Biomedical subjects

A L Fields

Publications and source records attributed to A L Fields.

33 records · Page 2Linked to original sources

PubMed1995

Promising new therapies in the treatment of advanced ovarian cancer.

Advanced stage ovarian cancer is the most lethal gynecologic cancer. Despite initial response rates of 60-80% with platinum-based chemotherapy, more than 75% of women with this malignancy die of complications associated with this disease. There is a pressing need to find new chemotherapeutic agents for patients with advanced ovarian cancer. Phase II studies have identified paclitaxel as the most active drug in ovarian cancer since the introduction of cisplatin in the 1970s. Phase III studies will define the role of paclitaxel as initial therapy. Camptothecins (topotecan, CPT-11, 9-amino-camptothecin) inhibit topoisomerase I. CPT-11 and topotecan have shown activity in Phase II trials. Gemcitabine, a pyrimidine antimetabolite, has shown activity in Phase II trials. Other promising drugs (docetaxel, treosulfan) are under investigation. Modulation of drug resistance is being explored in Phase I/II studies. Clinical trials have been initiated with buthionine-sulfoximine, an inhibitor of glutathione biosynthesis, which decreases the ability of resistant cells to inactivate platinum compounds and alkylating agents. Cyclosporin has been shown to increase cisplatin cytotoxicity. Phase I trials have demonstrated the feasibility of combining cyclosporin and cisplatin. Phase II trials of cyclosporin analogs (PSC 833) and paclitaxel in refractory ovarian cancer are ongoing. Promising leads in drug development should provide new therapies for patients with ovarian cancer. Further research in the modulation of drug resistance may identify new mechanisms or strategies with which to prevent the emergence of drug resistance.

Antineoplastic Agents↗

PubMed1994

Long-term follow-up of stage I cervical adenocarcinoma treated by radical surgery.

From 1972 to 1988 55 patients underwent radical abdominal hysterectomy, pelvic lymph node dissection for treatment of FIGO Stage I cervical adenocarcinoma. A minimum of 60 months follow-up was available on all surviving patients. A detailed retrospective analysis was conducted to determine the influence of radical surgery on survival and to identify prognostic factors for recurrence. A bilateral salpingo-oophorectomy was included as part of the primary surgery in 52 the patients. Histologic subtypes included endocervical adenocarcinoma (44), papillary carcinoma (5), clear cell carcinoma (3), and adenosquamous carcinoma (3). The 5- and 10-year disease-free survival was 85.5%. The median follow-up of the surviving patients was 78.5 months (range, 60 to 240 months). Eight patients recurred, all but 1 of whom died of disease. Median time to recurrence was 28 months (range, 6 to 47 months). Five patients recurred beyond 24 months. One patient recurred locally, 5 recurred regionally, and 2 developed distant recurrences. Lymph node metastases (P < 0.0001), histologic grade (P < 0.0001), depth of invasion (P = 0.0001), presence of paracervical disease (P = 0.0034), and size of the lesion (P = 0.0059) were shown to be significant determinants of recurrence. Two of the 3 patients with a single involved lymph node recurred. Age, parity, history of oral contraceptive use, histologic subtype, and lymph vascular space involvement were not statistically significant determinants of recurrence. Adjuvant whole pelvic radiotherapy did not influence regional recurrence or survival but may decrease local recurrence. Radical abdominal hysterectomy pelvic lymph node dissection is an appropriate treatment of patients with Stage I cervical adenocarcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗

PubMed1989

Effects of systemic inhibition of prostaglandin production on protein metabolism in tumor-bearing rats.

Two rat tumors, Morris hepatoma 7777 (MH) and Yoshida ascites hepatoma AH130 (YAH) were compared, and the influence of systemic inhibition of prostaglandin (PG) synthesis on muscle protein metabolism was evaluated. Tumor-bearing rats were compared with ad libitum- and pair-fed controls. Rats were also treated with naproxen, an inhibitor of PG synthesis. Tumors caused progressive anorexia and weight loss and resulted in decreased weight and/or protein content of the soleus, extensor digitorum longus, and epitrochlearis muscles. The extent of this wasting varied with muscle and tumor type. Muscle wasting induced by the tumors appeared to result from increased protein degradation and/or decreased protein synthesis, as determined in isolated epitrochlearis muscle. In YAH, reduced feed intake did not appear to be responsible for muscle wasting; however, in MH, it accounted for a significant proportion of the muscle loss. YAH produced large amounts of PGE2. Treatment of rats with naproxen inhibited tumor PGE2 production and muscle protein loss in rats bearing YAH. Naproxen had no effect on muscle weight or protein degradation in rats bearing MH. These results would appear to implicate PGE2 in the development of cachexia in the laboratory rat.

Amino Acids↗

PubMed1987

Phase II study of acivicin as a 72-hr continuous infusion in patients with untreated colorectal cancer. A National Cancer Institute of Canada Clinical Trials Group Study.

The National Cancer Institute of Canada (NCIC) Clinical Trials Group has carried out a phase II study of acivicin given as a 72-hour continuous infusion in previously untreated patients with measurable metastatic colorectal carcinoma. Toxicity in 24 patients was mild to moderate and consisted primarily of GI symptoms such as nausea, vomiting, diarrhea or CNS changes including drowsiness, lethargy, dizziness. No responses were seen in 23 evaluable patients. We did not find acivicin given as described to be effective in colorectal carcinoma.

Adult↗

PubMed1987

Accelerated loss of lean body mass in fasting rats due to activation of pyruvate dehydrogenase by dichloroacetate.

In order to test the hypothesis that increased pyruvate dehydrogenase (PDH) activity during fasting will result in accelerated loss of lean body mass, we administered sodium dichloroacetate (DCA) intraperitoneally to eight rats during the last three days of a six-day fast, while fasting control rats were given normal saline. DCA treatment resulted in an increased proportion of PDH in the active form in liver (26.5 +/- 4.3% v 13.4 +/- 0.5%, P less than 0.01). During the three-day period of administration, DCA treated rats lost more weight than control animals (42 +/- 2 v 25 +/- 1 g, P less than 0.001) and excreted more nitrogen in the urine (18.1 +/- 1.0 v 6.8 +/- 0.6 mmol/d, P less than 0.001). Calculations from nitrogen balance data suggest that 85% of the increase in weight loss of DCA treated rats over that of control animals was attributable to loss of lean body mass. We conclude that increased flux of pyruvate through the PDH reaction in the DCA-treated animals resulted in increased protein catabolism.

Acetates↗

PubMed1985

Retinol and postoperative colorectal cancer patients.

In order to determine whether low plasma levels of retinol and its carrier (retinol binding protein) are related to increased risk of cancer recurrence, these were measured in 103 patients who had had colorectal cancer surgically removed. According to the modification of the Dukes' classification, 66 had B2 tumours (with no nodal involvement' and 37 had C tumours (with lymph-node metastases). These patients were part of the Cross Cancer Institute Adjuvant GI Cohorts who were on the control arms receiving no further treatment. At the time of blood sample collection, they were believed to be free of neoplastic disease. The post-operative patients were found to be associated with subnormal circulatory levels of retinol (43.3 micrograms dl-1 vs 65.3 micrograms dl-1) and its carrier protein (4.6 mg dl-1 vs 5.7 mg dl-1), when compared with apparently healthy subjects. The latter being more markedly depressed in patients with "C" type tumour (3.8 mg dl-1) than that in those with "B2" type tumour (5.0 mg dl-1). These findings appeared to be persistent during the follow-up study when a second blood sample was collected, one to four months later from 40 patients. Furthermore, the initial plasma retinol level in conjunction with RBP was found to be even lower in 12 patients (35.1 micrograms dl-1, 3.7 mg dl-1) who subsequently had cancer recurrence than in those who remained free of apparent cancer (44.5 micrograms dl-1, 4.6 mg dl-1). The lowest initial values of retinol (19.3 micrograms; 18.8 micrograms dl-1) and RBP (2.4; 1.6 mg dl-1) recorded in the study were seen in the only two patients who died of the disease at the time of follow-up.

Adult↗

PubMed1985

Lactic acidosis--emphasis on the carbon precursors and buffering of the acid load.

We have compared the capacity of major organs to produce lactic acid from endogenous sources relative to their ability to buffer that proton load. We deduced that the ultimate source for the rapid production of a very large amount of lactic acid must be hepatic and/or muscle glycogen or exogenous glucose, because the quantity of endogenous glucose is quite small and the rate of net protein catabolism is too slow. Of the organs examined, only the liver of fed persons can produce sufficient lactic acid to markedly overwhelm its own buffer capacity plus that of the ECF and other tissues. Moreover, it is important to realize that a fasted (low hepatic glycogen) subject who lacks the stimulus for muscle glycogenolysis can only develop a modest degree of acute lactic acidosis owing to a limited precursor availability; under these circumstances, hypoglycemia and/or localized tissue necrosis could be the major threats to that patient. We present two examples with more chronic lactic acidosis without hypoxia emphasizing that tissue catabolism may be necessary to support high rates of lactic acid production, and we suggest that a high plasma lactate concentration need not be present to observe a large turnover of this metabolite.

Acid-Base Equilibrium↗

PubMed1985

Erosive gastroduodenitis with marked epithelial atypia after hepatic arterial infusion chemotherapy.

We report the case of a 59-year-old man who was treated with intraarterial chemotherapy for metastatic colonic adenocarcinoma. After the second course he developed persistent symptoms of nausea, vomiting, and pain. Endoscopic examination demonstrated severe erosive gastritis and duodenitis, and histological examination of the antral tissue showed severe atypia and histological appearances suggestive of in situ carcinoma. A 2-month course of sucralfate and cimetidine was used and successfully produced symptomatic relief as well as complete normalization of the dysplastic changes.

Adenocarcinoma↗

PubMed1984

Phase II study of acivicin in colorectal carcinoma: a National Cancer Institute of Canada study.

Twenty previously untreated patients with advanced colorectal carcinoma were treated with acivicin given in a 5-day iv schedule at a starting dose of 15 mg/m2, escalating to 26 mg/m2. Therapy was repeated every 3 weeks. Nineteen patients were evaluable for toxicity, which was mild and tolerable overall. Hematological toxicity was minimal, with only one patient developing severe myelosuppression at the starting dose. Nonhematological toxicity was also mild to moderate, occurring in 70% of the patients. Nausea, vomiting, and stomatitis were the most common side effects. CNS toxicity was moderate and occurred in 55% of the patients. Some patients found these symptoms distressing, although the treatment had to be discontinued in only one patient. There were no objective responses among 17 patients evaluable for response. This study indicates that acivicin given in a 5-day schedule is well-tolerated overall.

Adenocarcinoma↗

PubMed1982

Theoretical aspects of weight loss in patients with cancer. Possible importance of pyruvate dehydrogenase.

In the analysis of weight loss in cancer patients, consideration must be given to decreased caloric intake, increased caloric expenditure and abnormal losses of calories. When these factors do not adequately explain the degree of weight loss, this may be due to a specific loss of lean body mass, as the caloric density of muscle is much less than that of fat. The key enzyme for the protection of lean body mass in hypocaloric states is pyruvate dehydrogenase (PDH). During fasting, fast oxidation in host tissues leads to inactivation of PDH, preventing irreversible loss of pyruvate precursors which would have to be replaced by protein breakdown. A tumor in which PDH activity remains high in the fasting state would cause loss of lean body mass in the host. This report suggests that this phenomenon may be important in certain patients with cancer cachexia.

Amino Acids↗

PubMed1982

Evaluation of sodium acetate as a source of alkali therapy in an experimental aerobic model of lactic acidosis due to decreased pyruvate oxidation.

An "in vitro" model of one type of lactic acidosis was produced in rat hemi-diaphragms with inhibitors of pyruvate oxidation. In order to obtain this inhibition in the absence of hypoxia, two actions were sought; inhibiting the mitochondrial pyruvate transporter and lowering the rate of pyruvate diffusion into these mitochondria. alpha-Cyano-3-hydroxy cinnamate (CNCM) was utilized because it is a specific inhibitor of the mitochondrial pyruvate transporter. Aminooxyacetate (AOA) was employed because it leads indirectly to inhibition of the entry of cytoplasmic reducing power into mitochondria. As a result of the addition of this latter compound, pyruvate levels fell and this should decrease the rate of pyruvate diffusion into the mitochondria. Glucose was the only substrate provided to this tissue and its entry into the cells was promoted by insulin. The oxidation of U-14C glucose to 14CO2 was significantly reduced in the presence of CNCM and AOA, presumably reflecting the inhibition of pyruvate oxidation. Under these conditions, lactate accumulated and pyruvate fell; however, there was a significant accumulation of lactate plus pyruvate during the incubation period. This "in vitro" lactic acidosis was markedly diminished when acetate was also present. These results are consistent with the hypothesis that provision of an alternate substrate to the TCA cycle for ATP synthesis could lead to a decreased rate of glycolysis and thereby to a decreased rate of lactic acid accumulation in this "in vitro" model of lactic acidosis.

Acetates↗

PubMed1981

Chronic lactic acidosis in a patient with cancer: therapy and metabolic consequences.

Lactic acidosis is a life-threatening disorder in some cases. Treatment should be directed at the primary cause. Sodium bicarbonate should be added if the acidosis is very severe, or if the rate of hydrogen ion production is very rapid and not controlled. In contrast, with moderate degrees of steady state lactic acidosis and poor dietary intake, the risks of therapy with sodium bicarbonate or dichloroacetate may actually outweigh the benefits in a cachectic patient unless a dietary glucose and/or protein load is given.

Acidosis↗

PubMed1981

Regulation of energy metabolism in Morris hepatoma 7777 and 7800.

The pathway of fat oxidation in two experimental hepatomas was studied in order to demonstrate that a specific deficit in the energy metabolism of a tumor might contribute to the cachexia of the host. Forty-eight male Buffalo rats were divided into four groups of 12 each. One group was implanted s.c. with Morris hepatoma 7777 and one group was implanted with Morris hepatoma 7800, whereas the other two groups served as controls. All groups were fed standard rat chow diet ad libitum until the tumors reached 2 cm in diameter. The animals were then fasted for 24 hr prior to sacrifice and excision of tumor and liver for assays. During the period of tumor growth, the animals bearing the 7777 hepatoma lost weight, but the weight of the 7800 hepatoma-bearing rats did not differ significantly from that of the control animals. The livers of both groups of animals showed evidence of fatty acid oxidation in vivo and in vitro, and, as expected, during fasting, pyruvate dehydrogenase was inactivated and the rate of fatty acid synthesis was low. A qualitatively similar picture was seen with the better-differentiated 7800 hepatoma. In contrast, the 7777 hepatoma exhibited low levels of fatty acyl coenzyme CoA, no appreciable activity of carnitine palmitoyl transferase and fortified homogenates of the tumor were unable to oxidize palmitate. In keeping with these observations, pyruvate dehydrogenase remained in the active form, and fatty acid synthesis continued unabated in the fasted state in these tumors. Ketone bodies could not be oxidized by fortified homogenates of the liver or by either tumor, probably due to the lack of 3-ketoacid thiotransferase, which was undetectable in these tissues. We hypothesize that flow-through pyruvate dehydrogenase during fasting in Morris hepatoma 7777, occurring as a result of the defect in fat oxidation, contributes to the weight loss of these animals.

Acyl Coenzyme A↗

PubMedDate not supplied

Compliance with Papanicolaou smear screening following tubal ligation in women with cervical cancer.

To evaluate patient compliance with Papanicolaou (Pap) smear screening after tubal ligation compared with other methods of birth control in patients who develop cervical cancer, a retrospective review of 262 women with cervical cancer diagnosed at age < or = 70 years was undertaken at the Albert Einstein College of Medicine from January 1987 to December 1995. Demographic data, stage of the disease, histologic type, history of smoking, history of sexually transmitted disease (STD), and birth control use were recorded. The Pap screening history was obtained from all the patients. Women who had a bilateral tubal ligation (BTL) were compared with those who did not have this form of birth control. The date and result of their last Pap test prior to their diagnosis of cervical cancer was noted. Two hundred fourteen women with cervical cancer were evaluable. The clinical stage, mean age, history of smoking, and history of STD were similar for both groups. Gravidity among the BTL group was higher than in the non-BTL group (p < 0.01). Forty-eight (22.4%) women had a previous BTL. Twenty-seven of these 48 patients (56.3%) did not have a Pap smear within 3 years prior to the diagnosis of cervical cancer. Of the 166 patients, 61 (36.7%) did not have a Pap test within 3 years (p < 0.05). Fourteen women (29.2%) in the tubal ligation group never returned for a Pap test following the BTL. An average of 6.2+/-5.9 years elapsed since the last Pap test in the BTL group, with 4.0+/-5.1 years in the nontubal ligation group (p < 0.05). There was a correlation between the number of years since BTL (14.2+/-7.7) to the number of years since the last Pap test (6.2+/-5.9) (p < 0.05). Women who have had a BTL should be considered high risk because of poor screening compliance. A Pap test every 3 years is not adequate in this high-risk population group. We advocate improved counseling regarding the importance of continued annual Pap screening for women who are considering tubal ligation.

Adult↗

PubMedDate not supplied

Protein conversion to glucose: an evaluation of the quantitative aspects.

The amount of glucose that can be synthesized from a protein depends on its amino acid (AA) composition. This value is about 60 g from 100 g of liver or muscle protein and is based on a knowledge of the total AA content and the proportion of each AA that can be converted to pyruvate. The maximum quantity of glucose in grams that can be synthesized from administered AA solutions is the sum of the products of the number of moles of each AA times its percent convertible to pyruvate times the molecular weight of that AA.

Amino Acids↗