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Biomedical subjects

R C Young

Publications and source records attributed to R C Young.

At least 127 records · Page 7Linked to original sources
PubMed1991

Long-term follow-up of ProMACE-CytaBOM in non-Hodgkin's lymphomas.

Initial results from studies with third-generation combination chemotherapy regimens for the treatment of aggressive non-Hodgkin's lymphomas (NHL) demonstrated complete remission (CR) rates higher than those reported with first-generation regimens. Long-term follow-up of these studies is required to know if the increased number of CRs translates into an increased number of long-term disease-free survivors. In this report, results obtained with one of the third-generation regimens, ProMACE (prednisone/methotrexate/doxorubicin/cyclophosphamide/etoposide)-Cyta BOM (cytarabine/bleomycin/vincristine/methotrexate) are described. From 1981 to 1988, 193 patients with stage II, III, or IV aggressive NHL treated at the National Cancer Institute were randomly assigned to receive either ProMACE (day 1)-CytaBOM (day 8) or ProMACE (day 1)-MOPP (mechlorethamine/vincristine/procarbazine/prednisone) (day 8). With a median follow-up of 5 years, the CR rate was 86% for ProMACE-CytaBOM v 74% for ProMACE-MOPP (P = 0.048). A plateau in the disease-free survival curve is seen at 69% for ProMACE-CytaBOM v 54% for ProMACE-MOPP (P = 0.082). A plateau is also seen in the overall survival curves at 69% for ProMACE-CytaBOM v 53% for ProMACE-MOPP (P = 0.046). The Southwest Oncology Group also conducted a phase II study of ProMACE-CytaBOM in 78 patients with stages II to IV intermediate- or high-grade NHL to determine the CR rate and long-term disease-free survival of this regimen in a national cooperative group setting. The CR rate was 65%. With a median follow-up of 38 months, disease-free survival is 50% at 3 years and overall survival is 57% at the same time point.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1991

The calculation of actual or received dose intensity: a comparison of published methods.

Two recent reports of the same combination chemotherapy program, cyclophosphamide, doxorubicin, etoposide, methotrexate, cytarabine, vincristine, bleomycin, and prednisone (ProMACE-CytaBOM), in similar subsets of patients with advanced-stage aggressive-histology lymphoma used two different methods to report the actual dose-intensity (DI) data. One method treats DI as a property of a particular cycle of treatment within the entire population that received that cycle. The other treats DI as a characteristic of a particular patient's entire treatment course. We have applied both methods to the same set of data and provide evidence that the latter method is preferable for at least two reasons: (1) it more accurately reflects actual DI by clearly incorporating the duration of the actual treatment course and, thus, can be used to compare the administration of same or related regimens to distinct patient populations; and (2) it allows assignment of a numerical value to an individual patient's treatment course or a group of patients' treatment courses such that DI can be examined for its impact on treatment outcome just like any other prognostic factor. The observed differences in treatment outcome between the Southwest Oncology Group (SWOG) and National Cancer Institute (NCI) studies are not clearly related to differences in distribution of clinical prognostic factors in the two study populations. The differences in methods of reporting DI prohibit evaluation of the influence of dose-related variables on outcome in the two studies. Adoption of a standard method of calculating and reporting DI data would facilitate evaluation of the prognostic significance of DI.

Aged↗
PubMed1991

Clinical evaluation of intraperitoneal Pseudomonas exotoxin immunoconjugate OVB3-PE in patients with ovarian cancer.

OVB3-PE is an immunotoxin composed of a murine monoclonal antibody reactive with human ovarian cancer and conjugated to Pseudomonas exotoxin (PE). Twenty-three patients with refractory ovarian cancer were treated intraperitoneally (IP) with escalating doses of OVB3-PE to study toxicity, pharmacokinetics, antiimmunotoxin antibody formation, and antitumor response. Dose-limiting CNS toxicity occurred after repeated doses at 5 and 10 micrograms/kg. Other non-dose-limiting toxicities included transient elevation of liver enzymes, fever, and gastrointestinal toxicity. Pharmacokinetics of IP and serum OVB3-PE were determined in 16 patients. Peak peritoneal fluid levels exceeded the in vitro median effective dose at all doses tested. At doses of 1 to 2 micrograms/kg, the immunotoxin concentration in the peritoneal fluid remained constant for up to 8 hours and dropped to negligible levels after 12 hours. At the 5 and 10 micrograms/kg doses, levels remained high for up to 24 hours (greater than 100 ng/mL) and then gradually decreased and became undetectable (less than 4 ng/mL) after 72 hours. Serum levels of OVB3-PE were also analyzed in 16 patients. At doses of 1 micrograms/kg and 2 micrograms/kg, serum levels were not detectable (less than 5 ng/mL). However, after doses of 5 or 10 micrograms/kg, peak serum level occurred at 24 hours after each dose and dropped to negligible levels by 72 hours. Sera from 12 patients were analyzed for anti-PE antibodies and antibodies to mouse immunoglobulin (HAMA). All patients developed antibodies against PE within 14 days of therapy. Domain II of PE appeared to be the most immunogenic portion of the PE molecule. HAMA was detected on day 14 of therapy in nine patients, on day 21 in two, and on day 28 in one patient. No clinical antitumor responses were observed. We conclude that IP OVB3-PE at dose levels of 5 micrograms/kg (x 3) and 10 micrograms/kg (x 2) is accompanied by dose-limiting toxic encephalopathy. Neurologic toxicity is likely to be due to crossreactivity of OVB3 to normal human brain tissue, which was not appreciated during preclinical screening.

ADP Ribose Transferases↗
PubMed1991

Treatment of advanced-stage massive mediastinal Hodgkin's disease: the case for combined modality treatment.

In the initial series of 198 patients treated at the National Cancer Institute (NCI) with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy for Hodgkin's disease, a review of presenting chest radiographs available on 192 of these patients showed 49 patients with mediastinal masses greater than one third the greatest posteroanterior chest diameter. Five patients had stage IIB disease, and 44 had stage III or IV disease. Thirty-five (71%) patients achieved a complete remission with MOPP chemotherapy. Fourteen (40%) of the complete responders relapsed, but four of these achieved durable remissions in response to subsequent therapy. Thirty (61%) patients have died (14 induction failures, nine relapsed patients, seven complete responders in remission). Thus, with a median follow-up of 20 years (range, 15 to 23), the overall survival for the group is 39%, and the disease-free survival for the complete responders is 60%. A subset of 10 patients received mantle radiation therapy after maximal response to MOPP. One of these patients failed to achieve complete remission, but among the nine complete responders only one has relapsed. In contrast, 13 of 26 (50%) patients achieving a complete response to MOPP alone have relapsed (P2 = .0536). Although MOPP alone was not prospectively compared with MOPP plus radiation therapy in the treatment of advanced-stage massive mediastinal Hodgkin's disease in this series, the retrospective analysis shows a nearly significant difference in disease-free survival favoring combined modality treatment. The difference in tumor mortality between MOPP-treated (44%) and combined modality-treated patients (80%) was also nearly significant (P2 = .055). However, overall survival differences between patients treated with MOPP alone and those treated with combined modality therapy were not significantly different (P2 = 0.23) because of the mortality related to late complications of combined modality treatment.

Adolescent↗
PubMed1991

Radiation therapy versus combination chemotherapy in the treatment of early-stage Hodgkin's disease: seven-year results of a prospective randomized trial.

The study population included 136 patients with stage IA, IB, IIA, IIB, or IIIA1 Hodgkin's disease. The median follow-up is 7.5 years. Among the 30 patients with peripheral IA disease, all patients achieved a complete response (CR) with radiation therapy, and no patient has relapsed. Patients of other stages were randomized to receive radiation therapy or mechlorethamine, vincristine, procarbazine, and prednisone (MOPP). Among the 51 patients randomized to receive radiation therapy, 49 (96%) achieved complete remission, 17 (35%) have relapsed, and 10 (20%) have died. Fifty-two of the 54 (96%) assessable patients randomized to receive MOPP obtained CRs, seven (13%) have relapsed, and four (7%) have died. The projected 10-year disease-free survival of patients randomized to receive radiation therapy is 60%; for those randomized to receive MOPP, it is 86% (P2 = .009 in favor of MOPP). The projected 10-year overall survival for patients randomized to radiation therapy is 76%, and for MOPP-treated patients it is 92% (P2 = .051 in favor of MOPP). When the randomized patients with massive mediastinal disease or stage IIIA1 disease were excluded from the analysis, the disease-free (67% for radiation v 82% for MOPP) and overall survival (85% for radiation v 90% for MOPP) were not significantly different between the two arms. Subset analysis showed significant superiority of MOPP in the treatment of the following patient groups: stage IIIA1 or massive mediastinal disease, no B symptoms, initial erythrocyte sedimentation rate greater than 20 mm, four or more sites of disease, and younger than age 40 years. Preliminary analysis of this ongoing study shows that MOPP chemotherapy is at least as effective as radiation therapy in the treatment of the specific groups of early-stage Hodgkin's disease patients randomized. The final assessment of these two diverse treatment options will depend largely on the long-term survival and the incidence of early- and late-treatment complications for which patients are continuing to be observed.

Adolescent↗
PubMed1991

Treatment of advanced-stage Hodgkin's disease: alternating noncrossresistant MOPP/CABS is not superior to MOPP.

One hundred twenty-five assessable patients with advanced-stage Hodgkin's disease were randomized to receive mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) or MOPP alternating with lomustine (CCNU), doxorubicin, bleomycin, and streptozocin (CABS). The median follow-up is 7.7 years. The complete response rate was 60 of 66 MOPP-treated patients (91%) and 54 of 59 MOPP/CABS-treated patients (92%) (difference not significant). The level of the disease-free survival curve at longest follow-up is 65% for MOPP-treated patients and 72% for MOPP/CABS-treated patients (difference not significant). The overall survival at 12 years is projected at 68% for MOPP-treated patients and 54% for MOPP/CABS-treated patients (difference not significant). Thus, there were no significant differences in efficacy between MOPP and MOPP/CABS. However, MOPP/CABS was more emetogenic than MOPP, and four MOPP/CABS-treated patients went on to develop secondary acute leukemia. No MOPP-treated patients developed leukemia. High initial erythrocyte sedimentation rate (ESR) and high platelet counts adversely affected treatment outcome. MOPP-treated patients who received greater than 81% of the projected dose intensity of vincristine over the first three cycles had significantly improved disease-free survival rates over those receiving less than 81%. MOPP/CABS-treated patients who received greater than 82% of the projected dose intensity of vincristine had significantly better overall survival than those who received less than 82%. Disease-free survival on both arms was significantly better in patients who received greater than 84% of the projected dose intensity of all agents. The effect of dose intensity was particularly apparent in patients with poor prognostic factors where those who received greater than 84% of the projected dose intensity of all agents had significantly improved disease-free and overall survival.

Acute Disease↗
PubMed1991

Maximizing communication skills in graduate and postgraduate health-care education through medical writing.

Graduate and postgraduate health-care professional training and postdoctoral fellowship programs that deny trainees opportunities to practice both oral and written communication skills produce an incompletely trained health-care provider unable to compete for faculty positions at university hospitals and affiliated staffs. Therefore, it is imperative that program directors make medical writing a prerequisite to successful completion of postgraduate training programs. To make trainees as well as administrators and faculty aware of the importance of oral and written communication skills, a variety of oral abilities needed for presenting medical findings prior to publication are detailed. The use of 2 x 2 slides to support a presentation as well as transparencies, movies, and videotapes are considered. The poster session/scientific exhibit, now becoming more visible because of increasing attendance at professional meetings, is also explained. Written communication abilities are discussed. Consideration is given to the writing of professional manuscripts for publication in a refereed journal. Other types of written communication include case reports, clinicopathological conferences, letters to the editor, book reviews, books, and book contributions. The opportunity to learn needed skills must be offered in the postgraduate health-care curriculum. Mandatory medical writing will maximize the marketability of black health-care professionals for faculty staff placement. Moreover, the establishment of a "track record" early in a professional career will increase the likelihood that black health providers are awarded grants for research.

Audiovisual Aids↗
PubMed1991

Verbal memory and plasma drug concentrations in elderly depressives treated with nortriptyline.

Performance on a verbal memory task and affective state were assessed in geriatric major depressives before and during 6 weeks of treatment with nortriptyline (NT) in a fixed-dose design study. Higher plasma NT concentration was associated with poorer free recall but better affective outcome. In contrast, higher plasma Z-10-hydroxynortriptyline (Z-10-OH-NT) concentration was associated with more efficient free recall. Concentration-effect relationships were noted in patients later classified as cognitively unimpaired using the Dementia Rating Scale after optimal treatment, rather than in those with residual cognitive impairment.

Aged↗
PubMed1991

Hydroxylated metabolites of antidepressants.

Hydroxylated metabolites (OHMs) of antidepressant drugs are pharmacologically active. On chronic administration, unconjugated OHM plasma concentrations can be substantial compared to that of the parent compound, especially for secondary amine TCAs and bupropion. OHMs may contribute to toxicity and may contribute to, or attenuate, efficacy. Direct administration of OHMs may be associated with antidepressant effects.

Antidepressive Agents↗
PubMed1991

Gynecologic malignancies.

The combination of cisplatin and cyclophosphamide remains the preferred regimen for the primary treatment of advanced stage epithelial ovarian cancer. Maximal dose intensity, particularly that of cisplatin, is generally accepted as critical for optimal results, but the concept has not yet been rigorously validated by prospective, randomized trials. Since higher doses of cisplatin are associated with renal and neurologic toxicity, the accumulating evidence of equivalent response rates with the less toxic platinum analogue, carboplatin, is encouraging. Salvage chemotherapy remains unsatisfactory, although the remarkable responses observed this year in heavily pre-treated and platinum-resistant patients with the novel new agent taxol is promising. Further trials with this unique drug in combination with other agents in previously untreated patients, as well as in salvage settings, is eagerly anticipated. Although experience with intraperitoneal therapy is rapidly accumulating, the precise role for this route of delivery has yet to be demonstrated in prospective trials. The management of early stage ovarian cancer has become increasingly clarified. Several trials have now demonstrated that a subgroup of patients at low risk for recurrence do well with surgery alone, while a high-risk subgroup clearly benefits from adjuvant therapy. The identification of optimal regimens awaits further trials. In cervical carcinoma, trials utilizing a variety of radiation-sensitizing agents have failed to demonstrate superiority over that of hydroxyurea, which has been shown to improve survival in advanced disease. Preliminary experience with neo-adjuvant regimens administered prior to surgery or radiation therapy is promising, but survival advantages utilizing this approach have yet to be demonstrated. In endometrial cancer, cisplatin was shown to achieve response rates similar to those attainable with single agent doxorubicin, and in uterine mixed mesodermal tumors, ifosfamide was found to have significant activity.

Antineoplastic Agents↗
PubMed1990

Evaluation of platinum-DNA adduct levels relative to known prognostic variables in a cohort of ovarian cancer patients.

Single-agent chemotherapy with cisplatin or carboplatin can induce remissions in approximately 30% of previously treated patients with advanced stage ovarian cancer. Previous studies have shown that the extent of platinum-DNA adduct formation measured in WBC DNA of ovarian cancer patients treated with cisplatin or carboplatin is directly associated with disease response (Reed et al., Proc. Natl. Acad. Sci. USA, 84: 5024-5028, 1987). It has been unclear whether adduct level in WBC DNA is independent of known prognostic variables in this disease, or whether adduct level parallels a known prognostic variable that can be more easily monitored. In a cohort of 24 ovarian cancer patients treated with single-agent cisplatin or carboplatin, we retrospectively assessed the relationship between disease response, platinum-DNA adducts in WBC DNA, and each of eight prognostic variables by both univariate analysis and multivariate analysis. The prognostic variables evaluated included: response to previous treatment, Karnofsky status, total platinum dose prior to current therapy, stage of disease, age, bulk of disease at initiation of therapy, histological type, and histological grade. By univariate analysis, adduct level was strongly associated with disease response (two-sided P = 0.0058), with the next strongest associations with disease response being held by Karnofsky status (P = 0.125), stage of disease (P = 0.189), response to previous treatment (P = 0.352), total previous platinum dose (P = 0.358), and age (P = 0.374). No significant associations were found between adduct level and histological type or histological grade. Further, when patients were stratified by the number of cycles studied (one cycle, two cycles, or three cycles), higher levels of adduct were consistently seen in those patients responding to therapy. We conclude that, in this small cohort of refractory ovarian cancer patients treated with single-agent cisplatin or carboplatin, adduct level in WBC DNA appears to be more closely related to disease response than other previously identified prognostic variables.

Antineoplastic Agents↗
PubMed1990

Adjuvant therapy in stage I and stage II epithelial ovarian cancer. Results of two prospective randomized trials.

About a third of patients with ovarian cancer present with localized disease; despite surgical resection, up to half the tumors recur. Since it has not been established whether adjuvant treatment can benefit such patients, we conducted two prospective, randomized national cooperative trials of adjuvant therapy in patients with localized ovarian carcinoma (International Federation of Gynecology and Obstetrics Stages Ia to IIc). All patients underwent surgical resection plus comprehensive staging and, 18 months later, surgical re-exploration. In the first trial, 81 patients with well-differentiated or moderately well differentiated cancers confined to the ovaries (Stages Iai and Ibi) were assigned to receive either no chemotherapy or melphalan (0.2 mg per kilogram of body weight per day for five days, repeated every four to six weeks for up to 12 cycles). After a median follow-up of more than six years, there were no significant differences between the patients given no chemotherapy and those treated with melphalan with respect to either five-year disease-free survival (91 vs. 98 percent; P = 0.41) or overall survival (94 vs. 98 percent; P = 0.43). In the second trial, 141 patients with poorly differentiated Stage I tumors or with cancer outside the ovaries but limited to the pelvis (Stage II) were randomly assigned to treatment with either melphalan (in the same regimen as above) or a single intraperitoneal dose of 32P (15 mCi) at the time of surgery. In this trial (median follow-up, greater than 6 years) the outcomes for the two treatment groups were similar with respect to five-year disease-free survival (80 percent in both groups) and overall survival (81 percent with melphalan vs. 78 percent with 32P; P = 0.48). We conclude that in patients with localized ovarian cancer, comprehensive staging at the time of surgical resection can serve to identify those patients (as defined by the first trial) who can be followed without adjuvant chemotherapy. The remaining patients with localized ovarian cancer should receive adjuvant therapy, and with adjuvant melphalan or intraperitoneal 32P should have a five-year disease-free survival of about 80 percent.

Adult↗
PubMed1990

Mechanisms to improve chemotherapy effectiveness.

Although many effective anti-cancer agents are now available, their curative potential is compromised by a variety of problems related to tumor sensitivity, drug access, and pharmacokinetics. Central to the problem of inadequate chemotherapy is drug resistance. Drug resistance may be intrinsic, acquired, or induced, and it may develop to one drug or it may occur simultaneously to multiple agents (pleiotropic). Substantial progress has been made in our understanding of the mechanisms of drug resistance and techniques for overcoming that resistance. New evidence has emerged that highlights the importance of dose intensity in achieving successful drug treatment outcomes. Retrospective analysis of studies in breast, ovarian, colon cancer, and lymphoma suggest that new studies designed to optimize dose intensity may yield improved results. Several prospective trials have now corroborated the retrospectively derived importance of dose intensity as an independent factor in achieving improved survival. Finally, new techniques for drug delivery offer considerable promise. Chemotherapy by regional infusion and perfusion, implantable drug delivery systems, and continuous infusion of chemotherapy are unique novel techniques that may improve the efficacy of presently available chemotherapeutic agents even as new agents are developed.

Antineoplastic Agents↗