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Biomedical subjects

W M Linehan

Publications and source records attributed to W M Linehan.

At least 235 records · Page 13Linked to original sources
PubMed1987

The effect of 4MA, a potent inhibitor of 5 alpha-reductase, on the growth of androgen-responsive human genitourinary tumors grown in athymic nude mice.

The five alpha-reductase inhibitors are a newly developed family of compounds that block the intracellular conversion of testosterone (T) to dihydrotestosterone (DHT). 17-beta-N, N-Diethylcarbamoyl-4-methyl-4-aza-5-alpha-androstan-3-one (4MA), the most widely studied of these compounds, has been shown to inhibit the androgen-dependent growth of both normal animal tissues and of the Noble tumor, an experimental, hormone-responsive rat neoplasm. 4MA has been found to inhibit androgen-dependent growth without altering plasma levels of T or DHT. In the present study, we assessed the efficacy of 4MA in inhibiting the growth of PC-82 and R198, human androgen-responsive genitourinary malignancies. In the first experiment, 4MA was administered subcutaneously at a dose of 6 mg/kg/day to castrated and hormonally replaced groups of PC-82-bearing male athymic nude mice. 4MA therapy when compared to control therapy caused significant PC-82 growth inhibition in three different groups of hormonally replaced castrated mice: physiologic T-replaced (P less than .001), supraphysiologic T replaced (P less than .001), and supraphysiologic T and DHT replaced (P less than .001). There was no difference between the post therapy plasma levels of T or DHT in the control-treated and 4MA-treated mice. In the second experiment, the effect of 4MA (6 mg/kg/day S.Q.) was compared to that of castration and control therapy on the growth of R198. Both castration and 4MA therapy effectively inhibited R198 growth when compared to control therapy (P = .01 and .02, respectively), but there was no difference in the degree of growth inhibition seen with 4MA or castration (P = .45). Castration and 4MA-therapy significantly lowered plasma T levels when compared to control therapy; castration also significantly lowered plasma DHT levels, while 4MA and control therapy did not. These studies suggest that 4MA is effective in inhibiting the growth of human androgen-responsive tumors grown in athymic nude mice and that further studies with other 5 alpha-reductase inhibitors are indicated.

5-alpha Reductase Inhibitors↗
PubMed1987

Molecular markers of neuroendocrine development and evidence of environmental regulation.

We constructed a human pheochromocytoma cDNA library and used differential hybridization to human pheochromocytoma and human neuroblastoma cDNA probes to isolate genes that are highly expressed in the adrenal medullary neuroendocrine tumor, pheochromocytoma, but not in the more immature embryonal tumor of adrenal medulla, neuroblastoma. Two cDNA clones, pG8 and pG2, were more highly expressed in normal and neoplastic chromaffin tissue than they are in neuroblastoma. Furthermore, they are expressed in a remarkably limited number of other human tumors or normal tissues. pG8 is highly expressed in medullary thyroid carcinoma, another tumor of neural crest origin, which can occur in association with pheochromocytoma in the multiple endocrine neoplasia type II syndrome. pG2 is highly expressed in the adrenal cortex, an endocrine gland thought to be embryologically unrelated to the neural crest-derived adrenal medulla. The expression of both pG8 and pG2 can be induced in human neuroblastoma cells with dexamethasone, suggesting a mechanism by which glucocorticoids may influence development of a neuroendocrine phenotype.

Adrenal Gland Neoplasms↗
PubMed1987

Responses of the hypothalamic-pituitary-adrenal and renin-angiotensin axes and the sympathetic system during controlled surgical and anesthetic stress.

We studied the responses of plasma CRH, ACTH, cortisol, norepinephrine, epinephrine, and renin activity in 11 patients undergoing parathyroid or thyroid surgery after identical preoperative sedation and during isoflurane (Forane) anesthesia. During surgical exploration, plasma CRH levels [10 +/- 2 (+/- SEM) pg/mL] remained at basal (unstimulated) levels, and plasma ACTH (11.5 +/- 1.4 pg/mL), cortisol (24 +/- 4 micrograms/dL), and epinephrine (35 +/- 10 pg/mL) concentrations remained within their normal morning ranges. The majority of the patients had no evidence of pulsatile ACTH secretion during the operation, but, rather, secreted ACTH and cortisol continuously. There was a small elevation of plasma norepinephrine and PRA which was associated with a small increase in heart rate and decrease in blood pressure. Anesthesia reversal, endotrachial extubation, and the early recovery period were associated with marked mean peak increases in plasma ACTH (173 +/- 45 pg/mL), cortisol (35 +/- 6 micrograms/dL), and epinephrine (220 +/- 56 pg/mL) and the return of plasma norepinephrine and PRA to basal levels. All hormones returned to basal levels by the first post-operative day. The data suggest that with modern anesthetic techniques patients undergoing neck surgery had mildly elevated plasma ACTH, cortisol, and epinephrine levels. Glucocorticoid secretion during the operation was maintained primarily by continuous rather than pulsatile ACTH secretion. The immediate postoperative period was associated with profound elevations of plasma ACTH, cortisol, and epinephrine. The major determinant of ACTH, cortisol, and epinephrine secretion was anesthesia reversal and recovery and not surgical trauma.

Adrenocorticotropic Hormone↗
PubMed1987

Effects of interleukin-2 on renal function in patients receiving immunotherapy for advanced cancer.

Adoptive transfer of autologous lymphokine-activated killer cells in conjunction with recombinant interleukin-2 in patients with advanced cancer has produced significant regression of metastatic disease in selected patients. We analyzed the effects of interleukin-2 regimens on renal function in 99 consecutive patients. Interleukin-2 therapy with or without lymphokine-activated killer cells was associated with varying degrees of hypotension, fluid retention, azotemia, oliguria, and low fractional sodium excretion. After the patients completed the interleukin-2 regimens, their renal function improved promptly. Renal function values returned to baseline levels within 7 days in 62% of patients, within 14 days in 84%, and within 30 days in 95%. Pretherapy serum creatinine values above 1.4 mg/dL predicted the severity of azotemia and prolonged duration of renal functional recovery, interleukin-2 therapeutic regimens induce prerenal azotemia. Careful selection of patients and early detection of adverse physiologic changes may alleviate the side effects of interleukin-2 therapy.

Adolescent↗
PubMed1986

Danazol-induced cystitis: an undescribed source of hematuria in patients with hereditary angioneurotic edema.

From 1975 through 1983, 69 patients with hereditary angioneurotic edema were treated with danazol, a semisynthetic anabolic steroid. Hematuria developed in 13 of these patients (19 per cent). Careful evaluation of the genitourinary tract showed the presence of a distinct form of hemorrhagic cystitis in 10 patients. Clinically, 9 patients presented with microscopic and 1 with intermittent gross hematuria. Irritative bladder symptoms were reported by 2 patients. Neither the dose nor duration of danazol therapy correlated with the severity of the cystoscopic or pathological findings. Cystoscopically, a rather nonspecific pattern of erythema, submucosal telangiectasia and neovascularity was observed. Histopathologically, bladder biopsy typically showed numerous dilated submucosal vessels with hemorrhage, mucosal ulceration and occasional inflammatory cells. These changes regressed in all but 1 patient when danazol therapy was discontinued. Further studies are needed to elucidate the role of danazol itself or of the danazol-hereditary angioneurotic edema interaction in the pathogenesis of these abnormalities.

Adult↗
PubMed1986

Human prostate carcinoma causes hypercalcemia in athymic nude mice and produces a factor with parathyroid hormone-like bioactivity.

The mechanism of the calcium and phosphorus abnormalities associated with metastatic prostate carcinoma (CaP) is not yet understood. A tumor model was recently established in which 9479, a human CaP from a patient with prostate carcinoma-induced osteomalacia, was heterotransplanted into athymic nude mice (ANM). In the present study the effect of 9479 on ANM was evaluated. Serum calcium (Ca), phosphorus (P), parathyroid hormone (PTH), 1,25-dihydroxyvitamin D3(1,25-(OH)2D3) and urinary cAMP were measured. Ca was markedly elevated in ANM bearing 9479 vs. age-matched controls (C); the increased Ca returned to control level after tumor removal. Serum PTH was lower in 9479-bearing ANM vs. C while urinary cAMP and serum 1,25-(OH)2D3 levels were elevated. In the ANM bearing 9479, there was a decrease in serum P vs. C which returned to normal after tumor removal. Fractional P excretion was greater in 9479 animals than C. Extracts of 9479 were examined for the presence of parathyroid hormone-like bioactivity by measuring stimulation of intracellular cAMP in ROS 17/2.8 cells. Cyclic AMP stimulation which was found was shown to be inhibited by the competitive PTH antagonist [8Nle, 18Nle, 34Tyr]bPTH-(3-34) amide. These data suggest tumor induction of parathyroid hormone-like humoral modulation of calcium, phosphate and vitamin D metabolism in vivo associated with a parathyroid hormone-like prostate carcinoma product.

Animals↗
PubMed1985

Evidence that lymphokine-activated killer cells and natural killer cells are distinct based on an analysis of congenitally immunodeficient mice.

The in vitro incubation of lymphoid cells in RIL 2 results in the generation of LAK cells that are broadly lytic to autologous, syngeneic, and allogeneic fresh tumor cells, but which do not lyse fresh, normal cells. Strains of mice with congenital immunodeficiencies were tested both for the presence of NK cells and for their capacity to generate LAK cells after in vitro incubation with IL 2. Splenocytes obtained from two immunodeficient mouse strains (NIH-Beige-Nude and NIH-Beige-Nude-XID) failed to generate LAK cells, but displayed significant activity. Splenocytes from another immunodeficient mouse strain (NIH-Beige-XID) generated LAK cells but did not display NK cell activity. This dissociation of activation of LAK cells from NK cells among the immunodeficient strains indicates that the LAK and NK cell lytic systems are distinct.

Animals↗
PubMed1983

Comparison of four provocative tests for the diagnosis of gastrinoma.

In an attempt to determine the best provocative test for the diagnosis of gastrinoma, ten normal subjects, 13 patients with known gastrinoma, and one patient with presumed gastrinoma were administered four regimens: (1) rapid calcium infusion (2 mg Ca++/kg/min), (2) secretin (2 clinical units (CU)/kg/bolus), (3) long calcium infusion (12 mg Ca++/kg/3 h) and (4) a combination test consisting of a rapid calcium infusion followed immediately by secretin. Blood was drawn for serum gastrin levels before and following infusion of the test agents. The administration of rapid calcium followed by secretin provoked the greatest increases in serum gastrin above basal levels in both normals (29%) and patients (362%). Peak gastrin levels in patients were similar following the long calcium infusion (341%) but were less following the rapid calcium infusion alone (124%) and secretin alone (207%). There were no false-positive or false-negative tests with the calcium plus secretin when the criterion for diagnosis was either a 50% increase or a 200 pg/ml increase above the basal gastrin level. The distinct advantages (short test period, low patient morbidity, and relatively great potency) of the calcium plus secretin test make it an attractive alternative to other previously described provocative tests for the diagnosis of gastrinoma.

Adult↗
PubMed1978

The detection of elevated plasma levels of carcinoembryonic antigen in patients with suspected or established medullary thyroid carcinoma.

Plasma levels of carcinoembryonic antigen (CEA) and calcitonin (CT) were measured in 35 normal control subjects and in 37 patients with suspected or established medullary thyroid carcinoma (MTC). None of the normal control subjects had elevated basal plasma levels of either CEA (greater than 5 ng/ml) or CT (greater than 0.25 ng/ml). However, of the 37 patients with suspected or established MTC, 23 (62%) had elevated basal plasma levels of CEA (range 9.8--7,000 ng/ml) and 27 (73%) had elevated basal plasma CT values (range 0.30--500 ng/ml). Generally, patients with clinically apparent MTC, either primary or metastatic, had higher plasma CEA and CT levels than those with occult disease. A positive correlation was found (r = 0.785, p less than 0.01) when comparing basal plasma CEA and stimulated plasma CT levels in 20 patients. A marked increase above the basal plasma level of CT but not CEA was detected in each of six MTC patients following intravenous calcium or pentagastrin. These data demonstrate that basal plasma levels of CEA and CT were increased in a large percentage of patients with MTC. Plasma calcitonin levels unlike plasma CEA levels were more often elevated in patients with occult disease and were increased above basal following the intravenous administration of either calcium gluconate or pentagastrin.

Adolescent↗
PubMed1978

Provocative agents and the diagnosis of medullary carcinoma of the thyroid gland.

Twenty-six patients with known or suspected medullary thyroid carcinoma (MTC) and 21 normal control subjects were tested intravenously on four separate days with calcium gluconate (CG), 2 mg Ca(++)/kg/1 min.; pentagastrin (P), 0.5 ug/kg/ 5 sec.; calcium chloride (CC), 3 mg Ca(++)/kg/10 min.; and a combination of calcium gluconate and pentagastrin (CG + P). Calcitonin (CT) levels were determined by radioimmunoassay on plasma collected before and immediately following each test infusion. In none of the 21 control subjects was there a clear increase in CT above 200 pg/ml following any of the four provocative tests. Conversely, in all 26 patients with known or suspected MTC, plasma CT levels were markedly increased (>300 pg/ml) following the combined infusion of CG + P. The peak CT response was greater with CG + P than with a) CG alone (22 of 24 patients, p < 0.002), b) P alone (25 of 26 patients, p < 0.002), or c) CC alone (17 of 17 patients, p < 0.002). Of 12 MTC patients with undetectable basal calcitonin levels, all had peak responses greater than 300 pg/ml following CG + P, whereas such responses occurred less often following CG alone (8 of 12) or P alone (8 of 12). The results demonstrate that the combined administration of pentagastrin and calcium gluconate constitutes a more effective and reliable stimulus for CT secretion from MTC cells than the use of either agent alone, and appears the most useful single screening test for the detection of occult MTC.

Adolescent↗
PubMed1978

Medullary thyroid carcinoma: relationship of method of diagnosis to pathologic staging.

Medullary thyroid carcinoma (MTC) develops in virtually all patients affected with multiple endocrine neoplasia type II (MEN II), a disease inherited as an autosomal dominant trait. The thyroid tumor cells secrete calcitonin (CT) and the detection of elevated plasma levels (>300 pg/ml) of this hormone in MEN II kindred members strongly suggests the presence of MTC even though it may not be evident clinically. Intravenously administered calcium ion (Ca(++)) and pentagastrin (Pg) are potent CT secretagogues which are of particular value in establishing the early diagnosis of MTC. In evaluating seven kindreds with MEN II, we detected 90 patients with MTC. Depending on the method of diagnosis, they could be divided into three categories: Group 1; patients with no clinical evidence of MTC whose undetectable basal plasma calcitonin levels became elevated following intravenous Ca(++) or Pg, Group II; patients with no clinical evidence of MTC who had elevated basal plasma CT levels, and Group III; patients with clinically evident MTC. At the time of diagnosis of MTC, the patients in Group I were younger (20.5 +/- 1.9 years) than the patients in Group II (32.5 +/- 4.7 years, p < 0.005) and Group III (34.3 +/- 2.0, p < 0.00005). The incidence of residual MTC, as indicated by an elevated plasma CT level following provocative testing postoperatively, was less frequent in patients diagnosed biochemically ([6/34]; Group I, 4/26 and Group II, 2/8) than in those diagnosed clinically (Group III, 15/26, p < 0.002). Furthermore, regional nodes were involved less often in patients diagnosed biochemically ([5/28]; Group I, 2/22 and Group II, 3/6) than in those diagnosed clinically (Group III, 15/24, p < 0.02). Distant metastases were only evident in Group III patients. Patients with MEN II who had the diagnosis of MTC established biochemically rather than clinically, had a more favorable pathological stage of disease at the time of thyroidectomy. This was especially true if the biochemical diagnosis had been by provocative testing.

Adolescent↗