosine (C) transition was detected at position 1440 of the hHR21 open reading frame (T1440C). This variant did not alter the amino acid sequence and was likely to be a polymorphism. One patient with a particularly severe radiation reaction had a second sequence variant immediately adjacent to the first. This was a guanine (G) to adenine (A) transition (G1441A), resulting in a change of the amino acid sequence (glycine --> arginine) in a portion of the protein conserved in evolution. This suggests that this DNA alteration may be biologically significant. Restriction digest with the HpaII enzyme confirmed the presence of both sequence variants on the same allele. CONCLUSIONS: We describe the first two DNA sequence variants ever found in the hHR21 gene, in patients with clinical radiation hypersensitivity. Although no direct evidence for the involvement of hHR21 alterations in the radiosensitivity of the cancer patients examined has been demonstrated, the possibility exists that homozygous mutations or other mutations of this gene could contribute to radiosensitivity. A simple test is described that could be applied to screening for these variants in relevant populations.

Amino Acid Sequence↗

PubMed2001

Phase III comparison of high-dose paclitaxel + cisplatin + granulocyte colony-stimulating factor versus low-dose paclitaxel + cisplatin in advanced head and neck cancer: Eastern Cooperative Oncology Group Study E1393.

PURPOSE: To determine dose-response effects and the activity of paclitaxel combined with cisplatin in patients with incurable squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: Two hundred ten patients with locally advanced, recurrent, or metastatic disease were randomly placed in either Arm A, paclitaxel 200 mg/m(2) (24-hour infusion) + cisplatin 75mg/m(2) + granulocyte colony-stimulating factor, or Arm B, paclitaxel 135 mg/m(2) (24-hour infusion) + cisplatin 75 mg/m(2). Cycles were repeated every 3 weeks until progression or a total of 12 cycles for complete responses. Primary outcomes were event-free and overall survival. RESULTS: No significant differences in outcomes were observed between the high- and low-dose paclitaxel regimens. The estimated median survival was 7.3 months (95% confidence interval, 6.0 to 8.6). The 1-year survival rate was 29%, and event-free survival was 4.0 months. The objective response rate (complete response plus partial response) was 35% for the high-dose patients and 36% for the low-dose patients. Myelosuppression was the most frequent toxicity: grade 3 or 4 granulocytopenia, 70% of patients in Arm A and 78% in Arm B; febrile neutropenia, 27% of patients in Arm A and 39% in Arm B. Grade 5 toxicities occurred in 22 patients (10.5%). Treatment was terminated early in 31% because of excessive toxicity or patient refusal. CONCLUSION: This phase III multicenter trial showed (1) no advantage for high-dose paclitaxel and (2) excessive hematologic toxicity associated with both regimens. Therefore, neither of the paclitaxel regimens evaluated in this trial can be recommended.

Adult↗

PubMed2001

Gemcitabine and vinorelbine in patients with advanced lung cancer: preclinical studies and report of a phase I trial.

PURPOSE: This study was designed to assess the efficacy of gemcitabine plus vinorelbine using the mouse Lewis lung carcinoma model and to translate this regimen to a phase I clinical study of these two agents in patients with advanced lung cancer. MATERIALS AND METHODS: Using the mouse Lewis lung cancer model, employing growth delay and isobologram analysis, we demonstrated that gemcitabine, in combination with vinorelbine, produced additive activity with little increased toxicity over a wide range of doses. At the highest dose level studied, antagonism was observed. Based on these results, we initiated a phase IGemcitabine and vinorelbine in patients with advanced lung cancer: preclinical studies and report of a phase I trial study of this combination at the Dana Farber Cancer Institute (DFCI) in patients with untreated or once pretreated non-small-cell lung cancer (NSCLC) or once pretreated small-cell lung cancer (SCLC). Vinorelbine (given in an intravenous bolus) and gemcitabine (given in a 30-min infusion) were initially administered to patients at a dose of 15 mg/m2 and 500 mg/m2, respectively, on days 1, 8, and 15 of a 28-day cycle. Seven dose levels were subsequently explored over the course of the study. There was no intrapatient dose escalation. RESULTS: From November 1996 to March 1998, 40 patients were enrolled: 32 had NSCLC, 5 had SCLC and 3 had mixed disease (both SCLC and NSCLC). The patients were evenly divided by gender, the median age was 58 years (range 38 to 73 years), and the median ECOG performance status was 1 (range 0 to 2). All patients had normal renal and hepatic function and none had previously received gemcitabine or vinorelbine. Toxic reactions included mild to moderate fatigue, nausea, constipation, and, most significantly, neutropenia and thrombocytopenia. Phlebitis was a major problem when central venous lines were not used with 15% grade 1/2 events. The day-15 dose was held in 43% of patients at the expanded dose. No true maximum tolerated dose was reached after completion of seven dose levels. Dose level 4 (22.5 mg/m2 vinorelbine and 1,000 mg/m2 gemcitabine) was chosen for expansion and future study due to the potential increased ability of patients to receive the full doses on time. CONCLUSIONS: We conclude that this drug combination and dosage are feasible and have potential as either a front- or second-line chemotherapeutic regimen for advanced lung cancer, and phase II/III trials should be performed. However, hematologic toxicities, as found in this study, could probably be reduced with treatment on days 1 and 8 every 21 days, and current literature would suggest this to be the preferred schedule.

Adult↗

PubMed2001

Combined modality treatment for locally advanced squamous-cell carcinoma of the oropharynx in a woman with Bloom's syndrome: a case report and review of the literature.

We describe a case of locally advanced unresectable squamous-cell carcinoma of the oropharynx in a young woman with Bloom's syndrome. She was treated with radical radiation therapy and concurrent chemotherapy (cisplatin and 5-flurouracil). She was unable to complete treatment due to the development of severe side effects: confluent mucositis, moist desquamating skin reaction, severe diarrhea and severe myelosupression with neutropenic sepsis. The limited relevant literature is presented. We conclude that chemotherapy should be used with extreme caution in Bloom's syndrome patients.

Adult↗

PubMed2001

Lack of efficacy of topotecan in the treatment of metastatic or recurrent squamous carcinoma of the head and neck: an Eastern Cooperative Oncology Group Trial (E3393).

Recurrent or metastatic squamous carcinoma of the head and neck (RMSCHN) is a modestly chemoresponsive tumor; however, currently available agents have failed to improve survival. New active agents are needed for the treatment of this disease. Topotecan is a topoisomerase inhibitor that demonstrated initial promising activity in squamous carcinoma of the head and neck. The Eastern Cooperative Oncology Group conducted a phase II trial of topotecan to determine the efficacy and toxicity of a weekly treatment schedule in patients with RMSCHN. Patients with metastatic or locally recurrent squamous carcinoma of the head and neck were treated with topotecan 1.5 mg/m2 x 24 hours by continuous infusion on days 1, 8, 15, and 22 of each 35-day cycle. Patients were stratified in two cohorts: chemonaive and previously treated. Sixteen chemonaive and 16 previously treated patients were registered on study. Grade III/IV neutropenia and anemia occurred in 16% and 18% of patients, respectively. No responses were observed in either cohort. Median survival for previously untreated patients was 4.6 months and 3.2 months for previously treated patients. Topotecan failed to demonstrate efficacy in patients with RMSCHN. Further evaluation of this agent is not planned.

Adult↗

PubMed2001

Bleomycin, lomustine, cyclophosphamide, vincristine, procarbazine and prednisone (BLEO-CCVPP) in patients with Hodgkin's disease who relapsed after radiotherapy alone: a long-term follow-up study of the Eastern Cooperative Oncology Group (E3481).

Thirty-three evaluable patients with Hodgkin's disease who failed radiotherapy were treated on this phase II study with bleomycin, lomustine, cyclophosphamide, vincristine, procarbazine and prednisone given every 28 days for a minimum of eight courses. Twenty-five patients (76%; 95% CI=55.6-87.1%) achieved a complete remission, the median duration of which cannot yet be determined, but the probability of remaining in continuous complete remission at 10 years is.64. The median survival from entry on this study for all evaluable patients is 10 years, and 12 patients were alive at the time of this analysis with a median follow-up for them of 15.5 years. Of the 22 patients who died, 11 died of progressive or recurrent Hodgkin's disease and 11 died of other causes including 7 second primary neoplasms and at least one myocardial infarction. Both are now well known late complications of Hodgkin's disease treatment.

Adolescent↗

PubMed2000

Mutation analysis of BRCA1 and BRCA2 cancer predisposition genes in radiation hypersensitive cancer patients.

PURPOSE: The dose intensity of radiotherapy (RT) used in cancer treatment is limited in rare individuals who display severe normal tissue reactions after standard RT treatments. Novel predictive assays are required to identify these individuals prior to treatment. The mechanisms responsible for such reactions are unknown, but may involve dysfunction of genes involved in the sensing and response of cells to DNA damage. The breast cancer susceptibility genes BRCA1 and BRCA2 are implicated in DNA damage repair and the control of genome stability. The purpose of this study was to determine if clinical radiation hypersensitivity is related to mutations of the BRCA1 and BRCA2 genes. Such information is of potential use in the clinical management of BRCA mutation carriers and their families. METHODS AND MATERIALS: Twenty-two cancer patients who developed severe normal tissue reactions after RT were screened for mutations of BRCA1 and BRCA2, using various methods including protein truncation testing, direct DNA sequencing, and a PCR-based BRCA1 exon 13 duplication test. RESULTS: No mutations were detected in the 22 patients tested, despite screening for the majority of commonly described types of mutations of BRCA1 and BRCA2. CONCLUSION: These early results suggest that genes other than BRCA1 and BRCA2 probably account for most cases of clinical radiation hypersensitivity, and that screening for mutations of BRCA1 and BRCA2 is unlikely to be useful in predicting response to radiotherapy. However, it has not been excluded that some BRCA1 or BRCA2 heterozygotes might experience unexpected RT toxicity; further BRCA mutation screening on radiation sensitive individuals is warranted.

BRCA2 Protein↗

PubMed2000

Prognostic value of serum markers of bone metabolism in untreated multiple myeloma patients.

Bone involvement is a central feature of multiple myeloma (MM). We investigated whether serum markers of osteoblastic and osteoclastic activity correlate with the presence of bone disease and survival in 313 MM patients enrolled in a phase III trial (E9486). Five markers were measured, including osteocalcin (OC), carboxy-terminal propeptide of type I collagen (PICP), bone alkaline phosphatase (BAP), carboxy-terminal telopeptide of type I collagen (ICTP) and tartrate-resistant acid phosphatase (TRAP). We analysed the relationship between serum levels of these markers and the presence of bone manifestations, and survival. Serum levels of ICTP and BAP correlated significantly with bone pain, lesions and fractures. Serum level of ICTP was also higher in stage II-III compared with stage I disease. The serum level of ICTP was significantly associated with shortened survival in the univariate analysis. The median survival times were 4.1 and 3.5 years for low and high ICTP respectively (P = 0.02). There was a strong relationship between ICTP and beta-2-micrgolobulin (B2M). ICTP stands out as a significant marker of bone disease. Incorporation of these markers into clinical trials assessing the use of bisphosphonates in MM is needed to determine whether they might serve as indicators of effectiveness of these agents.

Acid Phosphatase↗

PubMed2000

Prognostic value of bone marrow angiogenesis in multiple myeloma.

We studied the prognostic value of angiogenesis grading and microvessel density estimation in newly diagnosed multiple myeloma. Seventy-five patients with newly diagnosed myeloma, treated on Eastern Cooperative Oncology Protocol E9486 and Intergroup study 0141 (S9321) at the Mayo Clinic, were studied. Bone marrow microvessels were examined using immunohistochemical staining for von Willebrand factor. Determination of microvessel density and angiogenesis grading was done in a blinded manner. There was a strong correlation between microvessel density and the plasma cell labeling index, rho 0.42, P < 0.001. Angiogenesis grade was also significantly associated with the plasma cell labeling index. Fifteen % of patients with low-grade angiogenesis had a high labeling index (>1%). In contrast, 47% of patients with intermediate or high-grade angiogenesis had high labeling indices (P = 0.02). Overall survival was significantly different among those with high-, intermediate-, and low-grade angiogenesis, with median times of 2, 4, and 4.4 years, respectively (P = 0.02). Similarly, patients with microvessel density >50/x400 field had poorer survival compared with those with 50 or fewer microvessels/field, median survival 2.6 versus 5.1 years, respectively (P = 0.004). There was a strong association between angiogenesis grade and microvessel density (P < 0.001). We conclude that bone marrow angiogenesis is a predictor of poor survival in newly diagnosed myeloma. Angiogenesis is correlated with the plasma cell labeling index but not the bone marrow plasma cell percentage. A simple visual grading of angiogenesis is an efficient alternative to microvessel density estimation.

Bone Marrow↗

PubMed1999

The addition of interferon or high dose cyclophosphamide to standard chemotherapy in the treatment of patients with multiple myeloma: phase III Eastern Cooperative Oncology Group Clinical Trial EST 9486.

BACKGROUND: Interferon (IFN) has demonstrated activity in the treatment of patients with multiple myeloma. A previous Eastern Cooperative Oncology Group (ECOG) study suggested that the rates of complete response (CR) and survival were increased with a regimen that alternated IFN with chemotherapy. The current study was designed to evaluate the effect of adding alternating cycles of IFN or early intensification with high dose cyclophosphamide (HiCy) to the VBMCP regimen for the treatment of multiple myeloma patients. METHODS: From February 1988 to May 1992, the ECOG entered previously untreated patients with active multiple myeloma on a study in which they were randomized to VBMCP (vincristine 1.2 mg/m(2) administered intravenously [i.v.] on Day 1, BCNU 20 mg/m(2) i.v. on Day 1, melphalan 8 mg/m(2) administered orally [p.o.] on Days 1-4, cyclophosphamide 400 mg/m(2) i.v. on Day 1, and prednisone 40 mg/m(2) p.o. on Days 1-7; 5-week cycles) or VBMCP + rIFN(alpha2), the latter given at 5 Mu/m(2) 3 times a week starting on Day 22 of each 6-week cycle after 2 initial cycles of VBMCP. Patients younger than 70 years were also randomized to a third treatment that substituted cyclophosphamide 600 mg/m(2) i.v. on Days 1-4 and prednisone 100 mg/m(2) p.o. on Days 1-4 for cycles 3 and 5 of VBMCP (VBMCP + HiCy). Treatment was continued for 2 years. RESULTS: Of the 653 patients entered, 628 were eligible for the study. All were evaluated for response. With median follow-up for surviving patients of 54 months, the median survival duration was 42 months-1 year longer than usually reported for melphalan combined with prednisone. A comparison of the three regimens revealed no significant difference in the rates of survival or objective response (OR). However, CRs were increased among patients treated with VBMCP + rIFN(alpha2) compared with VBMCP alone (18% vs. 10%, P = 0.03). Patients treated with VBMCP + rIFN(alpha2) had a longer response duration than patients treated with VBMCP alone (30 vs. 25 months, P = 0.035). There was a greater response rate with the IFN regimen among elderly patients (OR and CR = 67% and 31%, respectively) and patients with immunoglobulin A (IgA) myeloma (OR and CR = 83% and 29%, respectively). Severe infections were seen as often with VBMCP as with VBMCP + rIFN(alpha2) (13% vs. 15%), but they were more frequent with VBMCP + HiCy (25%). CONCLUSIONS: VBMCP + rIFN(alpha2) yields a higher rate of CR and a longer response duration than VBMCP alone but appears to make no difference in the rates of overall response or survival compared with VBMCP or VBMCP + HiCy. The superior ability of VBMCP + rIFN(alpha2) induction therapy to produce CR and more durable responses, as well as its activity in older patients and in those with IgA myeloma, suggest that this therapy has important biologic activity in myeloma and merits further clinical investigation.

Adult↗

PubMed1999

Using missing data methods in genetic studies with missing mutation status.

Because of current techniques of determining gene mutation, investigators are now interested in estimating the odds ratio between genetic status (mutation, no mutation) and an outcome variable such as disease cell type (A, B). In this paper we consider the mutation of the RAS genetic family. To determine if the genes have mutated, investigators look at five specific locations on the RAS gene. RAS mutated is a mutation in at least one of the five gene locations and RAS non-mutated is no mutation in any of the five locations. Owing to limited time and financial resources, one cannot obtain a complete genetic evaluation of all five locations on the gene for all patients. We propose the use of maximum likelihood (ML) with a 2(6) multinomial distribution formed by cross-classifying the binary mutation status at five locations by binary disease cell type. This ML method includes all patients regardless of completeness of data, treats the locations not evaluated as missing data, and uses the EM algorithm to estimate the odds ratio between genetic mutation status and the disease type. We compare the ML method to complete case estimates, and a method used by clinical investigators, which excludes patients with data on less than five locations who have no mutations on these sites.

Biometry↗

PubMed1999

Prognostic significance of the S-phase fraction of light-chain-restricted cytoplasmic immunoglobulin (cIg) positive plasma cells in patients with newly diagnosed multiple myeloma enrolled on Eastern Cooperative Oncology Group treatment trial E9486.

The bone marrow plasma cell labeling index (PCLI) as measured by bromodeoxyuridine uptake is a well-established independent prognostic factor for patients with newly diagnosed multiple myeloma, but the test is not easily done in most laboratories. The purpose of this study was to determine if the proliferative activity (% S-phase) as determined by two-color flow cytometry for cytoplasmic immunoglobulin (cIg) light chain and DNA content also had prognostic significance. As part of Eastern Cooperative Oncology Group clinical trial E9486, 500 patients had successful performance of the bone marrow PCLI. Of 349 patients who had flow cIg and DNA content cytometry, 210 had adequate data to reliably calculate S-phase %. Patients with low % S-phase fraction (<2%) had a significant overall survival advantage over patients high % S-phase fraction (>/=2%), median survivals 4.1 vs. 2.9 years (P = 0.032). Measurement of the S-phase % by flow cytometry gives significant prognostic information in patients with newly diagnosed myeloma. However, in multivariate analysis, S-phase % did not add prognostic information when PCLI was in the model. S-phase % added prognostic information only when all cases with flow measurement of S-phase % were included, and when PCLI was excluded from the model. Discriminating a population of only cIg positive cells proved difficult in patients with a low percentage of bone marrow plasma cells. Methodology to measure S-phase % in patients with a low percent plasma cells is needed before this technique can be used for diagnosis and prognosis in myeloma.

Aged↗

PubMed1999

Altered T cell repertoire usage in CD4 and CD8 subsets of multiple myeloma patients, a Study of the Eastern Cooperative Oncology Group (E9487).

Previous investigations have demonstrated that an expanding circulating T cell population is able to modulate the malignant clone in multiple myeloma. More recently, an expansion of T cell subsets exhibiting a restricted T cell repertoire has been detected in some MM patients. To further elucidate if a selected T cell expansion occurs in MM, we studied the T cell receptor (TCR) variable (V) region expression from a cohort of previously diagnosed and treated MM patients (N=37). The latter was done by assessing the reactivity of a panel of monoclonal antibodies specific for different V region families (alpha or beta) in combination with anti-CD4 or anti-CD8, for purified blood T cells from MM patients. TCR V region usage in MM patients was compared to blood T cells from age matched (N=13) control individuals. The multivariate analysis of variance did not uncover a difference for distribution of TCR V region usage between the normal controls and the MM cohort. However, there were individual MM patients who had expanded T cells with specific TCR V region expression when compared to the control group. Several MM patients had multiple, expanded CD4 and/or CD8 subsets based on TCR V region expression. The majority of MM patients had expanded T cell subsets that constituted less than 10% of the total blood T cell pool. However, a few MM patients (N=3) had larger percentages (range 34-84%) of these expanded T cell subsets within their blood T (CD3+) cells. The stage of disease and treatment status (currently on or off therapy) did not associate with the pattern of restricted T cell repertoire. Finally, a smaller cohort of newly diagnosed, untreated MM patients (N=13) also demonstrated an expanded T cell repertoire. However, these patients had more CD4 than CD8 cell subsets involved in the altered V region expression in several Vbeta families. Thus, these results add to the evidence that this malignant B cell disorder whether newly diagnosed or of longer duration, may be accompanied by an altered T cell repertoire characterized in part by expanded T cell clones.

CD4-Positive T-Lymphocytes↗

PubMed1999

Is flow cytometric DNA content hypodiploidy prognostic in multiple myeloma?

Hypodiploid multiple myeloma is uncommon when assessed by DNA content flow cytometry, having been reported in less than 6% of patients with newly diagnosed multiple myeloma. Previous studies have shown these patients to be unresponsive to therapy and to have short survival. To address this further, we studied 349 of 504 patients eligible for Eastern Cooperative Oncology Group (ECOG) treatment trial E9486 and laboratory correlative study E9487 who had marrow mononuclear cells available for ploidy analysis. Marrow samples were studied by dual channel flow cytometry, using propidium iodide to measure the DNA content and kappa and lambda light chain antisera to identify the clonal cells. A DNA index < 0.95 was considered hypodiploid. Five patients (1.4%) were found to have hypodiploid DNA content in their marrow plasma cells. Three of the 5 patients with hypodiploid myeloma had a partial objective response to chemotherapy, which is not different from the overall objective response rate for all patients enrolled on E9486. All five patients with hypodiploid multiple myeloma died within 4 years from diagnosis, but these patients had a similar overall median survival (2.6 years) compared to the patients with diploid DNA content. Our studies confirm the poorer survival of patients with diploid versus hyperdiploid myeloma; we cannot confirm, however, the previously reported very poor outcome associated with hypodiploid myeloma using DNA content flow cytometry. Hypodiploid DNA content of plasma cells by flow cytometry may not be as ominous a factor as previously reported.

Aged↗

PubMed1998

Plasmablastic morphology--an independent prognostic factor with clinical and laboratory correlates: Eastern Cooperative Oncology Group (ECOG) myeloma trial E9486 report by the ECOG Myeloma Laboratory Group.

We studied the prognostic significance of plasmablastic (PB) multiple myeloma (MM) in Eastern Cooperative Oncology Group Phase III trial E9486. Two reviewers independently reviewed 453 cases. They agreed on 37 PB (8.2%) cases and 416 non-PB cases, achieving an 85% concordance (P < .0001). These PB cases had significantly lower hemoglobin and serum albumin levels, higher calcium and beta 2-microglobuin levels, and higher percentage BM plasma cells (PC) by immunofluorescence. They had higher bone marrow PC labeling indices, higher serum soluble interleukin-6 receptor (sIL-6R) levels, and a higher probability of ras mutations. Three treatment regimens were used: vincristine, bis-chloro-ethyl nitrosourea (BCNU) melphalan, cyclophosphamide, and prednisone (VBMCP) alone; VBMCP with added cyclophosphamide (HiCy); or recombinant interferon alpha 2 (rIFNalpha2). Although the numbers are low, patients with PB had a significantly lower response rate versus non-PB MM when treated with VBMCP (treated, 47.1% v nontreated, 66.5% [P = .015]). Patients with nonresponding PB had a significantly higher progression rate than non-PB cases (30.6% v 11.8% [P < .0001]), especially with VBMCP alone (35.3% v 15.8% [P = .002]), and with added HiCy (37.5% v 9.8% [P < .0001]), but not with added rIFNalpha2. Event-free and overall survival of PB MM was shorter (median years, 1.1 v 2.7 and 1.9 v 3.7, respectively [P < .0001 for both]). In multivariate analysis, PB classification was also highly prognostic. There is no survival difference between the patients who were classified as PB by both reviewers versus patients classified as PB by only one reviewer. We conclude that PB MM is a discrete entity associated with more aggressive disease and shortened survival. Tumor cell ras mutations and increased sIL-6R may contribute to a higher proliferation rate and reduced survival. There were significant improvements in response and progression with the addition of HiCy and rIFNalpha2 to VBMCP, but the numbers were small and improved survival could not be shown.

Adult↗

PubMed1998

T-helper phenotypes in the blood of myeloma patients on ECOG phase III trials E9486/E3A93.

T-helper blood populations are frequently altered in multiple myeloma (MM). We measured the numbers of naive and activated cell subsets in the blood of a cohort of both previously untreated and treated MM patients. Two-colour flow cytometry to detect total CD4+, CD4+, CD4 5RA+ (naive) and CD4+, CD45RO+ (activated) subsets was then used to quantify the T-cell subsets in controls and MM patients. Previously treated MM patients either on or off treatment (n = 105) had significantly reduced (P< 0.0001) total CD4 and naive/activated cells than controls. Previously treated MM patients sampled for naive/activated cells while currently off therapy (n = 45) had no difference in the levels of CD4 and naive/activated cells compared to the currently treated patients (n = 60). However, newly diagnosed patients (n = 58) had a significantly reduced total CD4 (P = 0.023) and activated CD4 (P = 0.004), but not naive CD4 subsets, compared to controls. CD19+ cell levels above 125/microl were positively associated with higher T-helper cell levels. There was a strong positive association for better overall survival for patients with >395 CD4 cells/microl (P = 0.0001). These data indicate that MM patients at diagnosis have altered T-helper subsets, with a selective reduction in activated but not naive cells. Subsequent chemotherapy or the disease process contributes to a further reduction in CD4 cells. Importantly, the association of higher CD19+ cell levels with higher T helper cells indicates that certain myeloma patients can be identified with a more quantitatively intact immune system.

Adult↗

PubMed1998

Paclitaxel as the initial treatment of multiple myeloma: an Eastern Cooperative Oncology Group Study (E1A93).

The authors assess the activity and toxicity of paclitaxel in previously untreated patients with multiple myeloma. Eighteen patients with previously untreated multiple myeloma were enrolled. Paclitaxel was given in a dose of 250 mg/m2 by a continuous intravenous infusion for 24 hours every 21 days for four cycles. All patients received granulocyte colony stimulating factor in a dose of 5 microg/kg each day until the absolute neutrophil count was 10,000/mm3. All patients were evaluated after four cycles. Four (29%) objective responses were observed in the 14 eligible patients. No complete responses occurred. Three lethal toxicities were observed, two were the result of neutropenic sepsis. Sixty-one percent of patients experienced some type of severe nonhematologic toxicity. Patients who received four cycles of paclitaxel were given further treatment at the discretion of the investigator. The median survival of all eligible patients was 2.8 years, which is comparable with the median survival with melphalan and prednisone of 2.3 years or vincristine, carmustine, melphalan, cylophosphamide, and prednisone of 2.4 years. Paclitaxel in the dosage used in this study has prohibitive toxicity. The four (29%) responses in 14 evaluable untreated patients indicates that paclitaxel is active in the treatment of multiple myeloma. No complete remissions were recorded. Further studies using paclitaxel in a smaller dose, in combination with other agents, or using one of the paclitaxel analogs may be useful in the treatment of multiple myeloma.

Adult↗

PubMed1997

Childhood optic chiasm gliomas: radiographic response following radiotherapy and long-term clinical outcome.

PURPOSE: In children with chiasmal gliomas, radiation therapy can arrest progressive visual and neurologic impairment. We examined the radiographic response and clinical outcomes after irradiation. METHODS AND MATERIALS: Forty-two children (median age at diagnosis, 6.6 years) with chiasmal gliomas were managed as follows: 11 asymptomatic patients with neurofibromatosis-1 (NF-1) were observed only; 2 patients, less than 3 years old, underwent surgery and chemotherapy to delay irradiation; and 29 patients with progressive disease received radiation with or without prior surgery or chemotherapy. Time to radiographic response, long-term tumor control and late sequelae were reviewed for the 29 irradiated patients. RESULTS: The probability of at least 50% radiographic response at 24 months after irradiation was 18.1% and increased to 38.2% by 48 months and 45.9% by 60 months. By actuarial analysis, the median time for such radiographic response was 62 months. For the 29 irradiated patients, the 10-year freedom from progression and overall survival rates were 100% and 89%, respectively (median follow-up for surviving patients, 108 months). Stabilization or improvement in vision occurred in 81% of 26 evaluable irradiated patients. CONCLUSIONS: Notable radiographic response may be observed years after irradiation. Radiation therapy provides excellent long-term tumor control and vision preservation or improvement in the majority of patients with progressive chiasmal gliomas.

Adolescent↗