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Biomedical subjects

L Norton

Publications and source records attributed to L Norton.

At least 145 records · Page 8Linked to original sources
PubMed1993

Antitumor effects of doxorubicin in combination with anti-epidermal growth factor receptor monoclonal antibodies.

BACKGROUND: A variety of human tumors frequently express high levels of epidermal growth factor (EGF) receptor and its ligand, transforming growth factor alpha (TGF-alpha), which in some tumors is associated with poor prognosis. Monoclonal antibodies (MAbs) that block the binding of TGF-alpha or EGF to the receptor can inhibit proliferation of tumor cells that express the receptor. Studies suggest that these MAbs may enhance the antitumor effects of chemotherapy. PURPOSE: Our purpose was to study, in vitro and in vivo, the antitumor effects of doxorubicin in combination with anti-EGF receptor MAbs against tumor cells expressing high levels of EGF receptor. Our goal was to achieve maximum initial cytoreduction with high-dose doxorubicin in association with prolonged blockade of EGF receptor with MAbs. METHODS: Anti-EGF receptor MAbs 528 (isotype IgG2a) and 225 (isotype IgG1) were used in combination with doxorubicin against cells from human A431 squamous cell carcinoma and human MDA-468 breast adenocarcinoma. Both A431 and MDA-468 cells express high levels of EGF receptors and TGF-alpha. Cultured cells were treated with doxorubicin (range, 0-10 nM) in the presence or absence of MAb 528 or 225 (range, 0-30 nM). At 48 hours, doxorubicin-containing medium was removed, and treatment with antibody was continued for 5 days, when cell proliferation assays were performed. The activity of the agents and the combinations against well-established xenografts in BALB/c nude mice was also studied. In nude mice, doxorubicin was given at doses of 50-100 micrograms/20 g body weight on 2 successive days, and MAbs 528 and 225 were given at a dose range of 0-2 mg intraperitoneally twice a week. RESULTS: MAbs 528 and 225 both enhanced the antitumor effects of doxorubicin against A431 and MDA-468 tumor cells, producing additive growth suppression in cell cultures. MAb 528 increased the antitumor effects of doxorubicin by 32%-42%, and similar results were obtained with MAb 225. In BALB/c athymic mice, the treatment of well-established xenografts with either doxorubicin or anti-EGF receptor MAb alone temporarily inhibited growth, but the combination of both agents substantially enhanced antitumor activity over that of doxorubicin alone in A431 and MDA-468 cell xenografts. The combination treatment of mice bearing A431 xenografts resulted in tumor eradication of 40%-100% in the surviving mice in several independent experiments. The enhanced antitumor activity was dose dependent. CONCLUSIONS: Our results suggest that anti-EGF receptor MAbs substantially enhance the effects of doxorubicin against well-established xenografts of tumor cells expressing high levels of EGF receptors. IMPLICATIONS: Clinical trials with anti-EGF receptor MAbs are being conducted, and trials with anti-EGF receptor MAbs combined with doxorubicin are planned.

Adenocarcinoma↗
PubMed1993

Modeling the development of metastases from primary and locally recurrent tumors: comparison with a clinical data base for prostatic cancer.

For many types of cancer, patients who relapse locally following localized treatment such as surgery or radiation therapy are found to have a higher incidence of distant metastases than those who are locally controlled. In this study we developed a mathematical model to investigate whether the excess distant metastases arise mainly from the local recurrence or whether the primary tumors in this group of patients have an intrinsically higher metastatic potential than those of locally controlled patients of the same clinical stage. The parameters of the model were chosen to be representative of prostate cancer and the calculated results were compared with published clinical data for carcinoma of the prostate. The best agreement with the data was seen for parameters which imply somewhat more "aggressive" primary tumors for locally relapsing patients, yielding relatively high rates of micrometastatic dissemination prior to initial diagnosis. However, the model calculations indicate that more than half of the metastases in such patients originated in association with the development of a local recurrence. Therefore, achieving local control in this group of patients would be beneficial in improving long term survival.

Computer Simulation↗
PubMed1993

Formation of food aversions in cancer patients receiving repeated infusions of chemotherapy.

Patients receiving emetogenic chemotherapy for cancer have been found to develop aversions to normal dietary items consumed in close temporal relation to treatment administrations. These aversions are presumed to develop via conditioning processes as demonstrated in experimental studies of food aversion learning. The present study used a prospective, longitudinal design to evaluate the possible role of conditioning in the formation of aversions to normal dietary items in women receiving adjuvant chemotherapy for breast cancer. Patients were monitored for the development of aversions to foods and beverages consumed in the 24 hr periods before and after each of eight consecutive chemotherapy infusions beginning with the initial infusion. Data on the prevalence, course, and prediction of aversions to normal dietary items are reported. These results pointed to similarities and differences between aversions formed to normal dietary items during chemotherapy treatment and aversions formed to taste stimuli during experimental conditioning studies. In addition to their theoretical significance, results also suggest possible strategies for preventing the clinical problem of aversions to normal dietary items in chemotherapy patients.

Adult↗
PubMed1993

Systemic adjuvant therapy for breast cancer.

The use of systemic (drug) therapy postoperatively reduces the risk of relapse and death for patients with resectable invasive breast cancer. The Early Breast Cancer Trialists' Collaborative Group overview analysis confirmed the benefits of both polychemotherapy and tamoxifen in broad subgroups of patients. It remains a challenge, however, to quantify the risk of relapse and the benefit of therapy for individual patients. If the ipsilateral lymph nodes are free of metastases and the tumor is infiltrating ductal or lobular in histology and less than 1 cm in diameter, the risk of relapse is low, so the benefits of standard treatments are too small to warrant routine use. For node-negative patients with larger tumors or for those with positive lymph nodes, the benefits of therapy are significant, although many of these individual patients will not relapse. Hence, better prognostic methods, improving the accuracy of predicting an individual patient's risk, could allow for more rational treatment recommendations. The most widely used polychemotherapy combination incorporates three drugs: cyclophosphamide, methotrexate, and fluorouracil. The substitution or inclusion of doxorubicin, which is somewhat more toxic than the cyclophosphamide, methotrexate, and fluorouracil regimen, is justifiable in subsets of patients at higher risk of relapse, eg, those with metastatic involvement of four or more axillary lymph nodes. Because higher dose intensity (the amount of drug given per unit time) of chemotherapy improves relapse-free survival, phase II clinical trials are testing various dose-intensification strategies, and phase III trials are underway to determine their comparative efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Factors influencing prognosis in node-negative breast carcinoma: analysis of 767 T1N0M0/T2N0M0 patients with long-term follow-up.

PURPOSE: This study was undertaken to define prognostically favorable and unfavorable subgroups of node-negative breast carcinoma patients by employing conventional pathologic data. PATIENTS AND METHODS: Seven hundred sixty-seven women with T1N0M0/T2N0M0 breast carcinoma treated consecutively from 1964 through 1970 by modified or radical mastectomy without systemic adjuvant therapy were analyzed at a median follow-up duration of 18 years. RESULTS: Size and histologic type of the carcinoma were crucial discriminants of prognosis. We defined a prognostically favorable group of 219 patients (29%) with infiltrating duct or lobular carcinoma < or = 1.0 cm in diameter or special tumor types < or = 3.0 cm. This group had a relapse-free survival rate of 91% at 10 years and 87% at 20 years. The less favorable group (548 patients, 71%) with infiltrating duct or lobular carcinoma greater than 1.0 cm and special tumor types greater than 3.0 cm had relapse-free survival rates of 73% and 68% at 10 and 20 years, respectively. The frequency of nonmammary malignant neoplasms (NMMN) was similar to that of contralateral carcinoma. Deaths due to NMMN were seven times more frequent than deaths due to contralateral carcinoma. CONCLUSION: Nearly 30% of these node-negative patients, identified on the basis of tumor size and type, had an extremely favorable prognosis. There is insufficient evidence to warrant the routine use of adjuvant therapy in this group unless new forms of treatment prove to be less toxic and/or more effective in enhancing relapse-free survival. Early detection of NMMN should be an important part of the follow-up of node-negative breast carcinoma patients.

Breast Neoplasms↗
PubMed1993

An intensive sequenced adjuvant chemotherapy regimen for breast cancer.

Twenty-two women (17 pre- and 5 postmenopausal) with nodepositive, stage II breast carcinoma were treated with adjuvant chemotherapy consisting of 16 weeks of intensive CMFVP (cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone) administered in the original dose and schedule of the "Cooper regimen," followed by four monthly, 3-day cycles of escalating doxorubicin. Toxicity was related primarily to myelosuppression associated with the doxorubicin component of the treatment regimen. All patients recovered without sequelae. No patient developed significant cardiac toxicity. With a median follow-up of 43 months (range: 20-89 months), two postmenopausal patients and one premenopausal patient have relapsed at 35, 37, and 42 months, respectively. By Kaplan-Meier survival analysis, there is an 80.5% chance of disease-free survival to 42 months. The feasibility of administering adjuvant CMFVP followed by intensive doxorubicin has been established. The pilot results warrant comparative trial with the best of current regimens.

Adult↗
PubMed1993

Preliminary experience with paclitaxel (Taxol) plus recombinant human granulocyte colony-stimulating factor in the treatment of breast cancer.

Single-agent paclitaxel (TAXOL) was administered to 79 patients with stage IV breast cancer. Twenty-eight patients had no prior chemotherapy (for metastatic disease), and 51 patients had extensive exposure to other chemotherapeutic agents before beginning the 24-hour paclitaxel infusion. Routine use of recombinant human granulocyte colony-stimulating factor helped to ameliorate neutropenia, the dose-limiting toxicity, in some cases. Other toxicity was generally mild to moderate. Paclitaxel was more active in patients whose stage IV disease had not yet been exposed to chemotherapy, but activity was seen in the patients previously treated extensively as well. There is a strong clinical suggestion of non-cross-resistance with doxorubicin. In one case, an excellent response in previously irradiated skin was seen. Paclitaxel is a very promising agent for the treatment of metastatic breast cancer.

Adult↗
PubMed1992

Precholecystectomy endoscopic cholangiography and stone removal is not superior to cholecystectomy, cholangiography, and common duct exploration.

Thirty-four patients with suspected common bile duct stones were randomized to undergo endoscopic cholangiography and stone removal prior to open cholecystectomy or to have open cholecystectomy, operative cholangiography, and common bile duct exploration. Sixteen underwent the first protocol, and 18 the second. Analysis of the ability to clear stones from the common bile duct, morbidity, mortality, hospital stay, length of operation, and hospital cost showed no difference in outcome between patients treated by either method. These data suggest there is neither an advantage nor a disadvantage to treating patients with suspected duct stones by precholecystectomy endoscopic cholangiography and stone removal.

Adult↗
PubMed1992

Work patterns of male and female pharmacists. A longitudinal analysis 1959-1989.

A demand for better data about pharmacists as working health professionals led the authors to study the work patterns of 1,146 pharmacists over a 30-year period from 1959 to 1989. Work history data were used to determine gender-specific participation rates as a function of age, years in the work force, and date. Percent full-time (as opposed to part-time) work as a gender-specific function of age was also determined. Participation rates for males and females, widely disparate in the 1960s, have converged and are not significantly different. Graduates of the 1980s, both male and female, are remaining with pharmacy as an occupation at a significantly higher rate than earlier graduates. Percent full-time rates for women pharmacists are significantly lower than those for male pharmacists, although women have registered significant increases in percent full-time work in each decade from the 1960s to the 1980s. An unexpected finding was the overall reduced participation by graduates of the years 1970 to 1979. The findings of the study are helpful in explaining recent controversies about the adequacy of the supply of pharmacists. The form of the data bases constructed for this study could be used as a model for the study of other health professionals.

Adult↗
PubMed1991

Trimetrexate in untreated and previously treated patients with metastatic breast cancer: a Cancer and Leukemia Group B study.

Twenty-two patients with previously untreated metastatic breast cancer and nineteen patients with refractory metastatic breast cancer were treated with trimetrexate (TMTX). Patients received TMTX 8 mg/m2/day if previously treated or 12 mg/m2/day if previously untreated, both given by intravenous bolus days 1-5, every 21 days. None of the patients previously treated for metastatic disease responded to TMTX. There was one partial responder among the 22 patients with previously untreated metastatic disease. The primary toxicity was hematologic and occurred more frequently in patients with a pleural effusion, low serum protein or albumin, or poor performance status. There were three toxic deaths. The study for previously untreated patients required cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) after 4 cycles of TMTX. This study design for previously untreated patients allows the Cancer and Leukemia Group B (CALGB) to prospectively evaluate the activity of new agents in "chemotherapy-sensitive" metastatic breast cancer.

Antineoplastic Agents↗
PubMed1991

A human periodontal ligament fibroblast clone releases a bone resorption inhibition factor in vitro.

The conditioned media (CM) obtained from three lines of cloned human periodontal ligament (PDL) cells were analyzed to determine whether they altered the parathyroid hormone (PTH)-stimulated resorption rates (45Ca release) in 48-hour cultures of 45Ca-labeled rat long bones. One PDL cell line, PDL-5, produced a heat-resistant factor in its CM that inhibited the PTH-stimulated resorption by 43.8 +/- 9.7 (SE) percent (p less than or equal to 0.02), whereas the CM from the other cell lines were without statistically significant effect. The CM from the PDL-5 line did not diminish organ culture viability, as determined by 3H-thymidine incorporation, and did not enhance or diminish the resorption-inhibiting activity of calcitonin added to the PTH-stimulated cultures. The addition of CM from PDL-5 did not alter the bone-resorbing effect of interleukin-1 (IL-1). These results indicate that CM from PDL-5 inhibits only the PTH-induced and not the IL-1-mediated resorption processes, whose mechanisms are therefore likely to differ.

Analysis of Variance↗
PubMed1991

Prediction of prognosis in primary breast cancer by detection of a high molecular weight mucin-like antigen using monoclonal antibodies DF3, F36/22, and CU18: a Cancer and Leukemia Group B study.

Three monoclonal antibodies (MAbs) (DF3, F36/22, CU18) were used to monitor expression of distinct epitopes present within a family of mucin-like, breast carcinoma-associated molecules. Primary tumor specimens from more than 190 stage II breast cancer patients were evaluated for expression of the high molecular weight antigens. With a median follow-up of 6 years, patients whose tumors exhibited high immunoperoxidase staining scores (greater than 50% positive cells) with MAb DF3 had a superior disease-free survival ([DFS] 56% +/- 6% v 37% +/- 5% at 6 years; P = .0088) and overall survival ([OS] 72% +/- 5% v 59% +/- 5% at 6 years; P = .025). Staining scores with the other two antibodies did not correlate with improved prognosis. For MAbs DF3 and CU18, patients whose tumors exhibited predominantly apical cellular reactivity patterns had improved DFS, although differences reached conventional levels of statistical significance only with MAb CU18. In multivariate analyses, the prognostic value of MAb DF3 staining was independent of other identified prognostic factors. Furthermore, the concordance between primary and axillary lymph node metastases staining with each MAb was 73%, 80%, and 85% for MAbs DF3, F36/22, and CU18, respectively. These results suggest that staining with MAb DF3 identifies a group of node-positive women with a relatively favorable prognosis. Expression of the DF3 mucin-like glycoprotein is related to better differentiation, and staining with MAb DF3 provides an accurate and objective estimate of clinical outcome independent of histopathologic evaluation.

Adult↗
PubMed1991

Chemotherapy of metastatic Merkel cell cancer.

Out of 16 cases of Merkel cell cancer identified in the records of the Mt. Sinai Medical Center or affiliates, 11 patients developed systemic metastases. Literature review confirms the substantial possibility of dissemination. Both in our series and in the literature, cytotoxic chemotherapy produced a high rate of usually short-lived response, although one of our patients with disseminated metastases achieved complete remission for two years.

Adult↗