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Biomedical subjects

M A Tempero

Publications and source records attributed to M A Tempero.

At least 19 recordsLinked to original sources
PubMed2005

Serum CA19-9 response as a surrogate for clinical outcome in patients receiving fixed-dose rate gemcitabine for advanced pancreatic cancer.

The use of serial serum measurements of the carbohydrate antigen 19-9 (CA19-9) to guide treatment decisions and serve as a surrogate end point in clinical trial design requires further validation. We investigated whether CA19-9 decline represents an accurate surrogate for survival and time to treatment failure (TTF) in a cohort of 76 patients with advanced pancreatic cancer receiving fixed-dose rate gemcitabine in three separate studies. Statistically significant correlations between percentage CA19-9 decline and both overall survival and TTF were found, with median survival ranging from 12.0 months for patients with the greatest degree of biomarker decline (> 75%) compared with 4.3 months in those whose CA19-9 did not decline during therapy (P < 0.001). Using specific thresholds, patients with > or = 25% decline in CA19-9 during treatment had significantly better outcomes than those who did not (median survival and TTF of 9.6 and 4.6 months vs 4.4 and 1.5 months; P < 0.001). Similar results were seen using both 50 and 75% as cutoff points. We conclude that serial CA19-9 measurements correlate well with clinical outcomes in this patient population, and that decline in this biomarker should be entertained for possible use as a surrogate end point in clinical trials for the selection of new treatments in this disease.

Antimetabolites, Antineoplastic↗
PubMed2001

Outpatient treatment with (131)I-anti-B1 antibody: radiation exposure to family members.

UNLABELLED: The Nuclear Regulatory Commission (NRC) regulations that govern release of patients administered radioactive material have been revised to include dose-based criteria in addition to the conventional activity-based criteria. A licensee may now release a patient if the total effective dose equivalent to another individual from exposure to the released patient is not likely to exceed 5 mSv (500 mrem). The result of this dose-based release limit is that now many patients given therapeutic amounts of radioactive material no longer require hospitalization. This article presents measured dose data for 26 family members exposed to 22 patients treated for non-Hodgkin's lymphoma with (131)I-anti-B1 antibody after their release according to the new NRC dose-based regulations. METHODS: The patients received administered activities ranging from 0.94 to 4.77 GBq (25--129 mCi). Family members were provided with radiation monitoring devices (film badges, thermoluminescent or optically stimulated luminescent dosimeters, or electronic digital dosimeters). Radiation safety personnel instructed the family members on the proper wearing and use of the devices. Instruction was also provided on actions recommended to maintain doses to potentially exposed individuals as low as is reasonably achievable. RESULTS: Family members wore the dosimeters for 2--17 d, with the range of measured dose values extending from 0.17 to 4.09 mSv (17--409 mrem). The average dose for infinite time based on dosimeter readings was 32% of the predicted doses projected to be received by the family members using the NRC method provided in regulatory guide 8.39. CONCLUSION: Therapy with (131)I-anti-B1 antibody can be conducted on an outpatient basis using the established recommended protocol. The patients can be released immediately with confidence that doses to other individuals will be below the 5-mSv (500 mrem) limit.

Ambulatory Care↗
PubMed1998

Pancreatic cancer.

Despite the many advances reported during the past year, pancreatic cancer remains a profound therapeutic challenge. Helical CT has become the preferred staging study at many institutions. The role of chemoradiation therapy in a preoperative and postoperative setting is being defined. Gemcitabine has become first-line therapy for patients with advanced pancreatic adenocarcinoma. It is hoped that the increasing knowledge of the molecular biology of pancreatic carcinoma will lead to improvements in diagnosing, staging, and treating pancreatic adenocarcinoma.

Humans↗
PubMed1997

Patient-specific dosimetry of indium-111- and yttrium-90-labeled monoclonal antibody CC49.

UNLABELLED: The objective of this work was to develop patient-specific dosimetry for patients with metastatic gastrointestinal tract cancers who received 111In-CC49 IgG for imaging before therapy with 90Y-CC49 IgG. METHODS: Whole-body imaging of 12 patients, who received 111-185 MBq (3-5 mCi) of 111In-CC49, commenced in < 2 hr postinfusion and was continued daily for 4-5 days. SPECT data were acquired at 24 and 72 hr to determine the range of 111In-CC49 activity concentrations in tumors and normal organs. Time-activity curves were generated from the image data and scaled from 111In-CC49 to 90Y-CC49 for dosimetric purposes. Absorbed-dose calculations for 90Y-CC49 included the mean and range in tumor and normal organs. Computed 90Y-CC49 activity concentrations were compared with measurements on 10 needle biopsies of normal liver and four tumor biopsies. RESULTS: In 9 of 10 normal liver samples, the range of computed 90Y-CC49 activity concentrations bracketed measured values. This was also the case for 3 of 4 tumor biopsies. Absorbed-dose calculations for 90Y-CC49 were based on patients' images and activities in tissue samples and, hence, were patient-specific. CONCLUSION: For the radiolabeled antibody preparations used in this study, quantitative imaging of 111In-CC49 provided the data required for 90Y-CC49 dosimetry. The range of activities in patients' SPECT images was determined for a meaningful comparison of measured and computed values. Knowledge of activity distributions in tumors and normal organs was essential for computing mean values and ranges of absorbed dose and provided a more complete description of the absorbed dose from 90Y-CC49 than was possible with planar methods.

Absorption↗
PubMed1996

Unconjugated bilirubin inhibits in vitro cytotoxic T lymphocyte activity of human lymphocytes.

Septic complications have been major problems in the management of patients with obstructive jaundice and neonatal jaundice. This study investigates effects bilirubin on human T lymphocyte responses against allogeneic mixed lymphocyte reaction. In vitro exposure of human peripheral blood mononuclear cells (PBMNC) with unconjugated bilirubin at pathological levels (6 to 12 mg/dl) did not alter the subsets of CD3, CD4, CD8, CD14, CD19 and CD56 positive populations, or expression of costimulatory surface molecules CD2, CD3, CD4 and CD8. Further incubation of bilirubin-treated PBMNC with irradiated B lymphoid Raji cells after removal of the extracellular bilirubin resulted in a dose-dependent decrease of cytotoxic T lymphocyte (CTL) activity, DNA synthesis, and expression of Tac antigen (CD25) and transferrin receptor (CD71). However, no significant change of interleukin-2 (IL-2) production was observed after this incubation between bilirubin-treated and -untreated PBMNC. These results suggest that bilirubin inhibits the induction of CTL activity, and this defect may result from the impaired responsiveness against IL-2. These observations may help explain the increased infection observed in hyperbilirubinemic patients.

Antibodies↗
PubMed1996

Unconjugated bilirubin inhibits in vitro major histocompatibility complex-unrestricted cytotoxicity of human lymphocytes.

Septic complications have been major problems in the management of patients with obstructive jaundice and neonatal jaundice. This study investigates effects of unconjugated bilirubin on lymphocyte-mediated cytotoxicity against human tumor target cells. In vitro exposure of human peripheral blood lymphocytes (PBL) with bilirubin IX alpha in bovine albumin solution resulted in a dose-dependent decrease of both natural killer activity and antibody dependent cellular cytotoxicity (ADCC) activity. Inhibition of both activities correlated with the amounts of intracellular bilirubin. Expression of cell surface CD16, CD56 antigen, and IL-2 receptor beta chain was unchanged in bilirubin-treated PBL as compared to bilirubin-untreated PBL. When bilirubin-treated PBL were cultured with interleukin-2 (IL-2), a dose-dependent decrease of lymphokine-activated killing activity, ADCC activity, and DNA synthesis was observed. Expression of CD56 antigen and IL-2 receptor alpha chain was unchanged in bilirubin-treated PBL following IL-2 stimulation as compared to bilirubin free control. These results suggest that bilirubin inhibits major histocompatibility complex-unrestricted cytotoxicity in both unstimulated and IL-2 stimulated lymphocytes. These observations may help explain the increased susceptibility to infection observed in hyperbilirubinemic patients.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1996

Intracellular accumulation of unconjugated bilirubin inhibits phytohemagglutin-induced proliferation and interleukin-2 production of human lymphocytes.

Decreased immune responses have been documented in hyperbilirubinemic patients. This study investigates the effects of intracellular bilirubin accumulation on lymphoproliferative response to phytohemagglutin A (PHA). Human peripheral blood mononuclear cells (PBMNC) were preincubated with unconjugated bilirubin dissolved in bovine albumin solution at pathological levels seen in clinical hyperbilirubinemia (0-12 mg/dl), washed, and further cultured with PHA. DNA synthesis was measured by [3H]thymidine uptake. Interleukin-2 (IL-2) activity was determined by the CTLL proliferation assay. The amount of intracellular bilirubin and expression of cell surface antigens were analyzed by flow cytometry. In vitro exposure of normal PBMNC to bilirubin resulted in the accumulation of intracellular bilirubin and a decrease in DNA synthesis after PHA stimulation in a time- and dose-dependent manner. Addition of autologous untreated monocytes could not correct the decreased DNA synthesis of bilirubin-treated lymphocytes. IL-2 production by bilirubin-treated PBMNC after PHA stimulation was significantly decreased compared to bilirubin-untreated PBMNC. However, addition of exogenous IL-2 to pretreated PBMNC could not correct the decreased DNA synthesis. Expression of Tac antigen and transferrin receptor on bilirubin-treated lymphocytes after PHA stimulation was not significantly different from bilirubin-untreated cells. These results suggest that decreased PHA-induced T-lymphocyte proliferation following bilirubin-pretreatment may result from impairment of proliferation at a step beyond transferrin receptor expression. These observations may help explain the increased susceptibility to infection often observed in hyperbilirubinemic patients.

Antigens, CD↗
PubMed1996

Radiolabeled iododeoxyuridine: safety evaluation.

UNLABELLED: The emphasis of radiolabeled iododeoxyuridine (*IUdR) research at our institution to date has been to assess its safety as a potential therapeutic agent. Toward this goal, we have performed preclinical and clinical studies, using various routes of administration, to detect adverse changes in normal tissues in both humans and animals. As IUdR is rapidly dehalogenated by the liver, the intravenous route is unlikely to be successful in therapeutic efforts. We have therefore focused our attention on more "protected" routes: intra-arterial and intravesicular administration. METHODS: Studies were performed in farm pigs after multiple administrations of [125I]IUdR into the aorta, carotid artery and bladder. IUdR and metabolites were measured in venous blood samples at appropriate time intervals after administration, after which histologic examination of tissues was performed. Studies in human have been performed after intra-arterial administration of [123I]IUdR in patients with liver metastases and intravesicular administration in patients with bladder carcinoma, initially using [123I]IUdR and currently using both [123I]IUdR and [125I]IUdR. Blood samples for pharmacokinetics and metabolite analysis and tissue for autoradiography (when feasible) have been obtained. RESULTS: To date, no evidence of adverse effects on normal tissue or alteration of hematologic or metabolic indices have been seen in pigs or humans. When instilled in the bladder, there is little leakage of IUdR in the circulation. CONCLUSION: When [125I]IUdR is used as a therapeutic agent, we anticipate little or no effect on normal tissues.

Administration, Intravesical↗
PubMed1995

Comparison of subcutaneous and intravenous administration of recombinant human granulocyte-macrophage colony-stimulating factor for peripheral blood stem cell mobilization.

In an effort to determine whether subcutaneous or continuous intravenous infusion administration of rhGM-CSF results in better hematopoietic progenitor mobilization, the findings of two sequential clinical trials were reviewed. Patients who had received prior chemotherapy for leukemia, lymphoma, multiple myeloma, breast cancer, or other solid tumors and were candidates for high-dose therapy received rhGM-CSF, 250 micrograms/m2/day, either as a continuous intravenous infusion (trial 1) or subcutaneously (trial 2) for stem cell mobilization. At least five apheresis collection procedures were performed to collect a target number of 6.5 x 10(8) mononuclear cells (MNC)/kg. For the 37 patients in trial 1, the collections contained a median of 7.99 x 10(8) MNC/L (range 6.42-21.36) and a median of 5.27 x 10(4) CFU-GM/kg (range 0.28-19.35). In trial 1, 25 patients were autografted with their cells and recovered 0.5 x 10(9) granulocytes/L at a median of 12 days (range 6-16). For the 33 patients in trial 2, the autograft product contained a median of 7.63 x 10(8) MNC/kg (range 6.51-22.66) and 6.31 x 10(4) CFU-GM/kg (range 0.06-60.4). In trial 2, 25 patients were autografted. The median time to reach 0.5 x 10(9) granulocytes/L was 11 days (range 9-26). All patients received rhGM-CSF after peripheral stem cell transplant. No significant differences in the collected products or the time to hematopoietic recovery was found between the two trials (p > 0.05). The mobilization effects of subcutaneous rhGM-CSF in these pretreated patients were similar to those of intravenous rhGM-CSF.

Adult↗
PubMed1995

Modulation of tumor-associated antigen expression on human pancreatic and prostate carcinoma cells in vitro by alpha- and gamma-interferons.

Interferons (IFNs) are known to have antiviral effects and have been shown to enhance the expression of tumor-associated antigens (TAA) on different target cells. In our current study, we investigated the potential of IFN-alpha or IFN-gamma to enhance the expression of the TAAs recognized by monoclonal antibodies (MAbs) 19-9, B72.3, 17-1A, and BR55-2 on pancreatic cancer cell lines and the potential of IFN-gamma to modulate the expression of a single TAA, BR55-2, on nonpancreatic cancer cell lines. Expression of these TAAs, percentage of positive cells and mean fluorescence intensity, was measured by flow cytometry. In these studies, we provide evidence that one prostate (DU 145) and two pancreatic (HPAF and BxPC-3) cancer cell lines that moderately express BR55-2 can be upregulated by IFN-gamma treatment, with optimal enhancement occurring between 48 and 72 h with 1,000 IU/ml. Cell lines that highly expressed BR55-2 could not be further upregulated by the doses of IFNs tested during the various periods used. IFN-alpha or IFN-gamma treatments did not significantly change the levels of TAA expression on pancreatic cancer cell lines that bound MAbs 17-1A or 19-9. Cell lines that did not bind MAbs 17-1A, 19-9, B72.3, or BR55-2 before IFN treatments could not be induced to express these antigens after treatment. Although antigen expression does not ensure detectable therapeutic benefit, increased antigen expression on tumor tissues may augment the efficacy of MAbs bearing radionuclides, toxins, or effector cells to the tumor site. In each of these situations, the use of IFNs to enhance TAA expression, particularly IFN-gamma, may merit consideration.

Antibodies, Monoclonal↗
PubMed1995

Immunologic effects of levamisole in mice and humans: evidence for augmented antibody response without modulation of cellular cytotoxicity.

Selected immunomodulatory effects of levamisole were studied in patients with asymptomatic metastatic colon cancer and in a preclinical model (CF1 female mice treated with methyl-azoxymethanol acetate) for colon tumors. In the patient population studied, there was no augmentation of cellular cytotoxicity or alteration in lymphocyte subpopulations that participate in these functions. An increase in Fc receptor binding on circulating monocytes was apparent at the 4-week timepoint; however, a corresponding increase in antibody-dependent cellular cytotoxicity was observed in only one of the six patients studied. In most patients, cellular cytotoxicity diminished with time. No significant effects on cellular immunity or carcinogenesis were observed in our murine studies. However, treatment with levamisole did increase circulating immunoglobulin levels and IgM response in mice immunized with the T-dependent antigen keyhole limpet hemocyanin. This parameter was not tested in the human trial. Failure to demonstrate antitumor effects on cellular immunity by levamisole in both human and murine studies suggests that these effects, if they do exist, may involve immunological parameters that were not tested using our methods or that may not be apparent in patients with more advanced malignancy.

Adenocarcinoma↗
PubMed1995

Diagnostic use of radiolabeled antibodies for cancer.

Antibodies against a variety of tumor-associated antigens have been studied, as well as a number of modifications to the antibodies themselves, including Fab' fragments and chimeric, humanized, and human antibodies. The appropriate use of radioimmunoconjugates in the evaluation of cancer patients has not yet been clearly defined. Only a few studies have assessed their use, primarily through the intravenous route, in initial disease staging. To date, immunolymphoscintigraphy has not proven promising in the staging of cancers. More emphasis has been given to the use of IV radioimmunoconjugates to detect residual and recurrent disease, with generally favorable results. In addition, radioimmunoguided surgery, using small, handheld probes to detect foci of antibody accumulation, appears to be a valuable tool. As better production techniques become available and large clinical trials provide more clearly defined indications for radioimmunoconjugate use, these agents should enter the arena for routine diagnostic use.

Antibodies, Monoclonal↗
PubMed1994

Dose-related comparison of antibody-dependent cellular cytotoxicity with chimeric and native murine monoclonal antibody 17-1A. Improved cytolysis of pancreatic cancer cells with chimeric 17-1A.

Chimeric 17-1A antibody (IgG1 kappa) was constructed by linking variable region genes of murine monoclonal antibody 17-1A with genes for human kappa light chain and gamma 1 heavy-chain constant regions. This study was undertaken to compare in vitro antibody-dependent cellular cytotoxicity (ADCC) between the chimeric 17-1A (IgG1 kappa) and native murine 17-1A antibody (IgG2a kappa) with human peripheral blood mononuclear cells (PBMNC) against 7 human tumor (1 colon, 6 pancreas) cell lines. ADCC activity was measured by chromium-release assay. When freshly-isolated PBMNC from healthy donors were used for effector cells, significantly higher ADCC activity of chimeric antibody compared to murine antibody at optimal antibody dose (10 micrograms/mL) and lower doses (to 0.6 micrograms/mL) was observed against tumor cells with relatively high 17-1A expression. This high ADCC activity of the chimeric antibody persisted even when freshly-isolated monocyte-depleted PBMNC was used. When interleukin-2 activated PBMNC were used, comparable increases in ADCC were observed with both chimeric and murine antibody. These results suggest that chimeric 17-1A antibody is a more effective mediator of in vitro ADCC activity with human freshly-isolated PBMNC than the native murine antibody and this may be a better choice for clinical cancer trials evaluating possible immunotherapy with monoclonal antibody.

Animals↗
PubMed1994

Hypersensitivity to therapeutic murine monoclonal antibodies.

OBJECTIVE: To determine the predictive value of pre-treatment skin tests and in vitro IgE/IgG4 anti-murine monoclonal antibodies in patients treated with murine monoclonal antibodies. DESIGN: Patients treated at two cancer institutions were evaluated by skin testing and solid phase immunoassays to detect IgE and IgG4 specific anti-murine monoclonal antibodies. Skin testing by scratch and intradermal skin testing was done on patients before treatment with murine monoclonal antibodies. IgE & IgG4 specific anti-murine monoclonal antibodies were determined before treatment in all patients and at 1, 7, 14 and 21 days post-treatment in 1 patient. SETTING: Cancer patients undergoing murine monoclonal antibody treatment in two university medical centers were recruited for the study. PARTICIPANTS: Twelve patients, aged 41-75 years with gastrointestinal cancers (colon, stomach, pancreas or liver) with metastatic disease, who had relapses or conventional therapy were enrolled. Some patients had previous exposure to rodents, either as laboratory personnel or had kept them as pets. INTERVENTION: One patient who experienced an anaphylactic reaction to murine monoclonal antibody infusion was desensitized so therapy could continue. MAIN OUTCOME MEASURES: Skin tests, immunoassays, and patient history were correlated with adverse reactions to infusions of murine monoclonal antibodies. MAIN RESULTS: Skin tests (scratch method) and/or in vitro immunoassays may predict allergic outcomes in patients receiving infusions of murine monoclonal antibodies. Intradermal skin testing with murine monoclonal antibodies may result in false positive reactions and have less predictive value. Specific IgE or IgG4 were elevated in the two patients who experienced severe adverse reactions to murine monoclonal antibodies but not in those patients with no reactions and therefore, may have some predictive value. A history of past exposure to mice may also increase the risk of adverse reactions. In one patient, intravenous desensitization enabled treatment to proceed. CONCLUSION: Scratch skin tests, in vitro IgE and/or IgG4 immunoassays together with a past history of previous exposure to murine antigen(s) may predict potential allergic reaction to therapy with murine monoclonal antibodies.

Adult↗