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Biomedical subjects

M D Green

Publications and source records attributed to M D Green.

At least 19 recordsLinked to original sources
PubMed1992

Delay by internists in obtaining diagnostic biopsies in patients with suspected cancer.

OBJECTIVE: To investigate the degree and type of delays in performing diagnostic biopsies in medical patients with suspected malignancy. DESIGN: Retrospective survey of clinical histories of patients referred between January 1985 and March 1989. SETTING: Inner city teaching hospital internal medicine (non-oncologic) services. PATIENTS: Patients with gastrointestinal and lung cancers, adenocarcinoma of unknown primary site, and lymphomas were referred as inpatients by internists. Two hundred fifty-five patients were eligible, and 177 were evaluable. MAIN OUTCOME MEASURES: The number, type, and results of tests done before and after biopsy were analyzed. RESULTS: In 67% of patients the biopsied lesion was detected by the second day of evaluation; however, there was an 8- to 10-day delay before a biopsy was done. This delay was consistent across the four malignancy groups studied. Although logistic and other unavoidable delays occurred in 40% of the cases, in 60% delays could only be attributed to continued, frequently low yield, noninvasive tests. An average of 3.3 tests were made per patient, with only 24% leading to a definitive biopsy. CONCLUSION: Because of the performance of many other tests, a substantial delay exists in proceeding to biopsy during the diagnosis of cancer by internists.

Adenocarcinoma↗
PubMed1992

Comparative study of doxorubicin, mitoxantrone, and epirubicin in combination with ICRF-187 (ADR-529) in a chronic cardiotoxicity animal model.

In this study doxorubicin, epirubicin, and mitoxantrone were compared for their cardiotoxic potential in a chronic mouse model in an effort to identify and compare their mechanism(s) of toxicity. In addition, the cardioprotective ability of ICRF-187 [(+/-)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane] with each anticancer drug was evaluated in this model. The antioxidant capacity (superoxide dismutase, reduced glutathione, catalase, and glutathione peroxidase) was assessed following drug treatment. Five-week-old BALB/c mice received weekly i.p. injections of each drug or the drug and ICRF-187 over a 3-month period. ICRF-187 was administered 30 min prior to the anticancer drug. The hearts were examined by electron and light microscopy to assess subcellular changes, and the cardiac and hepatic antioxidant levels were measured concurrently. Chronic treatment with these drugs or each combined with ICRF-187 did not change the antioxidant levels relative to the control values. However, all three drugs caused cardiac damage during chronic exposure. Both epirubicin and mitoxantrone caused less severe damage than doxorubicin, and epirubicin was the least cardiotoxic of the three. ICRF-187 was cardioprotective for epirubicin and doxorubicin but not for mitoxantrone. These results suggest epirubicin acts by a mechanism similar to that of doxorubicin that is probably mediated by oxygen-free radicals, while mitoxantrone acts by a different mechanism to cause cardiotoxicity.

Animals↗
PubMed1992

Pilot study of escalating doses of carboplatin and cyclophosphamide in patients with advanced cancer.

In all, 18 patients with histologically proven advanced cancer received 400 mg/m2 carboplatin (CBDCA) plus 800 mg/m2 cyclophosphamide (level 1), and 14 others received 550 mg/m2 CBDCA plus 1100 mg/m2 cyclophosphamide (level 2). A maximum of six cycles was given if a response occurred. The dose-limiting toxicity was myelosuppression, with neutropenia being more marked than thrombocytopenia. At level 2, patients experiencing a febrile-neutropenic event showed a mean 24-h urinary creatinine clearance value of 1.1 ml/s (95% confidence limits 0.8-1.4 ml/s), whereas in those who remained afebrile it was 1.7 ml/s (95% confidence limits, 1.3-2.0 ml/s). This difference was significant (P less than 0.01). Other toxicities were only mild. Creatinine clearance is a predictor of febrile episodes after treatment with high doses of CBDCA and cyclophosphamide. We are now conducting a study using human granulocyte colony-stimulating factor to reduce the incidence of neutropenia with escalating doses of these drugs in an attempt to prevent febrile events.

Aged↗
PubMed1992

Phase II study of 10-EdAM in patients with squamous cell carcinoma of the head and neck, previously untreated with chemotherapy.

Fifteen patients with advanced head and neck cancer not curable with radiation or surgery were entered into a phase II study of 10-EdAM. None of the patients had received prior chemotherapy. 10-EdAM was administered intravenously at a dose of 80 mg/m2 each week. Four patients were not eligible for evaluation. Two died before completing four cycles of chemotherapy, one refused further treatment and one developed hepatic toxicity resulting in withdrawal. Of the remaining patients, three had a partial response. The major toxicities were leukopenia and mucositis.

Adult↗
PubMed1992

Effects of analysis method and forcing waveform on measurement of respiratory mechanics.

The respiratory system has been shown to exhibit nonlinear mechanical properties in the frequency (f) range of normal breathing, manifested by tidal volume (Vt) dependence. Calculations of respiratory system resistance (R) and elastance (E) from pressure-flow measurements during external forcing at a given f may be ambiguous, especially if non-sinusoidal forcing waveforms are used. We evaluated the degree to which R and E depended upon: (1) analysis method (Fourier transform, multiple regression and pressure-volume loop analysis) and; (2) shape of the forcing waveform (sinusoidal, quasi-sinusoidal and step). We measured pressure and flow at the mouth of 5 healthy, awake subjects, relaxed at functional residual capacity, during forcing with the three different waveforms in the normal range of f (0.2-0.6 Hz) and Vt (250-750 ml). During sinusoidal forcing, E and R were not affected by analysis method (P greater than 0.2). With Fourier transform and multiple regression, E was not affected by waveform shape (P greater than 0.05); with loop analysis, E was slightly (less than 10%) higher during quasi-sinusoidal and step forcing than during the sine (P less than 0.05). R was least affected by waveform shape with Fourier transform. We conclude that, in the f and Vt range of normal breathing: (1) respiratory system impedance is 'quasi-linear,' i.e. despite dependencies of R and E on Vt, non-linearities are not large enough to restrict interpretation of R and E at a given f and Vt; (2) it may be possible to measure R and E using non-sinusoidal forcing waveforms available on most clinical ventilators, incurring only modest error.

Adult↗
PubMed1992

Formate metabolism in micropigs.

The toxicity of methanol is directly related to the accumulation of formate which, in turn, is related to the adequacy of the folate-dependent metabolism of formate to carbon dioxide. Thus, humans who possess low hepatic folates and low 10-CHO H4folate dehydrogenase activity metabolize formate poorly and are sensitive to methanol. Conversely, most laboratory species do not exhibit methanol toxicity because they metabolize formate at high rates. Studies reported here show that the Yucatan micropig has the lowest hepatic folates of any animal species studied. Formate oxidation rates in micropigs were 23% of rates reported for rats. The half-life of formate disappearances from the blood was 74 min, a value twice that reported for rats. In addition, 10-CHO H4folate dehydrogenase activity and amount in micropig liver is markedly reduced. Micropigs may prove useful in studies of methanol poisoning due to their low capacity for formate oxidation and their reasonable size and ease in handling.

Animals↗
PubMed1992

Recent advances in parathyroid tumors and paragangliomas.

The management of parathyroid tumors has advanced mainly in the area of imaging with ultrasonography and nuclear scanning. Surgery remains the preferred treatment for parathyroid tumors and paragangliomas. Information about genetic aspects of parathyroid tumors has increased, but the rarity of parathyroid tumors and paragangliomas has limited the pace of advancement in knowledge about their biology and clinical aspects.

Humans↗
PubMed1992

Effect of tidal volume on respiratory system elastance and resistance during anesthesia and paralysis.

Recent studies have shown that the mechanical properties of the respiratory system at normal breathing frequency in awake humans depend on tidal volume. Few measurements of respiratory system properties during anesthesia have accounted for this dependence. From measurements of airway pressure, flow and esophageal pressure, we calculated elastances and resistances of the total respiratory system (Ers and Rrs), chest wall (Ecw and Rcw), and lungs (El and Rl) in supine human volunteers during quasisinusoidal volume forcing in a normal range of breathing (250 to 800 ml) at normal breathing frequency (0.2 Hz). Measurements were made (1) with subjects awake and voluntarily relaxed; (2) after isoflurane-N2O anesthesia (end-tidal isoflurane concentration 0.3 to 0.5%); and (3) after complete muscle paralysis with vecuronium. In all conditions, Ers, Ecw, El, Rrs, and Rcw decreased at 800 ml tidal volume compared with 250 ml; Rl showed a similar decrease in awake measurements only. Compared with awake measurements, each elastance tended to increase after anesthesia, but only the increase in Ers was significant. Compared with anesthesia, there was no effect of paralysis on any measurement. We conclude that (1) tidal volume dependence of respiratory system properties in the normal range of breathing occurs in the absence of muscle activity; (2) anesthesia increases Ers and (3) respiratory muscle activity appears to be inhibited by isoflurane-N2O anesthesia at end-tidal isoflurane concentration of 0.3 to 0.5% during normocapnia.

Adult↗
PubMed1992

ICRF-187 permits longer treatment with doxorubicin in women with breast cancer.

PURPOSE: To test potential protection by ICRF-187 against cumulative doxorubicin-dose-related cardiac toxicity, we conducted a randomized clinical trial in 150 women with advanced breast cancer. PATIENTS AND METHODS: Patients received fluorouracil (5FU) 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 every 21 days intravenously (IV) (control regimen, 74 patients), or the same regimen preceded by ICRF-187 1,000 mg/m2 IV (experimental regimen, 76 patients). RESULTS: We previously reported that ICRF-187 in this dose and schedule provides cardiac protection and does not substantially alter the noncardiac toxicity or antitumor efficacy of the control regimen. In this updated analysis of the entire patient cohort, we provide additional support for these findings and demonstrate that patients in the ICRF-187 group received more cycles (median, 11) and higher cumulative doses (median, 500 mg/m2) of doxorubicin than patients in the control group (median, nine cycles, P less than .01; and 441 mg/m2, P less than .05). Twenty-six patients in the ICRF-187 group received doxorubicin doses of at least 700 mg/m2, and among them, 11 patients received 1,000 mg/m2 or more. Only three patients in the control group received doxorubicin doses of 700 mg/m2; the maximum dose administered to one patient in this group was 950 mg/m2. ICRF-187 cardiac protection was demonstrated by difference in incidence of clinical congestive heart failure (CHF; two patients in the ICRF-187 group v 20 in the control group; P less than .0001) and by differences in resting left ventricular ejection fraction (LVEF) determined by multigated radionuclide (MUGA) scan from baselines and that required patient removal from study (five patients in the ICRF-187 group had a decrease in LVEF to less than 0.45 or a decrease from the baseline LVEF of 0.20 or more v 32 in the control group; P less than .000001). Among the 30 patients who had an assessable endomyocardial biopsy at cumulative doxorubicin 450 mg/m2, none of 16 in the ICRF-187 group and six of 14 in the control group had a score of 2 (P less than .05). ICRF-187 cardiac protection was observed in patients with and without prior chest-wall radiation or other risk factors for developing doxorubicin cardiac toxicity. CONCLUSION: By protecting against cumulative doxorubicin-induced cardiac toxicity, ICRF-187 permits significantly greater doses of doxorubicin to be administered to patients with greater safety.

Adult↗
PubMed1992

Activity of fludarabine in previously treated non-Hodgkin's low-grade lymphoma: results of an Eastern Cooperative Oncology Group study.

PURPOSE: Fludarabine (2-fluoro-arabanoside-monophosphate) is a new antimetabolite chemotherapeutic agent. We performed a multicenter, phase II study of this drug in previously treated patients with refractory or relapsed non-Hodgkin's lymphoma (NHL) to determine its response rate by histologic classification. PATIENTS AND METHODS: Sixty-two assessable patients were given 18 mg/m2 by intravenous (IV) bolus injection daily for 5 days, every 28 days. Forty-eight percent had previously had one chemotherapy regimen, and the remainder had had two regimens; 42% had had radiation. RESULTS: Patients received 273 cycles of fludarabine chemotherapy, with a median of two cycles and ranging up to 25 cycles. Sixty patients were assessable for response, including nine complete responses (CRs; 15%) and nine partial responses (PRs; 15%). The response rate for patients with lower-grade histology was 52% (13 of 25); the greatest response rate was seen in those with follicular small cleaved-cell lymphoma, including seven of 11 treated. Five responders remain in unmaintained remission; the median survival of responders is greater than 30 months. Toxicity included mild neutropenia and a 10% incidence of grade 3 neurologic toxicity with occasional reversible visual and auditory changes. CONCLUSION: Fludarabine is active in patients with previously treated NHL (particularly low-grade histologies). Future studies will examine its activity in combination with other chemotherapeutic agents in previously untreated patients.

Adolescent↗
PubMed1992

In vitro evidence for direct complexation of ADR-529/ICRF-187 [(+)-1,2-bis-(3,5-dioxo-piperazin-1-yl)propane] onto an existing ferric-anthracycline complex.

ADR-529 protects against anthracycline cardiotoxicity, possibly by preventing free radical induction. We hypothesize that this occurs by ADR-529 forming a ternary anthracycline-iron-ADR-529 complex. This study used 200-MHz Fourier-transformed NMR to demonstrate the ability of ADR-529 to do this. Peak assignments were by proton-correlated spectroscopy and proton-carbon heteronuclear-correlated spectroscopy. Ga3+ served as a probe for Fe3+, and D2O was the system solvent. Doxorubicin and epirubicin were the studied drugs. Proton spectra of multiple combinations (including pure standards as controls) were obtained. Both Ga3+ plus ADR-529 and Ga3+ plus doxorubicin showed evidence of complexation, as seen by appropriate peak shifts and changes in the associated coupling constants. Ga3+ plus ADR-529 plus epirubicin showed complexation different from that of Ga3+ plus ADR-529 or Ga3+ plus doxorubicin and consistent with the proposed structure. We conclude that ADR-529 would be able to form a ternary complex with an existing anthracycline-Fe3+ complex in an isolated aqueous environment.

Antibiotics, Antineoplastic↗
PubMed1991

Biomedical applications of high-performance liquid chromatography-mass spectrometry with continuous-flow fast atom bombardment.

This report describes the application of high-performance liquid chromatography combined with continuous-flow fast atom bombardment mass spectrometry to analytical problems in the biomedical laboratory. Applications include the compound-specific detection of diagnostic acylcarnitines in human urine, the separation and analysis of acyl-coenzyme A thioesters, and qualitative studies on complex mixtures of modified peptides (dansyl and dinitrophenyl derivatives). For each of these applications standard analytical columns (3.9 mm I.D.) and 1 ml/min flow-rates were employed with post-column stream splitting (1:100) before mass spectrometry. Various mobile phase compositions and solvent gradients were employed. The addition of 1-5% glycerol to the mobile phase was shown to have little effect on the chromatography. For all compounds studied (acylcarnitines, acyl-coenzyme A thioesters, and derivatized peptides) molecular weight information was obtained and sufficient sensitivity was achieved to allow unambiguous identification of trace components in complex mixtures.

Acyl Coenzyme A↗
PubMed1991

Reversal of a neurologic paraneoplastic syndrome with octreotide (Sandostatin) in a patient with glucagonoma.

A 69-year-old woman with classic glucagonoma syndrome had associated progressive neurologic disease manifest as dementia, ataxia, optic atrophy, and lower limb weakness. Visual evoked responses (VERs) were absent bilaterally. After an attempt at resection was unsuccessful, therapy was started with somatostatin analogue (Sandostatin, SMS 201-995). Over the ensuing 3 months, there was a decrease in the plasma glucagon level, resolution of the rash, weight gain, reversal of the dementia, and an improvement in coordination and limb weakness. Subsequent VERs revealed bilateral delayed responses.

Aged↗
PubMed1991

New anthracycline antitumor antibiotics.

Doxorubicin is an essential component of the treatment of aggressive lymphoma, childhood solid tumors, bone and soft tissue sarcomas, and breast cancer and additional indications are emerging. On the other hand, daunorubicin has occupied the central position of interest in the treatment of acute leukemia. Epirubicin has a spectrum very similar to doxorubicin but lesser toxicity. The ability to protect against cardiotoxicity with ICRF-187 further enhances clinical interest in exploiting modifications in doze intensity to therapeutic advantage. Idarubicin has at least equivalent activity to daunorubicin and doxorubicin in leukemia. New areas of research in relation to anthracycline antibiotics include introduction of new the analogs, insight into mechanisms of resistance, the reversal of multidrug resistance in vitro, the protection of cardiac toxicity, and the study of other important biochemical reactions relevant to cytotoxicity. Orally active anthracyclines such as idarubicin and compounds which lack cross-resistance with the parent drugs or have other mechanisms for cytotoxicity are being developed. It is likely that these modifications will lead to an expanding therapeutic spectrum for these already widely useful drugs.

Aclarubicin↗
PubMed1991

Recent advances in carcinoids and gastrointestinal neuroendocrine tumors.

The main advances in the management of carcinoid and gastrointestinal neuroendocrine tumors have been in the areas of imaging and therapy. New techniques have been developed to detect and identify the sites of tumor so that correct therapeutic decisions can be made. Although surgery remains the mainstay of treatment of localized and some cases of advanced disease, the use of biologic agents and new drugs has proven valuable in those patients in whom surgery is not indicated. These include interferon-alpha, the somatostatin analogue octreotide, omeprazole. Different methods of delivery have been investigated with mixed success. Future progress in the understanding and management of neuroendocrine tumors is likely to be slow due to their rarity and long natural history.

Carcinoid Tumor↗