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Biomedical subjects

B S Kramer

Publications and source records attributed to B S Kramer.

At least 55 records · Page 3Linked to original sources
PubMed1992

Vancomycin is not an essential component of the initial empiric treatment regimen for febrile neutropenic patients receiving ceftazidime: a randomized prospective study.

The use of vancomycin as part of the initial antibiotic therapy of febrile neutropenic patients has become a controversial issue. Some studies support its incorporation in the initial regimen, and others suggest that vancomycin can be added later. We examined this issue in a prospective, randomized trial. We randomized 127 febrile neutropenic patients to receive either ceftazidime alone or ceftazidime plus vancomycin as the initial empiric antibiotic treatment. We added vancomycin to the ceftazidime arm of the study when fever persisted after 96 h of monotherapy, when new fever occurred after this time, or when a moderately ceftazidime-resistant gram-positive bacterium was isolated. Each of these regimens had similar initial response rates, similar durations of initial fever, similar frequencies of new fever during therapy, similar microbiological cure rates, similar superinfection rates, and similar survival rates. We observed more renal and cutaneous toxicities in patients receiving vancomycin and ceftazidime as initial therapy. We conclude that ceftazidime is appropriate as initial therapy for febrile neutropenic patients and that the addition of vancomycin is appropriate when fever persists after 4 days of monotherapy or when fever recurs following an initial response.

Adolescent↗
PubMed1991

Analysis of the role of cancer prevention and control measures in reducing cancer mortality.

One goal of the war against cancer is to create declines in cancer mortality rates. A decrease in these rates can only occur in two ways: 1) a decrease in incidence rates and 2) a real increase in overall survival rates. Reductions in incidence rates can be envisioned to occur through three mechanisms (in order of the time course of cancer): 1) reduction or amelioration of environmental or lifestyle risk factors, 2) use of agents that prevent the occurrence of cancer by blocking the progression to cancer, and 3) early detection at a preneoplastic state combined with treatment that prevents or delays progression to invasive cancer. "True" increases in overall survival can occur by two mechanisms (in order of the time course of cancer): 1) early detection of cancer by screening tests and subsequent effective treatment and 2) advancements in treatment. Unique patterns or "fingerprints" of stage-specific incidence and overall incidence and of survival rates characterize the various cancer prevention and control mechanisms that can decrease mortality rates. The rates are presented for five organ sites that have shown reduced cancer mortality. The patterns of rates for breast cancer for women under the age of 65 years were most consistent with early detection. The testicular cancer fingerprints were most consistent with advances in treatment, whereas cervical cancer rates were most consistent with the detection of preneoplastic lesions. The stomach cancer fingerprints were indicative of reductions in lifestyle or environmental risks, and colorectal cancer rates were indicative of a combination of treatment advances and early detection. These fingerprint patterns can be extended to other situations in which mortality trends are changing in order to suggest possible causes of observed changes. Limitations of this model are also discussed.

Female↗
PubMed1991

Potential role of tamoxifen in prevention of breast cancer.

Despite advances in early detection and treatment of breast cancer, primary prevention has not been well explored, especially for women at increased risk of disease due to reproductive factors and family history. There are, however, suggestions that primary prevention of breast cancer may be a realistic objective. Randomized clinical trials of adjuvant therapy for early-stage breast cancer have demonstrated a 35% decrease in contralateral breast cancers among women receiving tamoxifen compared with controls, suggesting a potential role for tamoxifen in chemoprevention of breast cancer in women at increased risk of the disease. Adjuvant therapy studies also demonstrate that tamoxifen is well tolerated by most patients and suggest additional health benefits from alterations in plasma lipid levels and stabilization of bone mineral loss in women receiving tamoxifen. Aspects of tamoxifen pharmacology, laboratory research, and clinical experience which support its investigation as a chemopreventive agent for breast cancer are summarized, and potential toxic effects are discussed.

Bone Density↗
PubMed1991

Schedule-dependent in vitro combination effects of methotrexate and 5-fluorouracil in human tumor cell lines.

Because of conflicting reports of clinical synergy, we used the tetrazolium-based colorimetric (MTT) assay to test in vitro combination effects of methotrexate (MTX) plus 5-fluorouracil (FUra) in 4 schedules on 2 human non-small-cell lung cancer cell lines (adenocarcinoma, NC1-H23; bronchio-alveolar-cell carcinoma, NC1-H358), and 1 human colorectal adenocarcinoma cell line (SNU-C1). The complete 3 dimensional set of isoboles in the dose range under study was generated by a microcomputer-based method. We found that the combination effects of 8-hr sequential FUra-MTX, simultaneous administration of MTX-FUra, and 8-hr sequential MTX-FUra were clearly antagonistic for all 3 cell lines. In contrast, the combination cytotoxic effects of 24-hr sequential MTX-FUra were much more active. Our in vitro model thus clearly shows that MTX-FUra interactions are highly schedule-dependent. This provides a rational basis for testing sequential MTX-FUra with a longer administration interval than usually employed clinically.

Adenocarcinoma↗
PubMed1991

A pilot study of interferon alfa-2a in combination with fluorouracil plus high-dose leucovorin in metastatic gastrointestinal carcinoma.

Thirty-one assessable patients with metastatic adenocarcinoma of the gastrointestinal tract were entered onto a pilot study designed to assess the impact of recombinant interferon alpha-2a (rIFN alpha-2a) on the toxicity and pharmacokinetics of fluorouracil (5-FU) and leucovorin (LV). Patients received an initial cycle of 5-FU (370 or 425 mg/m2/d) with LV (500 mg/m2/d) for 5 days. If tolerated, the patient received the same dose of 5-FU/LV for the second cycle on days 2 to 6, with rIFN alpha-2a at 5 x 10(6) or 10 x 10(6) U/m2/d on days 1 to 7, or with 3 x 10(6) U/m2/d on days 1 to 14. In 26 matched cycles, rIFN alpha-2a administration was associated with an increased incidence of dose-limiting mucositis and diarrhea and a significantly lower median platelet nadir; rIFN alpha-2a did not significantly affect the median WBC or granulocyte nadir. Dose-limiting toxicity occurred in all six patients entered at 425 mg/m2/d of 5-FU/LV within two cycles. The majority of patients treated with 370 mg/m2/d of 5-FU/LV and 10 x 10(6) U/m2/d rIFN alpha-2a experienced grade 3 to 4 mucositis and diarrhea, whereas patients receiving 3 x 10(6) and 5 x 10(6) U/m2/d rIFN alpha-2a had acceptable toxicity. Administration of rIFN alpha-2a was associated with a dose-dependent decrease in 5-FU clearance. The increase in the area under the 5-FU concentration-time curve (AUC) was 1.3-fold and 1.5-fold in patients receiving 5 x 10(6) and 10 x 10(6) U/m2/d rIFN alpha-2a, respectively. Thus, the increase in 5-FU toxicity with rIFN alpha-2a may be explained by alterations in 5-FU pharmacokinetics. In 22 patients without prior 5-FU therapy, three complete (13.6%) and seven partial (31.8%) responses were seen, for an overall response rate of 45.4% (95% confidence interval, 24.4% to 67.8%). Since the 5 x 10(6) U/m2/d dose of rIFN alpha-2a increased the 5-FU drug exposure and was associated with acceptable toxicity, we recommend its further evaluation as given on days 1 to 7 in combination with 5-FU 370 mg/m2/d, with high-dose LV given on days 2 to 6.

Adenocarcinoma↗
PubMed1990

Enhancement of fluorinated pyrimidine-induced cytotoxicity by leucovorin in human lung cancer cell lines.

Reduced folates have been shown to increase the cytotoxicity of 5-fluorouracil (FUra) by stabilizing the fluorodeoxyuridine monophosphate:thymidylate synthase complex, thus increasing the block in the DNA synthetic pathway. Using an in vitro tetrazolium colorimetric (MTT) cytotoxic assay, we tested the effects of FUra and 5-fluorodeoxyuridine (FUdR) with and without leucovorin (LV) on a panel of 7 human lung cancer cell lines. LV at a concentration of 20 microM enhanced the cytotoxicity of FUra and of FUdR in all of the cell lines. Quantitatively, LV had a higher degree of enhancement on FUdR than on FUra cytotoxicity in 6 cell lines. There was equivalent enhancement in the only remaining line. The differential effects of LV on the cytotoxicity of FUra vs. FUdR in these lung carcinoma lines contrasts with a quantitatively similar enhancement of cytotoxicity between FUra and FUdR in colon cancer lines previously reported from our laboratory. This suggests that the metabolism of FUra may be different in these lung cancer cell lines.

Adenocarcinoma↗
PubMed1990

Chemosensitivity patterns and expression of human multidrug resistance-associated MDR1 gene by human gastric and colorectal carcinoma cell lines.

We compared the in vitro sensitivity patterns to cytotoxic drugs and expression of the multidrug resistance-associated MDR1 gene (also known as PGY1 gene) in four gastric carcinoma cell lines with those obtained in a panel of 11 colorectal carcinoma cell lines. In addition, we tested the effects of leucovorin on enhancement of fluorinated pyrimidine-induced cytotoxicity. We used a semiautomated tetrazolium dye assay [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (tetrazolyl blue)] (MTT) to compare the drug sensitivity of the gastric carcinoma cell lines with that of the colorectal carcinoma cell lines. The gastric carcinoma cell lines were more sensitive to some drugs, including doxorubicin and cisplatin, but not to the fluorinated pyrimidines. Addition of leucovorin at a clinically achievable concentration enhanced the cytotoxic effects of both fluorouracil and floxuridine in colorectal carcinoma cell lines, but it enhanced the effects of only floxuridine in gastric carcinoma cell lines. With the use of a slot blot assay, relatively low levels of MDR1 RNA were present in all four gastric carcinoma cell lines, while intermediate or high levels were present in most of the colorectal carcinoma cell lines. In general, our findings reflect clinical experience and may help in the design of clinical trials.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

The consumer's risk in clinical trials.

In any formal statistical test of the null hypothesis (the statement that a population parameter is equal to a specific value), there are two possible types of error. Type 1 or alpha error has occurred if the investigator rejects the null hypothesis when it is true. For example, an experimental treatment is declared an advance over standard treatment when it is not. Type 2 or beta error has occurred if the null hypothesis is not rejected when it is false. In this case, the investigator concludes that the experimental treatment is no different than the standard when it actually is. The two types of error can be conceptualized, respectively, as the consumer's risk and the producer's risk. In many reports of clinical trial methodology, it is the producer's risk that is emphasized. It is understandable why producer's risk would be of concern to authors of clinical studies. There are, however, numerous potential sources of consumer's risk. It is the latter type of risk that is the primary subject of this report.

Bias↗
PubMed1989

Lack of in vitro synergy between etoposide and cis-diamminedichloroplatinum(II).

Claims of synergy between etoposide and cisplatin have been based upon preclinical in vivo murine P388 models or upon human clinical trials in tumors such as lung cancer. Such in vivo studies are useful in exploring therapeutic synergy, i.e., an improved therapeutic strategy. The term "synergy" in this context is sometimes, however, taken to imply greater than additive kill of tumor cells. Unfortunately, it is virtually impossible to document supra-additive tumor cell kill in vivo, since in vivo curves of therapeutic effect are not linear and drugs are therefore not additive with themselves. Therapeutic synergy may, in fact, occur when two drugs are merely additive (or even antagonistic) with regard to cytotoxicity if the drugs have nonoverlapping host toxicity. The demonstration of true supra-additive cell kill would imply an interaction of the two agents at a cellular level and would have profound implications for biochemical studies. In order to determine whether the reported therapeutic synergy of etoposide and cisplatin is due, in part, to supra-additive cell kill, we used an in vitro tetrazolium-based colorimetric assay for cytotoxicity (MTT assay) and an isobologram analysis to test combinations of the two drugs against four human small cell and four human non-small cell lung carcinoma lines. Using a rigorous test for in vitro synergy, we could not establish a greater than additive cytotoxic effect on our cell lines. It thus appears that the clinical synergy between etoposide and cisplatin is not due to a supra-additive effect at the cellular level. Our results have implications for a variety of fields in which claims of "synergy" often appear.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Enhancement of fluorinated pyrimidine-induced cytotoxicity by leucovorin in human colorectal carcinoma cell lines.

Reduced folates have been shown to increase the cytotoxicity of 5-fluorouracil (5-FU) by stabilizing the 5-fluoro-2'-deoxyuridine-5'-monophosphate-thymidylate synthase complex, thus increasing the block in the DNA synthetic pathway. Using an in vitro colorimetric [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] cytotoxicity assay, we tested the effects of 5-FU and 5-fluoro-2'-deoxyuridine (FdUrd) with and without leucovorin (LV) on a panel of 11 human colorectal carcinoma cell lines. The effect of LV on 5-FU and FdUrd was quantitatively similar. A clinically achievable level of LV (20 microM) increased the cytotoxicity in all three replicate experiments in 10 of the 11 cell lines (P less than .05, binomial test). LV alone at a concentration of 20 microM had no effect on cell survival. In three cell lines, 50% inhibition of growth occurred at a clinically achievable area under the curve of 5-FU alone. With the addition of LV, one additional cell line showed 50% growth inhibition at a clinically achievable level of 5-FU. Hence large clinical trials may be necessary to detect a significant improvement in survival as a result of adding LV to the fluorinated pyrimidines.

Carcinoma↗
PubMed1988

Randomized phase II evaluation of iproplatin (CHIP) and carboplatin (CBDCA) in lung cancer. A Southeastern Cancer Study Group trial.

Cisplatin-containing regimens have shown activity in both small and non-small cell lung cancer. We therefore conducted a randomized Phase II trial of the new platinum congeners iproplatin and carboplatin in bronchogenic carcinoma. The overall response rate in chemotherapy-naive non-small cell patients with iproplatin was 3/48 (6%; 95% confidence interval 2-18%) and with carboplatin 6/50 (12%; 95% confidence interval 5-25%). The response rates in previously treated small cell patients were 0/16 and 1/18, respectively. Overall, neither agent has pronounced activity in bronchogenic carcinoma.

Adult↗
PubMed1987

Chemosensitivity testing of human colorectal carcinoma cell lines using a tetrazolium-based colorimetric assay.

The in vitro chemosensitivity of 11 human colorectal cell lines to seven chemotherapeutic agents was determined using a semiautomated tetrazolium-based colorimetric assay (MTT assay). Four of the cell lines were from primary tumors and seven from metastases. Eight lines were from patients with no prior chemotherapy. From assay results, we predict 5-fluorouracil (5-FU) to be the sole active agent of the seven tested. This is based on two observations: the range of drug concentrations which produced 50% inhibition of cell growth was greatest with 5-FU (388-fold versus 5- to 30-fold with the other six agents); and the area under the curve (AUC) which produced 50% growth inhibition was within a clinically achievable range only for 5-FU. Since the assay AUC of 5-FU at 50% inhibition was in a clinically achievable range for only two of the 11 cell lines, we performed a multivariate analysis to explore parameters which predict 5-FU sensitivity. In the best fitting model, sensitivity was positively correlated with cloning efficiency in media and with cell surface TAG-72 (a tumor-associated glycoprotein found on epithelial tumors of ovary, lung, colon, and breast origin) expression. If validated with an in vivo test such as the nude mouse model, the MTT assay could be very useful in new drug screening for colorectal carcinoma, for examining combination chemotherapy for synergy, for exploring strategies for biochemical modulation, and perhaps in individualizing therapy when cell lines can be established from a patient.

Antineoplastic Agents↗
PubMed1987

Impact of air filtration on nosocomial Aspergillus infections. Unique risk of bone marrow transplant recipients.

Bone marrow transplant recipients were found to have a 10-fold greater incidence of nosocomial Aspergillus infection than other immunocompromised patient populations (p less than 0.001) when housed outside of a high-efficiency particulate air (HEPA) filtered environment. Multivariate analysis demonstrated that number of infections, age, and graft-versus-host disease severe enough to require treatment were independent risk factors for development of nosocomial Aspergillus infection in this group. The use of whole-wall HEPA filtration units with horizontal laminar flow in patient rooms reduced the number of Aspergillus organisms in the air to 0.009 colony-forming units/m3, which was significantly lower than in all other areas of the hospital (p less than or equal to 0.03). No cases of nosocomial Aspergillus infection developed in 39 bone marrow transplant recipients who resided in this environment throughout their transplantation period compared with 14 cases of nosocomial Aspergillus infection in 74 bone marrow transplant recipients who were housed elsewhere (p less than 0.001). Thus, although bone marrow transplant recipients had an order-of-magnitude greater risk of nosocomial Aspergillus infection than other immunocompromised hosts, this risk could be eliminated by using HEPA filters with horizontal laminar airflow.

Air Microbiology↗
PubMed1987

An outlier theory of cancer curability. Tumor cell differentiation as a therapeutic goal.

Combinations of cytotoxic agents that cure a substantial percentage of patients with several childhood and adult malignancies are much less efficacious for the majority of solid tumors. Standard approaches for curability that rely solely on the concept of cytotoxicity may not be applicable for most epithelial and mesenchymal solid malignancies. Differentiation may play a more important role in cancer cure than heretofore suspected. Clinical and experimental evidence supports further investigation into models of inducing tumor cell differentiation. The question of why such models could predict for curative modalities of treatment is discussed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

The management of primary lymphoma of bone.

From October 1962 through April 1982, 21 patients with the diagnosis of primary lymphoma of bone (18 monostotic, stages IE and IIE; 3 polyostotic) were treated with curative intent. A combination of chemotherapy and radiation therapy was used in 11 patients, local treatment alone in 9 patients, and chemotherapy alone in one patient. Overall 5-year survival for the patients treated with curative intent was 56%. Standard work-up has changed over the 20-year study period. Five-year survival for the subset of eight stage I and II patients with full pretherapy staging was 83%. Prognosis was significantly correlated with extent of pretherapy staging. Treatment parameters that also seemed to predict outcome were the aggressiveness of chemotherapy and the use of irradiation or surgery for local-regional disease; the only local failure occurred in the patient who received chemotherapy alone. Complications of radiation therapy alone and in combination with chemotherapy are discussed and correlated with irradiation dose. Radiation therapy techniques are described, and a management approach is recommended.

Adolescent↗
PubMed1986

Spontaneous regression of testicular seminoma: case report.

A 33-year-old man had a 1-year history of a painless testicular mass and a 2-month history of an enlarging left supraclavicular mass. Biopsy of the supraclavicular mass showed classical seminoma. Massive abdominal lymphadenopathy was demonstrated by computerized tomography. Radical orchiectomy was performed and examination of the specimen showed only fibrous scar tissue consistent with regression of a primary tumor in the testis. While complete regression of a primary testicular tumor with progressive growth of metastases is well recognized in cases of nonseminomatous germ cell tumors, this phenomenon is reported rarely with seminoma.

Adult↗