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Biomedical subjects

R K Stuart

Publications and source records attributed to R K Stuart.

At least 19 recordsLinked to original sources
PubMed2003

Autologous bone marrow transplant in a patient with sickle cell disease and diffuse large B-cell lymphoma.

As the life expectancy of patients with homozygous sickle cell anemia (SCA) improves, SCA care providers are confronted with diseases of the adult SCA population rarely seen before. We report here a 40-year-old woman with SCA who developed diffuse large B-cell non-Hodgkin's lymphoma (NHL) that was treated with eight cycles of chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOPE), without complete remission. She subsequently underwent high-dose cyclophosphamide and total-body irradiation followed by autologous bone marrow transplantation (BMT). To reduce the risk of sickle cell crisis precipitated by G-CSF, she underwent hypertransfusion to maintain a low % hemoglobin S throughout her treatment course. Although she has required iron chelation therapy and shows no sign of modification of her underlying SCA, she remains in remission from NHL 12 years posttransplant. To our knowledge, this is the first reported case of autologous BMT in a patient with SCA. Our patient illustrates that SCA in itself does not preclude autologous stem cell transplantation for lymphoma in selected patients, and this report should encourage others to consider autologous BMT in adults with SCA where it represents a lifesaving therapy for malignant diseases.

Adult↗
PubMed2001

Localized non-Hodgkin's lymphoma of Waldeyer's ring: clinical features, management, and prognosis of 130 adult patients.

BACKGROUND: Waldeyer's ring (WR) is the primary site of non-Hodgkin's lymphoma (NHL) involvement in approximately 5% to 10% of all lymphoma patients, and it accounts for more than half of all primary extranodal lymphomas of the head and neck. Materials and Methods A retrospective review was performed of 130 adult patients with localized (stages I and II) WR-NHL seen at a single institution over 18 years. RESULTS: Patients had a median age of 55 years, and the male-female ratio was 1:5:1. Seventy five (58%), 46 (35%), and 9 (7%) patients had primary tonsillar, nasopharyngeal, and base of the tongue lymphoma, respectively. Forty-five (35%) and 85 (65%) had stage I and stage II disease, respectively. Most patients (109 patients, 84%) had diffuse large B-cell NHL (DLC). Chemotherapy (CT) was given to 58 (45%) patients, whereas 26 (20%) received radiation therapy (RTX), and 46 (35%) were managed with a combination of chemotherapy and radiotherapy (CMT). One hundred nine (84%), 16 (12%), and 5 (4%) patients attained complete remission (CR), partial remission (PR), and treatment failure, respectively, with no difference in CR rates between the three therapeutic modalities. Of those patients with DLC, 90 (83%), 15 (14%), and 4 (3%) demonstrated CR, PR, and treatment failure, respectively. In a multivariate analysis, the modified International Prognostic Index (IPI) was found to predict the attainment of CR. Over a median follow-up of 49 months; 76 (58%) of the patients were alive and disease-free, 5 (4%) were alive with evidence of disease, and the remaining 49 (38%) were dead. Most distant relapses were in nongastrointestinal extranodal sites. The median overall survival (OS) has not been reached; however, the projected 5-year OS was 58%. No OS difference was noted between patients with stage I and stage II. Cox proportional hazards model identified primary tonsillar site and a low-risk group as defined by the modified IPI were associated with favorable OS. The median event-free survival was 82.3 months, with the primary tonsillar site, and low-risk modified IPI group were associated with favorable EFS in a multivariate analysis. Probably because of the high frequency of patients with DLC, the outcome and the prognostic factors in those patients were not distinctive from those for the whole group. The CMT was not associated with a superior OS compared with either of the single modality treatments; however, it was associated with more favorable EFS. CONCLUSIONS: This series characterized the clinicopathologic features and outcome of adult patients with early stage WR-NHLs. No survival difference was noted between stage I and stage II, and the outcome was favorable. Primary tonsillar site and the low-risk group of the modified IPI predicted favorable OS and EFS. CMT is probably superior to single modality treatment; however, prospective studies are warranted.

Adolescent↗
PubMed2001

Immunotherapy of acute myeloid leukemia.

Most patients with acute myeloid leukemia (AML) respond initially to combination chemotherapy but later relapse. These patients often die from progressive disease or toxicities of further chemotherapy. At relapse, the patients' blasts are usually resistant to the drugs to which the patient has been exposed and frequently to other cytotoxic agents as well. Nevertheless, a number of these patients may be salvaged and achieve remissions with allogeneic stem cell transplants. In such cases, the pre-transplant conditioning regimens do not appear to account for the entire anti-leukemic efficacy. Immunological mechanisms for blast killing appear critical. There is tissue culture, animal and clinical evidence that stimulated donor T cells can recognize and kill leukemic blasts through recognition of alloantigens, differentiation antigens or leukemia-specific antigens as targets. We will review the molecular mechanisms for the generation of anti-leukemic T cells and discuss methods to improve the specificity and intensity of anti-leukemic T cell responses in the setting of allogeneic stem cell transplants, donor lymphocyte infusions, autologous anti-leukemic T cell infusions, and vaccine use in AML patients.

Acute Disease↗
PubMed2000

Adding high-dose tamoxifen to CHOP does not influence response or survival in aggressive non-Hodgkin's lymphoma: an interim analysis of a randomized phase III trial.

PURPOSE: CHOP is the standard regimen currently used in the management of the majority of patients with aggressive non-Hodgkin's lymphoma (NHL). However, CHOP only produces 30-35% long-term survival. We hypothesized that adding high-dose tamoxifen, which is known to have multiple drug resistance-modulatory effects, to the CHOP regimen could increase the response rate, and consequently enhance the survival of patients with NHL. PATIENTS AND METHODS: In a prospective, controlled, and randomized study, eligible adult patients with aggressive NHL were randomized between CHOP only (Group I), or CHOP plus high-dose tamoxifen (Group II). The primary aim was to assess the effect of tamoxifen on complete response (CR) rate, with the secondary evaluation of tamoxifen potential impact on survival. The interim analysis of this study is presented. RESULTS: Fifty-one and forty-seven evaluable patients were randomized to Group I and Group II, respectively. The median age of all patients was 53 y (range 18-78 y). The two groups had comparable distributions of the pretreatment prognostic variables. The CR for patients in Group I was 80% (41 patients) as compared with 74% (35 patients) in Group II (P=0.48). Likewise, there was no apparent difference in the partial remission rates between the two groups (6% vs 15%, respectively). Of patients who initially attained CR, 15 (37%) and 10 (29%) subsequently relapsed in Groups II and I respectively (P = 0.45). The NHL International Prognostic Index (IPI) was the only factor that predicted attaining CR. At the time of this interim analysis, the actuarial-estimated overall survival (OS) probability (+/-S.E.) for the entire population at 5 y was 58% (+/-6) with no survival difference between the two groups (P=0.51). Only attaining CR and the IPI predicted OS probability. The probability of remaining event-free at 5 y (+/-SE) for those achieving CR was 72% (+/-9), and there was no significant difference between the two treatment groups (P=0.68). Toxicity profile was similar in the two groups. CONCLUSION: Based on this interim analysis, combining high-dose tamoxifen, as used in this study, with the CHOP regimen has failed to have any favorable effect on the outcome of patients with aggressive NHL, and therefore cannot be recommended for future trials.

Adolescent↗
PubMed2000

High complete pathological response in locally advanced breast cancer using paclitaxel and cisplatin.

BACKGROUND: In an earlier study, we have demonstrated a high response rate in metastatic breast cancer using paclitaxel (P) and cisplatin (C). A phase II study using the same regimen (PC) has been conducted in locally advanced breast cancer (LABC). METHODS: A total of 72 consecutive patients with non-inflammatory LABC (T2 > or = 4 cm, T3 or T4, N0-N2, M0). Patients were scheduled to receive 3-4 cycles of the neoadjuvant PC (paclitaxel 135 mg/m2 and cisplatin 75 mg/m2 on day 1) every 21 days. Patients were then subjected to surgery and subsequently received 6 cycles of FAC (5-fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2) or 4 cycles of AC (doxorubicin 60 mg/m2, and cyclophosphamide 600 mg/m2). Patients then received radiation therapy, and those with hormone receptor positive tumors were given adjuvant tamoxifen intended for 5 years. RESULTS: The median age was 39 years (range, 24-78). Clinically, 7%, 58%, and 35% of patients had T2 > or = 4 cm, T3, and T4, respectively. Disease stage at diagnosis was IIB (33%), IIIA (27%), and IIIB (40%). Complete and partial clinical response to PC was demonstrated in 13 (18%), and 52 (72%) patients, respectively. Of those patients with evaluable pathologic response (68 patients), complete pathologic response (pCR) was achieved in 15 (22%) patients. At a median follow-up of 22 (+/- 3.5) months, 58 (81%) were alive with no recurrence, nine (12%) were alive with evidence of disease, and five (7%) were dead. None of the patients achieving pCR has developed any relapse. The median overall survival has not been reached for all 72 patients with a projected 3-year survival (+/- SE) of 90% (+/- 4%). The median progression-free survival (PFS) was 42.1 (+/- 4.8) months with a projected PFS of 74% +/- 7% at 3-years (for 68 patients). CONCLUSIONS: PC regimen in LABC produced a high pCR. The contribution of the other added modalities to survival could not be assessed.

Adult↗
PubMed2000

Immunobiology of allogeneic peripheral blood mononuclear cells mobilized with granulocyte-colony stimulating factor.

The use of mobilized peripheral blood (PB) stem cells for autologous transplantation initially generated much enthusiasm because of enhanced engraftment in comparison to marrow stem cells and avoidance of general anesthesia for the donor. Its application to the allogeneic setting seemed inevitable. For obvious ethical reasons, allogeneic donors are mobilized with cytokines only, mainly granulocyte colony-stimulating factor (G-CSF). Results from preliminary studies suggest that in comparison to standard bone marrow transplants, outcomes such as engraftment, host-versus-graft reaction, graft-versus-host disease, graft-versus-leukemia and immunological reconstitution may be different. Surprisingly, G-CSF, previously recognized as a late acting lineage-specific factor for neutrophil production, not only disrupts homeostasis between stem cells and their microenvironment, but also induces significant quantitative and qualitative changes in the accessory cell compartment, affecting lymphocytes, monocytes, natural killer, dendritic, and stromal cells. Furthermore, mobilization of huge numbers of non-professional antigen presenting cells (CD34+ stem cells) amplifies the tolerizing potential of PB stem cell grafts. Thus, G-CSF mobilization provides PB transplants with different immunobiologic properties in comparison to standard bone marrow grafts. Whether these immunobiologic differences will lead to better transplant outcomes remains to be shown through much awaited results of large randomized clinical trials.

Bone Marrow Transplantation↗
PubMed2000

Adjuvant active specific immunotherapy for stage II and III colon cancer with an autologous tumor cell vaccine: Eastern Cooperative Oncology Group Study E5283.

PURPOSE: A randomized phase III clinical trial of adjuvant active specific immunotherapy (ASI) with an autologous tumor cell-bacillus Calmette-Guérin (BCG) vaccine was conducted to determine whether surgical resection plus ASI was more beneficial than resection alone in stage II and III colon cancer patients. PATIENTS AND METHODS: Patients (n = 412) with colon cancer (297 with stage II disease, 115 with stage III disease) were randomly allocated to an observation arm or to a treatment arm in which they received three weekly intradermal vaccine injections of 10(7) irradiated autologous tumor cells beginning approximately 4 weeks after surgery. The first two weekly injections also contained 10(7) BCG organisms. Patients were observed for determination of time to recurrence and disease-free and overall survival. RESULTS: This was a negative study in that after a 7.6-year median follow-up period, there were no statistically significant differences in clinical outcomes between the treatment arms. However, there were disease-free survival (P =.078) and overall survival (P =.12) trends in favor of ASI when treatment compliance was evaluated, ie, patients who received the intended treatment had a delayed cutaneous hypersensitivity (DCH) response to the third vaccination (induration >/=5 mm). Also, the magnitude of the DCH response correlated with improved prognosis. The 5-year survival proportion was 84.6% for those with indurations greater than 10 mm, compared with 45.0% for those with indurations less than 5 mm. CONCLUSIONS: When all randomized patients were evaluated, no significant clinical benefit was seen with ASI in surgically resected colon cancer patients with stage II or III colon cancer. However, there was an indication that treatment compliance with effective immunization results in disease-free and overall survival benefits.

Adjuvants, Immunologic↗
PubMed1999

Locally advanced breast cancer in Saudi Arabia: high frequency of stage III in a young population.

In the Kingdom of Saudi Arabia (KSA), breast cancer constitutes 18% of all cancers in Saudi women. Whilst locally advanced breast cancer disease is unusual in Western countries, it constitutes more than 40% of all non-metastatic breast cancer in KSA. The relative frequency of locally advanced disease among our breast cancer population and the lack of a uniform consensus in the literature about its optimal management have prompted this retrospective analysis of the medical records of patients with Stage III breast cancer patients seen at King Faisal Specialist Hospital and Research Center between 1981 and 1991. In all, 315 patients were identified. Their median age +/- SD was 46 +/- 11.6 years which is distinctly different from the 60-65 years median age in industrial Western nations. Most patients were younger than 50 years (64%) and premenopausal (62%). Patients were approximately equally divided between Stage IIIA and Stage III B. Patients received multimodality treatment, including surgery, adjuvant chemotherapy, tamoxifen, and adjuvant radiotherapy. Sixty-one patients were excluded from survival analysis as they were considered lost to follow-up. Of the remaining 254 patients, 73 (29%) were alive and disease free, and 18 patients (7%) were alive but with evidence of the disease. The remaining 163 (64%) had died from breast cancer or its related complications. Their median overall survival (OS) was 54 months, (95% CI, 27 to 121 months) and the median progression-free survival (PFS) was 28.8 months (95% CI, 14.2 to 113 months). Cox proportional hazard model identified Stage III B and the number of positive axillary lymph nodes as poor predictors of OS and PFS. Radiotherapy was the only adjuvant modality that affected survival favourably. The prognosis of patients with Stage III disease remains poor despite the use of a multimodality approach. The overall young age of our patients may have contributed to the poor outcome. Moreover, the adverse effect of Stage III B disease (as compared with Stage III A) and axillary nodal status was evident. Whilst the favourable effect of radiotherapy on survival was demonstrated, the lack of independent efficacy of other modalities (adjuvant chemotherapy and tamoxifen) or the apparent deleterious effect of neoadjuvant chemotherapy should be addressed with discretion in such retrospective analysis. Optimal management of patients with locally advanced breast cancer disease should be appraised in well designed, prospective, randomised studies.

Adult↗
PubMed1999

Primary gastric non-Hodgkin's lymphoma: clinical features, management, and prognosis of 185 patients with diffuse large B-cell lymphoma.

BACKGROUND: Primary gastric non-Hodgkin's lymphoma (PG-NHL) is common in Saudi Arabia. This has prompted the analysis of a large series of patients with PG-NHL having high-grade diffuse large B-cell lymphoma (DLCL) in order to define the clinical features and outcome of this disease. PATIENTS AND METHODS: The data of all adult patients in the series with PG-NHL having DLCL histology were retrospectively reviewed. Patients were eligible if they had biopsy-confirmed diagnoses obtained by endoscopy or following laparotomy. RESULTS: Over a 16-year period, 185 patients with DLCL PG-NHL were identified and their data were reviewed. Patients had a median age of 54 years. In 53% of them only one initial therapeutic modality was given, while 47% were managed by a multi-modality approach. One hundred forty patients (76%), 19 (10%), and 26 (14%) attained complete remission (CR), partial remission, and no response/progressive disease, respectively. Multivariate analysis showed that poor performance status and advanced stage were negatively associated with the likelihood of attaining CR. Over a median follow-up of 54 months, 118 (64%) of the patients were alive and disease-free, 17 (9%) were alive with evidence of disease, and the remaining 50 (27%) were dead. The projected 5-year and 10-year overall survivals (OS) (+/- SD) were 68% (+/- 4%) and 61% (+/- 6%), respectively. The Cox proportional hazards model identified the same variables of response as adverse prognostic factors of survival. Using the influence of performance status, and stage, a prognostic index was constructed to recognize three prognostically distinctive risk categories with overall survival proportions of 87%, 61%, and 45%, respectively. The unadjusted International Prognostic Index, however, failed to classify patients into prognostically meaningful risk strata. Of the 140 patients who achieved CR, the median disease-free survival (DFS) was not reached, but the predicted 5- and 10-year DFS were 82% and 75%, respectively. A multivariate analysis identified poor performance status as the only independent prognostic covariate that adversely influenced DFS. Our analysis showed that compared with single-modality management, multi-modality strategy attained significantly higher CR, and advantageous OS and DFS. CONCLUSIONS: This large series characterized the clinico-pathologic features and outcome of patients with DLCL PG-NHL. Performance status, and stage significantly influenced patient outcome. A prognostic index was developed and it identified three prognostically distinctive risk groups; however, prospective validation is warranted.

Adult↗
PubMed1999

Phase I and pharmacologic study of a 3-hour infusion of paclitaxel followed by cisplatinum and 5-fluorouracil in patients with advanced solid tumors.

A Phase I and pharmacological study of paclitaxel administered as an outpatient, 3-h i.v. infusion just before a 5-day regimen of daily cisplatinum (CP) and a continuous infusion of 5-fluorouracil (5-FU) was performed in patients with advanced solid tumors. A secondary objective was to determine the objective response rate to this regimen. Forty-two patients were enrolled and were evaluable for toxicities. Eighteen patients were previously untreated, whereas the rest had received prior treatment with radiation (J. H. Schiller et al., J. Clin. Oncol., 12: 241-248, 1994), chemotherapy (M. J. Kennedy et al., Clin. Cancer Res., 4: 349-356, 1998), or both modalities (J. H. Schiller et al., J. Clin. Oncol., 12: 241-248, 1994). The paclitaxel dose was escalated from 100-135-170-200-225 to 250 mg/m2, whereas i.v. 5-FU and CP doses were fixed at 1.0 g/m2/day continuous infusion and 20 mg/m2/day, respectively, daily for 5 days. Granulocyte colony-stimulating factor (G-CSF; 5 microg/kg/day) was administered s.c. from day 6, routinely after 250 mg/m2 dose of paclitaxel or after a lower dose of paclitaxel if ANC <500/microl or febrile neutropenia was observed. Patients were treated every 28 days. Plasma and urine samples were collected to determine the pharmacokinetics of paclitaxel. In previously untreated patients, the maximally tolerated dose of paclitaxel in the drug regimen was determined to be 170 mg/m2 without and 250 mg/m2 with G-CSF support. At the higher dose level, mucositis and thrombocytopenia were dose-limiting. In previously treated patients, these toxicities were observed at all dose levels of paclitaxel > or =135 mg/m2. With increasing doses of paclitaxel, a disproportionate increase in the peak concentrations, as well as the area under plasma concentration time-curve, was seen. This nonlinearity was due to saturable total body clearance and volume of distribution of paclitaxel (P < 0.001). The apparent plasma elimination half-life was unaffected by the dose of paclitaxel. CP and 5-FU had no apparent effect on the metabolism of paclitaxel. Among 32 patients evaluable for response, 22 demonstrated an objective response, including five complete remissions. Therefore, a regimen of 3-h infusion of 250 mg/m2 paclitaxel before CP and FU is tolerable with G-CSF (as above) support in previously untreated patients. The regimen also seems to be highly active against breast and esophageal cancers.

Adult↗
PubMed1998

Transfusion management of an IgA deficient patient with anti-IgA and incidental correction of IgA deficiency after allogeneic bone marrow transplantation.

A patient with multiple myeloma was noted to have an IgA deficiency during investigation of a possible transfusion reaction due to IgA deficiency and anti-IgA. Because of the patient's age, otherwise good health, and early stage of disease, he was enrolled in a research treatment protocol that involved an allogeneic bone marrow transplant (BMT). The BMT successfully put the patient in complete remission from his multiple myeloma and corrected his IgA deficiency. Class-specific IgG anti-IgA antibody that had been identified prior to BMT was no longer detectable in his plasma. Anaphylactic transfusion reactions were successfully avoided by using a combination of IgA-deficient and washed blood components including the marrow graft, and IgA-reduced intravenous immunoglobulin.

Adult↗
PubMed1998

Breast cancer in the eastern province of Saudi Arabia.

In the Kingdom of Saudi Arabia (KSA), hospital and population based statistics have shown that breast cancer has the highest crude frequency rate among Saudi women. The scarcity of reports about the disease in the KSA has been the impetus to this analysis about breast cancer in the eastern province of KSA. Data on female patients with invasive breast carcinoma seen at King Fahd Hospital of the University in the eastern province of KSA, were retrospectively reviewed. The analysis intended to examine the pattern of the disease and the outcome for patients. Between 1985 and 1995, 292 patients were identified. Their median age +/- SD (standard deviation) was 42 +/- 10.5 years. Most patients were younger than 50 years (78%) and were predominantly premenopausals (79%). Only 25 (9%) of patients had stage I cancer, whilst 130 (44%), 90 (30%), and 47 (16%) had stage II, III, and IV, respectively. Among patients with known axillary nodal status (242 patients), only 37% were node-negative whilst 32% and 31% had 1-3, and > or = 4 positive nodes, respectively. Adjuvant chemotherapy and tamoxifen were commonly offered; nonetheless, other adjuvant modalities were rarely utilised. The median follow-up +/- SD of all patients was 62.3 +/- 8.9 months: 152 patients (52%) were alive with no evidence of disease, 25 (9%) were alive with evidence of disease, and 115 (39%) were dead from breast cancer or its related complications. The median survival of the entire group was not obtained, but the 10-year projected survival was 55%. For stage I and II patients, 118 (76%) were alive with a projected 10-year actuarial survival of 64%. On the other hand, only 51 (57%) of patients with stage III disease were alive with a median survival of 41.5 months (95% Confidence interval (CI), 18.9 to 51.3). Patients with stage IV disease demonstrated a poor outcome with a median survival of 23.5 (95%, CI 12.2 to 31.4). Multivariate analyses were performed to explore the influence of independent variables on overall survival (OS) for patients with non-metastatic disease. Besides the expected adverse effect of disease progression, the favourable influence of adjuvant chemotherapy and tamoxifen prevailed. The amount of benefit gained from tamoxifen, however, was small. Similar analyses were undertaken to determine the influence of independent variables on progression-free survival (PFS). These analyses ascertained the adverse effects of advanced stage and the favourable impact of adjuvant chemotherapy. Breast cancer in the KSA has features that are distinctive from those of industrialised countries. Survival data, however, were comparable. The favourable influence of adjuvant chemotherapy was evident on both OS and PFS. Adjuvant tamoxifen, however, had little effect. Due to its infrequent use, the role of other adjuvant modalities could not be asserted.

Adult↗
PubMed1995

The influence of serum tumor necrosis factor-alpha and interleukin-6 concentrations on nonhematologic toxicity and hematologic recovery in patients with acute myelogenous leukemia.

To confirm the reported correlation of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) serum concentrations with nonhematologic toxicity after cytotoxic chemotherapy and to examine their possible effects on hematopoiesis, we evaluated serum TNF-alpha and IL-6 concentrations every 3 days during 21 chemotherapy cycles in 11 patients with acute myelogenous leukemia (AML) and one patient with chronic myelogenous leukemia in blast crisis (CML-BC). All patients developed grade IV hematologic toxicity. In 13 patient cycles, grade III-IV nonhematologic toxicity developed: hepatic (nine), pulmonary (six), and stomatitis (five). In these patient cycles, IL-6 concentrations increased from 10.1 pg/mL (4.6-15.6, 95% CI) before nonhematologic toxicity to 64.8 (5.3-124.2, 95% CI) at the onset of toxicity (p = 0.02). TNF-alpha concentrations were not detectable before nonhematologic toxicity but increased to 20.4 pg/mL (not detectable [ND]-45.5, 95% CI) at the onset of grade III-IV toxicity. In six patient cycles, grade II nonhematologic toxicity developed: hepatic (five), pulmonary (one), and stomatitis (two). In these six, IL-6 concentrations increased from 12.1 pg/mL (6.8-17.4, 95% CI) before toxicity to 21.4 (11-31.8, 95% CI) at the onset of toxicity (p = 0.03). TNF-alpha concentrations were detectable in one patient cycle before toxicity and detectable in only two patient cycles at the onset of toxicity. The peak IL-6 and TNF-alpha concentrations did not correlate with the onset of nonhematologic toxicity in 87% of patient cycles. In patient cycles with a cumulative IL-6 area-under-the-serum concentration vs. time curve (AUC) > 1000 pg/mL.d, platelet recovery (> 30 x 10(9)/L and platelet transfusion-independent) occurred earlier at 21.9 days (18.7-25.1, 95% CI) compared to the 30.6 days (23.6-37.5, 95% CI, p = 0.02) in patient cycles with an IL-6 AUC < 1000 pg/mL.d. Patient cycles with a cumulative TNF-alpha AUC > 150 pg/mL.d required a mean of 17.5 units of red blood cells (RBCs) (9.3-25.7, 95% CI) compared to patient cycles with an AUC < 150 pg/mL.d, which required only 8.9 units of RBCs (6.2-11.7, 95% CI, p = 0.03). The peak concentration and AUC for IL-6 and TNF-alpha were not significantly different between those receiving growth factors (G-CSF, six; GM-CSF, one) and those not receiving growth factors (14). Endogenous IL-6 and TNF-alpha serum concentrations increase in patients who experience nonhematologic toxicity and correlate with hematologic recovery after chemotherapy.

Antineoplastic Agents↗
PubMed1994

Disposition of folic acid and its metabolites: a comparison with leucovorin.

A pharmacokinetic study of folic acid and its metabolites was conducted to provide a basis to consider folic acid as a therapeutic alternative to leucovorin. Leucovorin has been used in various folate antagonist rescue regimens and to modulate fluorouracil activity in the treatment of solid tumors. Although leucovorin is typically administered intravenously in fluorouracil modulation therapy, limited oral administration trials have yielded equivalent responses. Because metabolites rather than leucovorin are the predominant circulating species after oral administration, these clinical results indicate that metabolites themselves can be modulating agents. Folic acid could be an attractive alternative to leucovorin provided it effectively elevates the same plasma metabolites. Hence, folic acid at doses of 25 and 125 mg/m2 was administered orally and intravenously to normal volunteers. Plasma folic acid and its reduced folate metabolites were monitored over a 24-hour period by use of a previously developed radioenzymatic method. The metabolites that accumulated--5-methyltetrahydrofolate, 5,10-methylenetetrahydrofolate, tetrahydrofolate, and 10-formyltetrahydrofolate--were the same metabolites that were observed previously after leucovorin administration. Folic acid metabolites accumulated more slowly and persisted longer than leucovorin metabolites, which can be attributed to slower metabolism of the fully oxidized vitamin. Based on these results, it is concluded that folic acid could be an attractive therapeutic alternative to leucovorin for fluorouracil modulation.

Adult↗
PubMed1994

Medical therapy of prostate cancer.

Prostate cancer is now the most commonly diagnosed male malignancy and the second most common cause of male cancer death in the U.S. There is no standard role for medical therapy in the treatment of localized disease, although ongoing trials are investigating possible adjuvant and neoadjuvant roles. Subtotal androgen ablation by surgical or medical means is standard therapy for advanced disease, but such therapy does not exterminate the androgen-independent clone which is hypothesized to develop very early in the course of the disease. The current favored medical therapy for subtotal androgen ablation is the use of a depot formulation of an LHRH agonist accompanied initially by an antiandrogen. Once first-line hormonal therapy has failed, there is little to be gained by any other hormonal therapy, although withdrawal of the hormone(s) might itself be a therapeutic maneuver. Cytotoxic agents presently have no standard role in the management of prostate cancer. Future effective therapies for prostate cancer are being presaged by advances in prostate tumor biology.

Humans↗
PubMed1993

Autologous bone marrow transplantation for leukemia.

Autologous bone marrow transplantation for leukemia was developed to extend the apparent curative potential of myeloablative therapy with allogeneic bone marrow transplantation to leukemia patients without histocompatible marrow donors. The conceptual problem with this approach is obvious: if the need for the transplant is based on overt or occult contamination of the marrow by leukemia, the use of autologous marrow seems destined to failure because of reinfusion of leukemia cells along with the harvested marrow. For this reason, ex vivo antileukemic treatment ("purging") of remission marrow was developed to justify autologous transplants for leukemia. Clinical trials involving thousands of patients worldwide have demonstrated curative potential of autologous bone marrow transplants, using purged or untreated remission marrow, for selected patients with acute myelogenous leukemia and acute lymphocytic leukemia. Purging appears to contribute to increased leukemia-free survival, at least in a subset of patients who are at very high risk of relapse, but this has not been tested in a prospective randomized trial and remains controversial. In acute myelogenous leukemia, in which the greatest experience exists, procedure-related mortality is much less for autologous than for allogeneic transplants; however, since leukemia relapse is much more frequent for autologous than for allogeneic transplants, the long-term disease-free survival is similar. In general, autologous transplants are preferred for older individuals and those without matched related donors, whereas allogeneic transplants are preferred for younger patients with matched related donors. Leukemia relapse has greatly limited the success of autologous transplants for acute lymphocytic leukemia. Autologous transplants for the chronic leukemias are in a much earlier stage of investigation. Autologous transplantation for leukemia is a fertile area for research. Important topics include conditioning regimens with improved antileukemic efficacy, the value of purging and the best method(s) for leukemia stem cell purging or normal stem cell selection, the possibility of inducing an autologous graft versus leukemia reaction, the use of immunomodulatory cytokines for postgrafting immune system manipulation, and the use of hematopoietic growth factors for ex vivo stem cell expansion and postgrafting support of marrow recovery.

Animals↗