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Biomedical subjects

R L Stephens

Publications and source records attributed to R L Stephens.

At least 73 records · Page 4Linked to original sources
PubMed1989

Intracisternal injection of a TRH analogue stimulates gastric luminal serotonin release in rats.

Intracisternal injection of TRH analogue, RX 77368, which has been previously shown to induce a vagal-dependent stimulation of gastric acid secretion and contractility dose-dependently (10-300 ng) stimulated serotonin release into the gastric lumen of conscious pylorus-ligated rats. The stimulation of gastric acid and serotonin release occurred 15 and 30 min, respectively, after intracisternal injection of RX 77368 (100 ng) and lasted for over 2 h, as measured in urethan-anesthetized rats with gastric fistula. Cervical vagotomy and atropine pretreatment (0.1 mg/kg) completely abolished the RX 77368-stimulated gastric serotonin and acid output in acute gastric fistula rats, whereas in pylorus-ligated rats atropine pretreatment markedly reduced RX 77368-stimulated gastric fluid volume and serotonin output, but not serotonin concentration. Systemic administration of bethanechol chloride, histamine, or pentagastrin, at doses that elicited gastric acid secretory responses similar to that of intracisternal TRH analogue, produced little or no intraluminal serotonin release. These results demonstrate that intracisternal injection of TRH analogue induced a marked and sustained release of serotonin into the gastric lumen that is mediated by vagal-dependent mechanisms unrelated to enhanced acid secretion. Activation of muscarinic receptors appears to be involved, but the relative ineffectiveness of bethanechol in this system suggests that (an)other vagally mediated neurochemical event(s) stimulated by intracisternal RX 77368 acts in conjunction with muscarinic receptor activation to produce intraluminal serotonin release. The functional significance of serotonin release into the gastric lumen in relation with intracisternal TRH analogue-induced alterations of gastric secretion, motility and blood flow, and lesion formation remains to be elucidated.

Animals↗
PubMed1989

Serotonin depletion potentiates gastric secretory and motor responses to vagal but not peripheral gastric stimulants.

Vagal stimulation is known to release gastrointestinal serotonin. The effect of depletion of serotonin stores on vagally stimulated gastric acid secretion and motility was studied in rats. Pretreatment of rats with parachlorophenylalanine (p-CPA) did not alter basal gastric acid and serotonin secretion but produced a 57% reduction in the intraluminal gastric release of serotonin and a 43 to 100% potentiation of the gastric acid secretory response elicited by intracisternal injection of the stable thyrotropin-releasing hormone analog, RX 77368, in conscious pylorus-ligated rats or urethane-anesthetized rats with an acute gastric fistula. Dose-response studies revealed that the gastric acid secretion induced by submaximal but not high doses of RX 77368 was elevated significantly by p-CPA pretreatment. p-CPA also enhanced the gastric acid output produced by submaximal, but not high doses of the vagal stimulant baclofen, [beta-(p-chlorophenyl)-gamma-aminobutyric acid]. In contrast, p-CPA pretreatment had no effect on gastric acid secretion stimulated by bethanechol, histamine or pentagastrin. Selective depletion of central serotonin stores by pretreatment with the neurotoxin 5,7-dihydroxytryptamine given alone, or combined with parachloroamphetamine did not alter RX 77368-stimulated gastric acid secretion. In addition, gastric contractility stimulated by intracisternal injection of RX 77368 was significantly enhanced by p-CPA but not by 5,7-dihydroxytryptamine pretreatment, whereas the contractile response to carbachol was not altered by p-CPA pretreatment. These results suggest that depletion of peripheral but not central serotonergic stores potentiate gastric acid secretion and contractility induced by vagally, but not peripherally acting gastric stimulants. Thus, peripheral serotonin may exert an inhibitory tone on vagally stimulated gastric acid secretion and motility in the rat.

Animals↗
PubMed1988

Simultaneous chemotherapy-radiotherapy with prophylactic cranial irradiation for inoperable adeno and large cell lung carcinoma: a Southwest Oncology Group Study.

From September 1980 to March 1983, 30 cases were registered in a Southwest Oncology Group Study. Twenty-four cases were evaluable and constitute the basis for this report. Patients were diagnosed with adenocarcinoma or large cell lung carcinoma. Tumors were considered inoperable but able to be encompassed in a single radiotherapy (RT) port. Seventy-two percent of measured tumors were 4 cm in diameter or bigger (range 2 cm to 10 cm). RT was given initially to the primary lung tumor and ipsilateral hilar, mediastinal, and supraclavicular nodes, at 2 Gy per day; total dose was 44 Gy. The areas involved by tumor were boosted with 10 Gy more. Prophylactic cranial irradiation (PCI) was started at the same time with 15 treatments of 2.75 Gy. A 2-week rest period was instituted after the first 11 treatments. Chemotherapy (CT) was given from day 1 which consisted of 5-Flourouracil, 500 mg./M2, (bolus day 1 and 8) Vincristine, 1 mg./M2, and Mitomycin C, 5 mg./M2 both given on day 1. Cycles were repeated at 28 day intervals for 3 cycles and at 6 week intervals for 5 more cycles, or until progression, with persistent disease. Eight cases (33%) achieved complete response (CR), and 5 (21%) partial response (PR). Overall median survival was 37 weeks and 2 years survival was 8%. CR patients had the best chance for long-term survival. Relapses were evenly distributed between extra and intrathoracic sites, with the latter even between the inside and outside the RT field. No patient died with clinical evidence of metastasis to the brain (MB), although one was found to have MB at autopsy. Toxicity was severe in 7 cases (29%) and 2 deaths are considered toxicity related. When comparing these results to those from the literature, we found this protocol has achieved a slightly higher CR rate than what is expected with RT alone, without survival improvement. As CR patients have the best prognosis, simultaneous CT-RT might offer some promise, but at the expense of increased toxicity. PCI was effective in preventing or delaying MB, and thus deserves further investigation. We should caution that the study of possible long-term effects of PCI could not be assessed because of the short median survival of the patients. It is possible that a less aggressive time-dose fractionation to the brain might be as effective as the one used in this protocol.

Adenocarcinoma↗
PubMed1988

Identification of putative methanol dehydrogenase (moxF) structural genes in methylotrophs and cloning of moxF genes from Methylococcus capsulatus bath and Methylomonas albus BG8.

An open-reading-frame fragment of a Methylobacterium sp. strain AM1 gene (moxF) encoding a portion of the methanol dehydrogenase structural protein has been used as a hybridization probe to detect similar sequences in a variety of methylotrophic bacteria. This hybridization was used to isolate clones containing putative moxF genes from two obligate methanotrophic bacteria, Methylococcus capsulatus Bath and Methylomonas albus BG8. The identity of these genes was confirmed in two ways. A T7 expression vector was used to produce methanol dehydrogenase protein in Escherichia coli from the cloned genes, and in each case the protein was identified by immunoblotting with antiserum against the Methylomonas albus methanol dehydrogenase. In addition, a moxF mutant of Methylobacterium strain AM1 was complemented to a methanol-positive phenotype that partially restored methanol dehydrogenase activity, using broad-host-range plasmids containing the moxF genes from each methanotroph. The partial complementation of a moxF mutant in a facultative serine pathway methanol utilizer by moxF genes from type I and type X obligate methane utilizers suggests broad functional conservation of the methanol oxidation system among gram-negative methylotrophs.

Alcohol Oxidoreductases↗
PubMed1988

TRH analogue, RX 77368, injected into dorsal vagal complex stimulates gastric secretion in rats.

Medullary sites inducing gastric acid secretion in response to microinjection of the stable analogue of thyrotropin-releasing hormone (TRH; RX 77368, pGlu-His-[3,3'-dimethyl]-Pro-NH2) were investigated in urethan-anesthetized rats. Gastric acid output was recorded every 2 min through a double gastric cannula constantly perfused with 0.9% saline solution maintained at pH 5.5 using an automatic titrator. Unilateral microinjection of RX 77368 (10-100 ng in 50-nl volume) into the dorsal vagal complex (DVC), the dorsal vagal nucleus and nucleus tractus solitarius, induced a significant dose-dependent stimulation of gastric acid secretion. The peak response occurred within 50 min and lasted over 1 h. Other medullary sites, including the lateral, dorsal, and parvocellular reticular nuclei; the medial longitudinal fasciculus; and the medial cuneate nucleus injected with RX 77368 (10-100 ng), were inactive. The TRH metabolites, TRH-OH and His-Pro diketopiperazine (100 ng), injected into the DVC did not influence gastric acid secretion. The stimulation of gastric acid secretion induced by DVC injection of TRH was abolished by vagotomy. These results demonstrate that 1) the DVC is an important site of action for TRH-induced stimulation of gastric acid secretion, 2) TRH action in the DVC is not secondary to the formation of TRH metabolites, and 3) the effect is expressed by vagal efferent pathways. These findings added to the high concentration of TRH-immunoreactivity and receptors in the DVC suggest a role for endogenous TRH in the regulation of vagal outflow to the stomach.

Animals↗
PubMed1988

Flow cytometry DNA analysis on tumor cell subpopulation of human tumor specimens by exclusion of lymphohemopoietic cells.

We describe a new flow cytometry procedure in which DNA analyses can be obtained selectively on pure, freshly obtained tumor cell subpopulations of human tumor specimens. This procedure is based on exclusion from analysis of the contaminating lymphohemopoietic cells mixed with tumor cells in tumor specimens. This exclusion is made possible by labeling all lymphohemopoietic cells with an antibody to HLe-1 (HLE), which is present on all lymphohemopoietic cells but on no other cells, and by gating against these labeled cells when analyzing for DNA. For the model system, a 1:1 mixture of normal human peripheral blood leukocytes and either of two human cancer cell lines, HEp-2 and MCF-7, normal leukocyte contamination can be reduced to 3.1% while retaining 94.7% of tumor cells for DNA analysis. Four examples of human tumor samples, two cases each of malignant effusions and lymph node metastases, were analyzed with this procedure. The results clearly indicate that this new method will improve ploidy analysis/aneuploidy detection and will make it possible to obtain more accurate cell-cycle analyses of tumor cells than have previously been possible. This new procedure will contribute to clinical and biological studies involving DNA of human tumors.

Adenocarcinoma↗
PubMed1988

Adjuvant therapy in large bowel adenocarcinoma: long-term results of a Southwest Oncology Group Study.

The Southwest Oncology Group (SWOG) colorectal adjuvant study 7510 went through two phases. From 1975 to 1977, 309 patients were randomized to chemotherapy alone or the same chemotherapy plus immunotherapy. From 1977 until 1980, 317 patients were randomized among the same two therapy programs and a control group. With a minimum follow-up in either phase of greater than 7 years, data are now mature. They show no difference in relapse-free survival (RFS) nor overall survival (OS) in either the two-way phase or in the three-way phase. There is no indication, except possibly in one very small subset, that the addition of immunotherapy to chemotherapy provides an improvement in OS or in RFS. Using data from patients accrued after randomization to the control group, we fail to find evidence that either chemotherapy alone or chemoimmunotherapy improves OS or RFS when contrasted to outcomes obtained by patients on the control arm. In fact, we have significant evidence, at the P = .016 level, that chemotherapy does not improve OS by at least 50%; we also have significant evidence, at the P = .011 level, that chemoimmunotherapy will not improve OS by at least 25%. No evidence of efficacy was demonstrated for either treatment regimen, even though enough therapy was given to result in significant toxicities. Acute toxicity was at least moderate, but not fatal, in 75% of patients. Recognizable delayed toxicity included rare cases of fatal renal failure and acute leukemia.

Adenocarcinoma↗
PubMed1987

A phase II trial of combination chemotherapy in patients with metastatic carcinoid tumors. A Southwest Oncology Group Study.

A prospective Phase II trial of combination chemotherapy in patients with metastatic carcinoid tumors was conducted by the Southwest Oncology Group. The therapy included 5-fluorouracil, Adriamycin, cyclophosphamide, and streptozotocin (FAC-S) or the same combination without Adriamycin (FC-S) in patients with heart disease. Seventy-four patients were entered and two were ineligible. Sixty-nine of the 72 were histologically reviewed. Six patients were declared ineligible after this review. Fifty-six patients received FAC-S, and nine received FC-S (one patient was inevaluable). The response rates were 31% and 22%, respectively. The median survival of all patients was 10.8 months. The analyses of various clinical and histologic parameters indicated that responses were more common in patients with gastrintestinal carcinoids; there was also a tendency toward shorter survival in patients with tumors that had a higher mitotic rate or the atypical and/or undifferentiated histologic pattern. The FAC-S combination can produce objective responses in patients with metastatic carcinoid tumors, but these are generally partial and brief. It was also concluded that currently available chemotherapy is inadequate.

Adult↗
PubMed1987

Klinefelter's syndrome and extragonadal germ cell tumors.

A 25-year-old man presented with diffuse metastatic pure choriocarcinoma, thyrotoxicosis, and cardiac tamponade. No discernable testicular primary tumor was found. The patient's peripheral blood karyotype was 47, XXY and phenotypic features of Klinefelter's syndrome were present. The patient was treated with aggressive combination chemotherapy followed by salvage surgery and remains in complete remission 3 years after diagnosis. Pure choriocarcinoma, although rare as a primary testicular neoplasm, accounts for 15% of extragonadal germ cell tumors in general and 30% of germ cell tumors in patients with Klinefelter's syndrome. Historically, the diagnosis of pure choriocarcinoma has been thought to convey a very poor prognosis. The occurrence of hyperthyroidism is unique to tumors containing choriocarcinomatous elements and the management of this disorder is discussed. Treatment of extragonadal germ cell tumors is also discussed with special reference to the roles of combination chemotherapy and salvage surgery.

Adult↗
PubMed1987

Phase II trial of vinblastine in previously treated patients with ovarian cancer: a Southwest Oncology Group Study.

Sixty-eight patients with relapsing, epithelial type ovarian carcinoma were entered into a Phase II study of vinblastine. Vinblastine was administered as a continuous intravenous infusion over five days at a starting dose of 1.7 mg/m2/day every 3 weeks. There were 44 fully evaluable and 6 partially evaluable patients. Forty-one of these patients had had only one prior treatment regimen. Grade 3 or 4 leukopenia occurred in 12 patients (24%), but Grade 3 or 4 thrombocytopenia occurred in only 2 patients. There were two clinical complete responses of 18 and 36 weeks duration and one partial response of 6 weeks for an overall response rate of 7%. We conclude that vinblastine, administered in optimal dose and schedule, has little clinical activity in previously treated patients with ovarian cancer.

Drug Evaluation↗
PubMed1987

Phase II trial of vinblastine in previously treated patients with ovarian cancer: a Southwest Oncology Group Study.

Sixty-eight patients with relapsing, epithelial type ovarian carcinoma were entered into a Phase II study of vinblastine. Vinblastine was administered as a continuous intravenous infusion over 5 days at a starting dose of 1.7 mg/m2/day every 3 weeks. There were 44 fully evaluable and 6 partially evaluable patients. Forty-one of these patients had had only one prior treatment regimen. Grade 3 or 4 leukopenia occurred in 12 patients (24%), but Grade 3 or 4 thrombocytopenia occurred in only 2 patients. There were two clinical complete responses of 18- and 36-week durations and one partial response of 6 weeks for an overall response rate of 7%. We conclude that vinblastine, administered in optimal dose and schedule, has little clinical activity in previously treated patients with ovarian cancer.

Adult↗
PubMed1987

Combination chemotherapy using adriamycin, DTIC, cyclophosphamide, and actinomycin D for advanced soft tissue sarcomas: a randomized comparative trial. A phase III, Southwest Oncology Group Study (7613).

The term soft tissue sarcoma refers to a large variety of malignant tumors arising in extraskeletal connective tissues that connect, support, and surround discrete anatomic structures. All visceral organs also contain a connective stroma that can undergo malignant transformation. Because of the histological similarities of this group of tumors and their relative rarity, treatment prescriptions for patients that have disseminated disease are most often uniform. In this study, we asked the question whether adding a third drug (cyclophosphamide or actinomycin D) to Adriamycin (Adr [Adria Laboratories, Columbus, OH])-(3,3-dimethyl-1-triazeno)- imidazole-4-carboxamide (DTIC) would improve the response rate and/or survival. A unique feature of this cooperative group clinical trial was the mandatory pathology review of the histological material. All patients of the Southwest Oncology Group between June 1, 1976, and November 17, 1979, who had a biopsy-confirmed diagnosis of a soft tissue sarcoma with convincing clinical or biopsy-documented evidence of metastatic disease were eligible for the study. Patients were randomized to receive (1) Adr, 60 mg/m2 intravenously, day 1, and DTIC, 250 mg/m2 every 3 weeks (104 patients); (2) Adr and DTIC as in (1) and cyclophosphamide, 500 mg/m2, day 1 (112 patients); or (3) Adr and DTIC as in (1) and actinomycin D, 1.2 mg/m2, day 1, (119 patients). There was no statistically significant difference in response rates (33%, 34%, and 24%) (P = .25). Median durations of response were 31 weeks in the Adr-DTIC arm, 26 weeks in the cyclophosphamide-DTIC-Adr arm, and 23 weeks in the Adr-DTIC-Actinomycin D arm (P = .78). Median durations of survival were 37, 42, and 50 weeks, respectively. Again, no statistically significant differences were observed (P = .59). Toxicities from each of these treatment arms were formidable and were equivalent. Prognostic factor analysis showed a prognosis based on bone marrow reserve, sex, and pathology subtype favorable to patients.

Adolescent↗
PubMed1986

High dose AZQ in renal cancer. A Southwest Oncology Group phase II study.

Fifty-seven patients with renal cancer were treated with AZQ, utilizing one of three IV push schedules. Only one partial response was seen in 55 evaluable patients, and considerable myelosuppression was encountered. Gastrointestinal toxicity was more severe in those patients who had received prior treatment. At these higher doses AZQ is deemed an inactive agent in patients with renal cell carcinoma, at least when the drug is administered as a push schedule.

Antineoplastic Agents↗
PubMed1986

Methotrexate cerebrospinal fluid pharmacokinetics in a patient with lymphoma treated with methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone.

The role of "moderate-dose" systemic methotrexate in preventing central nervous system lymphomatous relapse is unknown. Certain patients with diffuse non-Hodgkin's histologic subtypes have an increased risk of relapse in the central nervous system, and it would be helpful to know if intravenous "moderate-dose" methotrexate might treat or possibly protect the meninges from involvement. In part, the rationale behind the recent regimen of methotrexate, bleomycin, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), and dexamethasone (m-BACOD) is to protect the central nervous system, and the empiric proof of this protection awaits the follow-up results of trials currently underway. In the meantime, the systemic and cerebrospinal fluid pharmacokinetics of moderate-dose intravenous methotrexate were studied in one patient whose histologic subtype places him at high risk for central nervous system involvement. Although the central nervous system levels of methotrexate in this patient never reached 1 X 10(-6) M, the levels exceeded 1 X 10(-7) M for at least 24 hours. The implications of peak dose versus sustained exposure to a lower dose of methotrexate are discussed.

Antineoplastic Combined Chemotherapy Protocols↗