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The frequency of peripheral blood erythrocyte variants exhibiting allelic loss of glycophorin A (N/M antigen) has been used previously as a biological dosimeter to assess somatic mutations in bone marrow cells from external whole-body irradiation. The aim of the present study was to determine whether this marker could be used as a measure of bone marrow genotoxicity induced by 131I in the treatment of thyroid cancer. Flow cytometry of immunolabeled erythrocytes was performed to enumerate glycophorin A variants before and after eight therapy doses of 131I administered to five patients with differentiated thyroid carcinoma. Bone marrow radiation exposure from each dose was calculated from the integrated retention of 131I in the whole body and in the blood. In addition, the accumulated dose to the bone marrow received from earlier 131I therapy was calculated for each patient. Regression analysis was performed on the frequency of two glycophorin A variant cell types (N/O and N/N) as a function of accumulated dose to the bone marrow. Frequency of N/O variant cells showed a significant dose-related increase with a slope of 10.9 x 10(-6) per sievert. This dose effect is about one-half that previously observed after whole-body external irradiation at high dose rate. This decreased response could be explained by the low dose rate of the radiation to the bone marrow from 131I.

The letters by Drs Whitmore and Margolis criticize the cross-sectional nature of our study, 1 which demonstrated an association between etretinate use and decreased BMD. They note that biases or chance occurrence could account for an association when disease assessment and exposure are made at the same time. We agree that pretreatment assessments of BMD would have been desirable, if possible. However, many of these patients have been treated with retinoids since they were first studied in the United States in the 1970s, long before densitometry was commonly available. Radiologic assessment of bone density, a much less sensitive technique, was the standard at the time and is not really a fair comparison. So then, what are the biases noted and can they realistically explain the association that we identified? Margolis suggests that "it is just as plausible... that the individuals selected for study... had osteoporosis and were chosen to receive

Background and Design: Osteoporosis has been observed with chronic hypervitaminosis A but has not been established as a toxic effect of synthetic retinoid therapy in humans. This cross-sectional study was designed to assess bone mineral density (BMD) during long-term therapy with the retinoids etretinate or isotretinoin. Twenty-four patients were evaluated for osteoporosis with the standard techniques: single- and dual-photon absorptiometry. They received 50 g or more of etretinate (15 patients) or isotretinoin (nine patients) for 2 years or longer for the treatment of skin diseases (ichthyosis [nine patients], Darier's disease [six patients], xeroderma pigmentosum [four patients], skin cancer [three patients], or psoriasis [two patients]). In each of the two treatment groups, BMDs (measured in grams per square centimeter) were measured at five standard sites (ie, lumbar spine, femoral neck, trochanter, Ward's triangle, and radius) and evaluated against a standardized database to control for age, sex, and weight. In addition, for each measurement site, BMDs (controlled for age, sex, and weight) were compared between the two groups, as a direct control for each other. Observations: Compared with those of the age-, sex-, and weight-matched controls, the BMD values of the etretinate group were significantly decreased at four of the five measurement sites: femoral neck (90.6%, P =.0001), Ward's triangle (87.8%, P =.0001), trochanter (87.8%, P =.0012), and radius (85.0% P =.039). In contrast, the BMDs in the isotretinoin group did not differ from control values except for an elevation at the lumbar spine ( P =.039). When the two groups were compared, the mean BMDs were significantly lower in the etretinate group when measured at the lumbar spine, trochanter, and radius ( P Conclusions: This study identified osteoporosis in patients who received long-term therapy with etretinate but not isotretinoin. Prospective studies of BMD would be useful to further define retinoid-associated osteoporosis. (Arch Dermatol. 1995;131:1263-1267)

This conference focuses on the controversies about managing thyroid cancer, emphasizing the possibility that the treatment of patients with potentially fatal thyroid cancer may be improved. Although the mortality rate from thyroid cancer is low, it is the highest among cancers affecting the endocrine glands (excluding the ovary). Exposure to radiation during childhood in the 1930s and 1940s increased the incidence of but not the mortality from thyroid cancer, because these tumors are mainly papillary cancers developing in young adults. These rates may change as the exposed cohort ages. Risk factors that increase mortality include older patient age and the growth characteristics of the tumor at diagnosis, the presence of distant metastases, and cell type (for example, the tall-cell variants of papillary cancer, follicular cancer [to be distinguished from the more benign follicular variant of papillary cancer], medullary cancer, and anaplastic cancer). Local metastases in lymph nodes do not seem to increase the risk for death from papillary cancer, but they do increase the risk for death from follicular and medullary cancer. In the latter, mortality is decreased by the early detection and treatment of patients with the familial multiple endocrine neoplasia syndrome 2a. There are excellent tumor markers for differentiated cancer of the parafollicular and of the follicular cells (serum calcitonin and serum thyroglobulin levels, respectively). Measuring the calcitonin level allows early diagnosis of familial medullary cancer, whereas measuring the thyroglobulin level, although useful only after total thyroidectomy, allows early recognition of recurrence or metastases of papillary or follicular cancer. Initial surgery, protocols for follow-up, and the use of radioiodine for the ablation of any residual thyroid and the treatment of metastatic cancer are discussed. Because these tumors resist currently available chemotherapy regimens, possible ways to increase the effectiveness of radioiodine therapy are considered as are new approaches to treatment.

The effect of calcitonin gene-related peptide (CGRP) on the feline lower esophageal sphincter (LES) was determined and correlated with its anatomic distribution as determined by immunohistochemistry. Intraluminal pressures of the esophagus and LES were recorded in anesthetized cats. In separate cats, gastroesophageal junctions were removed after locating the LES manometrically and stained for CGRP-like immunoreactivity (LI) and substance P-LI (SP-LI) by indirect immunohistochemistry. CGRP-LI in the LES was most prominent in large nerve fascicles between the circular and longitudinal muscle layers and only rarely seen in nerve fibers within the circular muscle. The myenteric plexus contained numerous CGRP-LI nerve fibers but cell bodies were not seen. Many CGRP-LI nerve fibers in the myenteric plexus and occasional varicose nerves in the circular muscle demonstrated colocalization with SP-LI. Colocalization of CGRP-LI with SP-LI was also seen in the perivascular nerves of the submucosal and intramural blood vessels and in varicose fibers in the lamina propria of the gastric fundic mucosa. In the esophagus, CGRP-LI nerves extended through the muscularis mucosa and penetrated the squamous epithelium to the lumen. CGRP, given intra-arterially caused a dose-dependent fall in basal LES pressure, with a threshold dose of 10(-8) g/kg (2.63 pmol/kg). At the maximal effective dose, 5 x 10(-6) g/kg (1.31 x 10(3) pmol/kg), CGRP produced 61.0 +/- 6.0% decrease in basal LES pressure. At this dose, mean systemic blood pressure fell by 40.9 +/- 7.8%. The LES relaxation induced by a submaximal dose of CGRP (10(-6) g/kg, 262.7 pmol/kg), 50.3 +/- 3.2% relaxation was partially inhibited by tetrodotoxin (26.9 +/- 10.8% relaxation, P less than 0.025). The inhibitory effect of CGRP was not affected by cervical vagotomy, hexamethonium, atropine, propranolol, or naloxone. The LES contractile response to the D90 of SP (5 x 10(-8) g/kg, 37.1 pmol/kg) was not altered by CGRP 10(-8) or 10(-6) g/kg and the CGRP relaxation effect was not altered by the threshold dose of substance P (5 X 10(-9) g/kg, 3.71 pmol/kg).(1) CGRP-LI is present at the feline LES and is primarily seen in large nerve fascicles which pass from the intermuscular plane and through the circular muscle layer to the submucosa and in mucosal nerves. (2) CGRP colocalizes with SP-LI in some varicose nerve fibers of the circular muscle of the esophagus, LES and fundus, in perivascular nerves of the submucosal and intramucosal blood vessels, and in nerves of the lamina propria of the gastric fundus. (3) The luminal penetration of CGRP-LI nerves in the squamous mucosa of the esophagus suggests a sensory func

We have previously reported a high degree of selective binding of monoclonal antibody (MAb) B72.3 to a wide range of carcinoma versus normal tissues. While the diagnostic targeting of a primary or metastatic carcinoma lesion with a MAb is an end unto itself, it should also be considered as a first step toward the use of the MAb in tumor therapy. As we proceed with the use of MAbs in therapeutic applications, we are concomitantly characterizing the MAbs and associated tumor antigens to better understand their composition and nature ultimately in order to be able to manipulate their interaction. In this article we will discuss the use of MAbs in several aspects of clinical oncology, including tumor targeting clinical studies using MAb B72.3. These studies also include the regulation of tumor antigenic expression using preclinical models. We will present data on the use of a biological response modifier, recombinant human leukocyte (alpha) interferon (rHu-IFN-α), to amplify antigenic expression in carcinoma cells. We will discuss the use of MAb B72.3 in the localization of metastatic lesions in colorectal cancer patients, the findings of simultaneously administered B72.3 (i.v. and i.p.), and the pharmacokinetics associated with MAb administration. Finally, we will discuss the potential clinical uses of genetically engineered recombinant/chimeric MAbs, MAbs conjugated to toxins, drugs and/or radionuclides, MAb combinations, and second generation MAbs of predefined specificity.

Fab fragments of monoclonal antibodies (MoAb) to melanoma, radiolabeled with 131I, were evaluated as diagnostic reagents to determine their ability to localize systemic--MoAb injected intravenously (IV)--or nodal metastatic disease--injected subcutaneously (SQ) at a site proximal to draining lymph nodes. Sixty-one scans were performed (40 IV, 21 SQ) in 59 patients who had injections of 0.2-50 mg of 131I coupled (0.2-12 mCi) antibody. These included 48.7, which identifies a high molecular weight antigen (HMW), or 96.5, which identifies a transferrin like molecule, p97. 125I coupled nonspecific Fab 1.4, reacting with murine leukemia virus, or the whole antibody BL3, reactive with a human B cell idiotypic determinant, was generally used in tandem with the patients injected SQ as a nonspecific control. All patients had immunohistochemical studies performed on biopsied lesions and demonstrated binding to the antibodies injected. Of the IV patients, 22/38 (58%) had (+) scans, 13 at SQ or nodal sites, four at visceral sites, and five at visceral and SQ sites. Patients with clinical stage II disease had SQ injection of MoAb, including 11 additional patients injected with the whole antibody 9.2.27 (anti-HMW) labeled with 111In (6 patients) or 131I (5 patients). Nodal dissection was performed 2-4 days later. All 111In coupled antibodies demonstrated excellent nodal delineation without specific identification of tumor deposits. Of the 21 patients injected SQ with MoAb, 17 had confirmed tumor in nodes. Of patients injected with Fab fragments, 4/8 (50%) had specific uptake of MoAb, although only two were successfully imaged. Increased uptake of antimelanoma antibodies was observed in some patients in lymph nodes not containing tumor and was possibly related to antigen shedding. Clearance of labeled antibody from the injection site occurred with a half life of 16-50 hours. Toxicity was limited to local discomfort at the site of SQ injection. Melanoma metastases can be identified with IV or SQ injection or radiolabeled antibodies. These reagents may be useful in the diagnosis or therapy of human melanoma. Further evaluation will be required before they could be considered clinically useful.

The purpose of this study was to determine the mechanism by which distal esophageal acidification increases lower esophageal sphincter (LES) pressure in the anesthetized cat. Intraluminal pressures and myoelectric activity were recorded using fixed, localized manometric catheters and serosal bipolar silver-silver chloride electrodes. The increase in LES pressure (27.1 +/- 4.9 mmHg) and spike activity (133.8 +/- 22.6 spikes/min) following distal esophageal acidification were greater than after saline (P less than 0.001). These responses were abolished by either tetrodotoxin (intravenously) or intraluminal ethyl aminobenzoate. The responses were not antagonized by bilateral cervical vagotomy or by atropine, hexamethonium, phentolamine, propranolol, diphenhydramine, cimetidine, cinanserin, naloxone, haloperidol, or proglumide. Tachyphylaxis to substance P abolished the LES pressure and spike responses to exogenous substance P and to distal esophageal acidification but had no effect on the LES responses to phenylephrine (25.0 micrograms/kg iv) or pentagastrin (0.5 microgram/kg iv). The putative substance P antagonist [D-Pro2,D-Trp7,9]substance P was a partial antagonist and a weak agonist on the LES. Large doses of [D-Pro2,D-TRP7,9]substance P (200.0 micrograms/kg iv) gave a 61.3 +/- 19.3% inhibition of the LES pressure response to acid (P less than 0.05). Intravenous tetrodotoxin partially antagonized the LES response to substance P (10.0 micrograms/kg iv). These studies suggest that the increases in LES pressure and spike activity following distal esophageal acidification occur through a spike-associated enteric neural reflex that involves substance P as a neurotransmitter.

A retrospective study was undertaken of patients with systemic lupus erythematosus in whom serum amylase had been determined. Sixty-three patients were identified, and of these 53 had abdominal pain at the time of the amylase measurement. Twenty-seven (51 percent) had a normal serum amylase, and 12 of this group had defined reasons for the abdominal pain. Of the 26 patients with hyperamylasemia, 6 had extrapancreatic causes for the elevated amylase. In 20 patients (37 percent of those with abdominal pain) the clinical diagnosis of pancreatitis was made. The amylase levels showed no correlation with renal function nor with dose of corticosteroid. Four patients with pancreatitis were identified in whom no contributing factor other than SLE could be ascertained. No serious complication of the pancreatitis was seen, and recovery occurred despite continued steroid therapy. Pancreatitis is not a rare occurrence in SLE, and may be related in part to the vasculitis seen during periods of disease activity.

We report the electrical correlates of esophageal and lower esophageal sphincter contraction in humans using a bipolar ring electrode assembly mounted on a catheter. No spike activity was seen in the resting state in the esophagus or lower esophageal sphincter. Swallowing induced both electrical spike activity and contractile activity in both areas. The delay in the proximal and distal esophagus from swallowing to the onset of electrical activity was 0.3 +/- 0.1 s and 3.3 +/- 0.2 s, respectively, and from swallowing to the onset of contractile activity the time was 1.9 +/- 0.1 s and 5.2 +/- 0.2 s. respectively. The rate of propagation of electrical activity was constant throughout the esophageal body while contractile activity was propagated more rapidly in the middle third of the esophagus. Spike activity preceded the peak of esophageal contractions in 100% of swallows. Lower esophageal sphincter relaxation was initiated without spike activity, but the postswallow lower esophageal sphincter contraction was preceded by spike activity in 100% of cases. Basal lower esophageal sphincter pressure was maintained in the absence of spike activity. Spontaneous esophageal contractions, seen in patients with symptomatic diffuse esophageal spasm, were spike-independent in 70% of cases. Prolonged repetitive contractions, once initiated, were also spike-independent. Thus, with the use of intraluminal ring electrodes, we suggest that the human esophagus and lower esophageal sphincter are capable of generating both spike-dependent and spike-independent contractions. The latter may be prominent in patients with esophageal motor disorders.

The purpose of this study was to determine the patterns of gastrointestinal and anal sphincter motility in 25 consecutive patients with severe constipation. Three patterns of abnormal motility were observed in 68% of the patients: (a) isolated anal sphincter dysfunction (20%), (b) a generalized disorder of gastrointestinal motility (24%), and (c) rectosigmoid dysfunction (24%). The remaining patients had either a previously unrecognized primary disorder leading to constipation or the irritable bowel syndrome. Duration of symptoms, laxative usage, or other historical features failed to distinguish each of the groups. Anal sphincter dysfunction was diagnosed by demonstrating impaired sphincter relaxation during rectal distention. Generalized motor disorders were diagnosed by demonstrating impaired colonic and esophageal function together with an abnormality in gastric emptying. Rectosigmoid dysfunction was manifest by an impaired rectosigmoid motor response to feeding without evidence of other organ dysfunction. These studies indicate that a high percentage of patients with more severe degrees of constipation have a serious but sometimes treatable disorder of bowel function, rather than the irritable bowel syndrome.

Intraluminal pressures and myoelectric activity were recorded from the feline antrum, pylorus, and duodenum in response to intraduodenal amino acid solutions. Mixed amino acids (0.02 mg/ml, 3.0 ml) increased the amplitude of pyloric contractions (59.7 +/- 7.9 mmHg) and pyloric spike activity (73.7 +/- 6.8% of slow waves with spike activity) compared with a saline control (P less than 0.001). The selectivity of these responses was determined with specific amino acids. L-Tryptophan (10 or 40 mM) produced a response similar to the mixed amino acid response, while L-phenylalanine or L-glycine (10 or 40 mM) had no effect. Intra-arterial tetrodotoxin, intraluminal ethyl aminobenzoate, or intravenous naloxone (1.0 mg/kg) abolished the pyloric responses to amino acids (P less than 0.02). Bilateral cervical vagotomy had no effect. Cholecystokinin octapeptide (CCK-OP) produced dose-dependent increases in the amplitude of pyloric contractions and in pyloric spike activity. The ED50 dose of CCK-OP (1.0 microgram/kg iv) gave an increase in pyloric pressure of 155.6 +/- 49.9 mmHg and in spike activity of 77.7 +/- 9.4%, similar to mixed amino acids or tryptophan. These effects of CCK-OP were not antagonized, however, by a dose of naloxone (1.0 mg/kg) that blocked the maximal pyloric response to leucine-enkephalin. We concluded intraduodenal mixed amino acids or tryptophan increase phasic, spike-dependent pyloric contractions in the cat via nonvagal, naloxone-sensitive neural pathways, phenylalanine, a structurally similar essential amino acid, had no effect on the feline gastroduodenal junction, and the pyloric responses to exogenous CCK-OP are mediated by pathways distinct from the responses to tryptophan or mixed amino acids.

The instillation of gastric contents, 0.5 ml/kg (pH 4.3), containing small food particles into the left diaphragmatic lobe of the lungs of 49 rabbits caused severe aspiration pneumonitis. Administration of methylprednisolone, 30 mg/kg, intramuscularly, every eight hours for three days to 26 of the 49 rabbits did not alter the rate of roentgenographic resolution of the pneumonitis. Corticosteroids did decrease the fibroblastic response of the lung to the aspirate, but also interfered with healing of granulomatous lesions.

131I-labeled monoclonal antibodies were used in therapeutic trials in two potentially useful clinical situations: disseminated melanoma (intravenously administered Fab fragments; 21 patients) and disseminated peritoneal adenocarcinomatosis (intraperitoneal injection of IgG; 5 patients). Acute toxicity observed is consistent with mild bone marrow suppression of acute radiation syndrome and the observed toxicity is dose related in a manner that conforms to the expected human response to total body irradiation. For single doses of both i.p. administered and intravenously administered 131I-labeled anti-tumor antibodies, 100 rad to red marrow, calculated by the absorbed dose fraction method (MIRD), appeared to be a threshold below which significant acute toxicity was unlikely.

Utilizing a double antibody radioimmunoassay for human TSH we compared distribution of serum TSH in 167 normal individuals and 51 patients with idiopathic euthyroid goiter. In addition to being clinically euthyroid both groups had normal total thyroxine, and free thyroid index. Forty-two percent of the goiter group had high TSH and the general distribution of TSH values in the goiterous patients was significantly higher than normal (P less than 0.001). Anlysis of subgroups of the normal and goiter populations indicated that the high TSH could not be attributed to age, sex, use of birth control pills or differences between diffuse and multinodular goiter. TSH levels were significantly higher in patients with goiter less than 1 yr compared to goiter greater than 1 yr (P less than 0.025). In patients with goiter greater than 1 yr the TSH levels remained significantly higher than normal (P less than 0.025). These results support the hypothesis that TSH plays a role in the genesis of idiopathic goiter. The elevation may be present only early in the course of goiter development but is also present in a significant number of patients with long standing goiter.

The variability of the fasted duodenal contractile pattern and the patterns of contraction during the fed phase was examined in normal volunteers. Prolonged recordings from the duodenum and proximal jejunum were achieved using a series of transducers mounted on a 2.3-mm catheter. A total of 58 interMMC intervals and the response to 18 meals was examined. There was marked inter- and intrasubject variability in the fasted state, even within one study. The phase II pattern was examined in detail and propagated single peaks, propagated clusters, and repeated propagated clusters are described. Single peaks could be propagated as rapidly as 16 cm/sec. Single peaks were propagated more rapidly than propagated multiple peaks. During phase III, duodenal contractions occurred at 11.3 +/- 0.09/min and jejunal contractions at 10.73 +/- 0.15/min. The rate of progression of the onset of phase III was 0.145 +/- 0.015 cm/sec. The effect of the caloric content of the meal was examined by determining the effect of 150-kcal, 300-kcal, and 600-kcal meals on the fed pattern. Increasing caloric content increased the duration of the fed pattern but had no effect on the total or normalized motility index or on the change in motility index over time during the fed pattern. The types of contractions seen during the fed pattern are described. Propagated clusters over at least 16 cm are common during the fed phase in normals, with 10% of all contractions seen during the fed phase being propagated over 28 cm. No difference in the patterns of contractions or their propagation was seen with the different caloric contents of the meals.(ABSTRACT TRUNCATED AT 250 WORDS)

The fast Fourier transform (FFT) has been used to determine frequency components of colonic slow-wave activity. We studied the effect of (1) recorder filter characteristics, (2) number of data points and, (3) data window overlap technique and ingestion of a 1000-kcal meal on the resulting power spectrum. Human rectosigmoid slow-wave activity was recorded in nine normal subjects and stored on FM tape for computer analysis. The dynograph filter characteristics were tested using square wave signals, and derived compensation factors were applied to the FFT before viewing. The dynograph filter, when set to optimize visualization of slow waves, attenuates low frequencies nonlinearly. Failure to compensate for the dynograph filter results in inaccurate detection of slow-wave frequencies. FFT of 1-min data gives a different power spectrum than an FFT of 4 min data, indicating a rapidly changing waveform. FFT's of 1 min of data when examined over time fail to demonstrate a consistent frequency spectrum, confirming this conclusion. The lower frequencies in the normal human rectosigmoid are present at the greatest power. These studies indicate that the colon has slow waves of irregular frequencies, in contrast to the stomach or small intestine. No change in the dominant frequency was seen following the ingestion of a 1000-kcal meal.

T101 monoclonal antibody recognizes a pan-T-cell antigen present on normal T cells and also found in high concentrations in cutaneous T-cell lymphoma. We used this antibody, radiolabeled with 111In, in gamma-camera imaging to detect sites of metastatic cutaneous T-cell lymphoma in 11 patients with advanced disease. In all patients, [111In]T101 concentrated in pathologically or clinically detected nodes, including those in several previously unsuspected nodal regions. Concentrations (per gram of tissue) ranged from 0.01 to 0.03 percent of the injected dose and were consistently 10 to 100 times higher than previously reported on radioimmunodetection. Focal uptake was seen in skin tumors and heavily infiltrated erythroderma but not in skin plaques. The specificity of tumor targeting was documented by control studies with [111In]chloride or [111In]9.2.27 (anti-melanoma) monoclonal antibody. Increasing the T101 dose (1 to 50 mg) altered distribution in nontumor tissues. These studies suggest that imaging with [111In]T101 may be of value in identifying sites of cutaneous T-cell lymphoma. In contrast to the targeting of solid tumors, the mechanism of localization appears to be related to binding to T cells, which can then carry the radioactivity to involved sites.

Intraluminal pressures and serosal myoelectric activity were recorded simultaneously from the esophagus, lower esophageal sphincter (LES), and stomach of chloralose-anesthetized cats. The LES demonstrated intermittent spike activity basally without slow waves and was distinct from esophagus and fundus. LES spike activity was not correlated with basal sphincter pressure. Dose-dependent increases in both spikes and pressure occurred with bethanechol, phenylephrine, or pentagastrin. Increased spike activity preceded the onset of the pressure rise and peaked during the rise in pressure. Changes in LES pressure and spike activity following these agents were correlated closely (r = 0.92, P less than 0.01). Atropine and isoproterenol inhibited pressure and spike activity similarly. Intrinsic reflexes to endogenous stimuli gave parallel spike and pressure changes. Distal esophageal acidification produced an increase in LES pressure that was correlated with increased spike activity. LES spike activity and pressure were inhibited similarly by antral distension or gastric acidification. Dissection of the distal esophagus from the diaphragm or bilateral cervical vagotomy had no effect on either LES spike activity or pressure. These studies indicate that a) LES myoelectric activity consists of spike discharges that are not correlated to resting pressure, b) abrupt changes in sphincter pressure following either intrinsic reflexes or neurohormonal agents are closely associated with similar changes in spike activity, and c) spike activity and sphincter pressure are intrinsic to the LES.

The generation of differential GPS corrections for general navigation purposes must consider the effects of selective availability, ionosphere, data link latency, and processing time. The U.S. Coast Guard Differential GPS Harbor Entrance program has developed a differential GPS reference station system design that successfully addresses these concerns. This paper presents a high-level description of this design and some of the test data that led to the critical design decisions.

The purpose of this study was to determine the intrinsic functions of the feline pylorus in vitro. The myoelectric and pressure characteristics of the intact pylorus, antrum, and duodenum, free of extrinsic hormonal or neural influences, were studied in an in vitro bath that allowed separation of the bathing medium surrounding the different bowel segments. Basal recordings revealed a zone of tonic high pressure of 28.4 +/- 3.5 mmHg (mean +/- SEM) at the pylorus. The basal slow wave frequencies in the pylorus and duodenum were 2.8 +/- 1.4 and 12.6 +/- 0.6 cycles/min, respectively. Spontaneous action potential-associated phasic contractions of the pylorus were noted in 38% of preparations. Enteric nerve stimulation with direct electric current (10 Hz, 1 ms, 10-50 V) applied proximal to the pylorus gave relaxation of the pylorus at the lower voltages and rebound excitation at higher voltages. Electrical stimulation distal to the pylorus yielded phasic contractile pyloric response during the entire stimulus. The duodenal instillation of 0.5 N HCl produced action potential-associated phasic contractions of the pylorus and duodenum but not the antrum. Pyloric responses to electrical stimulation or acidification were abolished by tetrodotoxin (10(-5) M). Bethanechol (10(-6) M) or substance P (10(-7) M) produced a contractile response at the site of stimulation but this response was not transmitted to include adjacent bowel segments. These studies suggest that the pyloric sphincter with its intrinsic reflex properties can be studied in vitro.

High molecular weight antigen (HMWA) is a tumor-associated proteoglycan of human malignant melanoma. I-131 labeled Fab fragments of these specific antibodies were used for preliminary feasibility studies for radioimmunodetection and therapy of human subjects who had inoperable metastatic melanoma. Ten patients received tracer doses of 5-13 mCi (185-481 MBq) of I-131 (anti-HMWA) Fab. All patients (8/8) who had melanoma lesions greater than 1 cm by correlative diagnostic methods had one or more lesions that had localization to tumor of the radiolabeled Fab. In all, 17 of 23 (74%) documented metastases were seen. There were no false positives in this series. Two patients who had avid uptake received potentially radiotherapeutic doses of 142 mCi (5,254 MBq) (one patient) and 181 mCi (6,697 MBq) and 193 (7,141 MBq) (total: 374 mCi or 13,838 MBq) (one patient). For both of these patients, whole body imaging studies showed that the localization of the high dose I-131 Fab was predominantly in tumor. The patient who received the larger dose showed a greater than 50% reduction in the size of pelvic and pericaval nodes, with stabilization of disease at the smaller nodal size for a period of three months. On whole body images, the anti-Fab HMWA appears to be more tumor selective than Fab preparations that target the p97 antigen for melanoma, and there is less uptake in liver.

Prokinetic drugs enhance the motility of the luminal organs of the gastrointestinal tract. Few drugs developed in this decade are likely to have a greater impact on the treatment of disorders of the gastrointestinal tract. Bethanechol and metaclopramide have proven the potential utility of this class of drugs, whereas newer agents promise to have both a greater margin of safety and tolerability and a broader scope of utility. The efficacy of these agents is reviewed for the treatment of impaired motility from gastroesophageal reflux to severe chronic constipation.

The unequivocal diagnosis of esophageal chest pain requires the demonstration of simultaneous manometric changes and chest pain. Numerous provocative agents have been used to enhance the diagnostic value of esophageal manometry. Our aims were to: evaluate consecutively a large group of patients with proven noncardiac chest pain and normal baseline manometric studies, using edrophonium chloride, 10 mg, and determine the value of provocative testing in clinical practice. One hundred twenty patients with normal standard baseline esophageal manometries were studied using blinded testing with edrophonium chloride and followed clinically by questionnaire. A positive response of both chest pain and manometric changes was observed in 34%, a negative response in 49%, and an indeterminate response in 17% of patients. Baseline manometric features, including high-amplitude contractions, did not predict the response to edrophonium chloride. Following edrophonium chloride administration, the change in amplitude, duration, and number of repetitive contractions from baseline was significantly greater in positive responders. Edrophonium decreased the velocity of propagated contractions in positive responders (P less than 0.05), but not in nonresponders. Response to edrophonium chloride could not be predicted by patient age, sex, or clinical symptomatology. Seventy percent of patients in both groups had symptoms indistinguishable from ischemic heart disease. After making a specific diagnosis of esophageal chest pain, patients showed a marked clinical improvement, with a significant decrease in physical limitation, emergency room visits, hospital and CCU admissions, and in further cardiac testing. We conclude that provocative testing with edrophonium chloride will make it possible to definitively implicate the esophagus in over 30% of patients with normal baseline manometric findings and noncardiac chest pain.

Previous studies demonstrating increased adrenergic tone in symptomatic patients with mitral valve prolapse prompted a study of the response of symptomatic patients with mitral valve prolapse to adrenergic stimulation. Sixteen such patients had plasma catecholamines and 24 hour urinary epinephrine plus norepinephrine values that were greater than those of control subjects (473.3 ± 92.8 pg/ml versus 292 ± 15 and 44.7 ± 2.3 μg/g creatinine versus 29.8 ± 2.3; p < 0.01 and < 0.001, respectively). Twenty-four hour urinary sodium was lower in the patient group than in the control group (75 ± 7.4 versus 141 ±11 mEq; p < 0.01), with an inverse relation between urinary sodium and norephinephrine in the patient group (r = - 0.78) but not in the control group.Isoproterenol infusions, 0.5, 1.0 and 2.0 μg/min for 6 minutes, produced a dose-related, greater increase in heart rate in the mitral valve prolapse group than in the control group (16.1 ± 2.3 versus 10 ± 2; 31.8 ± 3.5 versus 19.6 ± 3; 48 ± 4.1 versus 27 ± 3; p< 0.01 with 0.5, 1.0 and 2.0 μg, respectively). The greater increase in heart rate resulted in a significantly shorter diastolic time in the patient group than in the control group (26.4 ± 2 s/min versus 30.6 ± 2; 27 ± 1.5 versus 30.6 ± 2; 26.6 ± 2 versus 30.9 ± 2; p < 0.01 with 0.5, 1.0 and 2.0 μg, respectively). The QT interval was 25 ms shorter than electromechanical systole (QS2) in the normal group and 26.5 ms shorter than QS2in the mitral valve prolapse group at rest; during isoproterenol infusion QT-QS2values were different in the mitral valve prolapse and control groups (3.3 ± 3 versus -7.0 ± 3; 31.9 ± 2.8 versus 10 ± 4; 52 ± 9.2 versus 29 ± 8; p < 0.01 with 0.5, 1.0 and 2.0 μg/min, respectively). Isoproterenol infusion also reproduced symptoms on a dose-related basis in 14 patients with mitral valve prolapse but not in control subjects (excluding palpitation).Symptomatic patients with mitral valve prolapse and high rest values of catecholamines were hypersensitive to isoproterenol infusion, suggesting that some of the symptoms are catecholamine-related or mediated.

A simplified, low iodine diet was developed for outpatient use prior to I-131 scanning and therapy in thyroid cancer. Iodine intake of five subjects on the diet was approximately 50 micrograms a day and this level was maintained for four weeks. The diet required only minimal instruction to be followed reliably. This level of iodine intake may increase radioiodine uptake in thyroid carcinomas.

We have previously demonstrated a high degree of selective binding of monoclonal antibody (MAb) B72.3 to carcinomas of the colon, ovary, and breast in contrast to normal adult tissues using in vitro assays. In this report we demonstrate selective tumor localization in colorectal cancer patients after intravenously administering 131I-labeled MAb B72.3 IgG. Radiolocalization Indices (RI) (i.e. cpm 131I-labeled MAb per gram of tumor vs cpm per gram of normal tissues), were obtained by direct analyses of biopsy materials. Using an RI of greater than or equal to 3 as a positive localization, tumor lesions in various sites from 17/20 patients scored positive. In eight of these patients, all tumor lesions demonstrated RIs of greater than 3, while in five patients RIs of some lesions were greater than 10 and as high as 30-46. Seventy percent (99/142) of the tumor lesions showed RIs of greater than 3, while only 12 of 210 histologically confirmed normal tissues examined showed RIs of greater than 3. These tissues were either adjacent to the tumor or the draining tumor masses or, as in the case of two patients, was caused by high levels of circulating immune complexes that deposited in the spleen. Positive scintigraphic images (confirmed at surgery) were observed in 14/27 patients. No toxicity or adverse reactions were observed with either MAb. These studies provide absolute quantitative analyses of the actual delivery of radiolabeled MAb to carcinoma lesions vs a wide range of adjacent and distal normal tissues and establishes the means for other diagnostic and potential therapeutic applications of this antibody alone, or in combinations with other monoclonal antibodies.

We report 3 cases of hepatic venocclusive disease occurring in renal transplant patients receiving azathioprine and combine our experience with 4 other previously reported cases. The data suggest a clinical syndrome characterized by (a) delayed clinical onset, (b) striking male predominance, (c) presentation with jaundice followed by evidence of portal hypertension, and (d) poor prognosis. One of our patients, who is still alive 40 mo after the first onset of symptoms of liver disease, showed striking clinical improvement with discontinuation of azathioprine and subsequent deterioration on reinstitution. We suggest that azathioprine may be closely linked with the development of venocclusive disease in renal transplant patients and that the frequency of this disorder may be more common than previously reported. To attempt to prevent a fatal outcome, this group of patients should be closely monitored for the earliest signs of hepatic venocclusive disease through periodic serum bilirubin and alkaline phosphatase determinations. Patients with abnormal tests should undergo liver biopsy. If hepatic venocclusive disease is found, prompt withdrawal of azathioprine is indicated.

Disseminated malignant melanoma is incurable with presently available therapeutic regimens. Average survival of patients with this disease ranges from a few months to 1 year. Frequently, the disease is disseminated before surgical therapy removes the primary lesion and this dissemination is frequently unsuspected [1]. Significant improvements are needed in both the therapeutic and diagnostic aspects of management of patients with disseminated melanoma.

The development of monoclonal antibodies that recognize tumor-associated antigens has led to significantly greater practical possibilities for producing highly specific radiolabeled antibodies for diagnosis and therapy of human tumors. A number of problems remain before this technique will be ready for routine clinical application however. Achieving the high target to background ratio that are predicted on theoretical grounds is a major challenge in cancer investigation.

Monoclonal antibody (MAb) B72.3 has been previously shown, by in vitro assays, to have a high degree of specificity for carcinomas of the colon, ovary and breast versus normal adult tissues. B72.3 IgG was labelled with 131I and injected i.v. into 20 patients with known or suspected colorectal cancer. All patients subsequently underwent surgical exploration, with tumor and selected normal tissues removed for staging purposes. The selective localization of 131I-MAb B72.3 IgG was demonstrated in biodistribution studies in which the % ID/g of each tumor was compared with that of the normal tissues, thus providing a relative RI for each lesion. Of the tumor lesions, 70% (99/142) had an RI of at least 3 (i.e., 3 times greater uptake per gram than normal tissues), and 31% of the tumor lesions had RIs of over 10. Only 12 of 210 (6%) histologically normal tissues had RIs of greater than 3; either these tissues were adjacent to or draining tumor masses or, as in the case of 2 patients, the high RI values were apparently due to deposition of immune complexes in the splenic tissues. Several parameters were studied to determine factors that might influence MAb localization. Whereas tumors of all histologic types localized the MAb, 31% of the well-differentiated mucinous carcinomas displayed tumor-to-normal ratios greater than 10, while less than 5% of the lesions of other tumor types demonstrated similar localization. The expression of the antigen (TAG-72) detected by MAb B72.3 in these tumors, as studied by immunohistochemical techniques using tissue sections, did not always correlate with the outcome of the MAb distribution. No differences in MAb uptake were observed among the carcinoma lesions from numerous anatomic locations, demonstrating the ability of i.v. administered B72.3 to reach all the tumor sites. Furthermore, autoradiographic studies of tumors showed good penetration of the MAb into the medial areas of the tumors, regardless of their size.

At the National Institutes of Health, an apparatus was developed to radiolabel monoclonal antibodies for use in both imaging and radioimmuno-therapy. Up to 600 mCi of I-131 can be safely handled in this labeling hood which is shown schematically in Figure 1. The hood was designed so that two iodinations could be performed at the same time. Often these include specific and nonspecific (isotype matched) antibodies. To construct the apparatus, a standard fume hood was reinforced with steel and a steel frame was assembled inside the hood to support standard two inch lead bricks. The frame itself has two doors of steel encased lead. The entire apparatus is covered by a plexiglass safety box which has on its upper surface four fan and charcoal filter units to trap volatilized radioiodine. The internal components of the apparatus include a reaction vessel, a Sephadex gel filtration chromatography column, a gamma detector, product and waste vials, tubing and three-way stopcocks connecting these items, and a peristaltic pump. Small bore arterial pressure tubing (internal volume of 0.55 ml per 12 inch segment) with luer lock fittings connect the reaction vial to the column and the column to the product and waste vials. The reaction vial sits in a lead pig on top of a flat vortex mixer whose speed is controlled by a variable voltage supply. The peristaltic pump in the system is capable of driving fluid through the relatively rigid arterial pressure tubing at a rate of 1 ml per minute.

The serum gastrin response to a standard test meal was evaluated in patients with familial medullary thyroid carcinoma (MTC) and in normal subjects. Patients with MTC and elevated plasma calcitonin levels had a lower gastrin response to the test meal than did normal persons or MTC patients who had normal calcitonin levels postthyroidectomy. There was no significant difference between the mean gastrin response of the normal group and that of the MTC patients with normal calcitonin levels. The serum gastrin response was studied before and after thyroidectomy in four patients. In all four, the post-operative response was greater than the preoperative one . We conclude that patients with MTC may have reduced gastrin responses to a test meal. This effect may be related to circulating calcitonin, somatostatin, or other factors related to familial MTC.

The hybridoma technique of Kohler and Milstein (1975) permits one to develop monoclonal antibodies (MoABS) against tumor-associated antigens that are highly specific, of very strong avidity for the antigen, and available in large quantities as purified protein. In the last few years, MoABS have been developed against tumor associated antigens for most of the common solid tumors: lung, colon, breast, pancreas, prostate, ovary; as well as some that are not so common, such as melanoma and soft-tissue sarcomas. In addition, MoABS that recognize antigens on hematopoietic neoplasms, such as T- and B-cell lymphomas have been developed. In principle, these monoclonal antibodies can be used as carriers for targeting radionuclides to tumors in vivo, as a means of diagnosis and therapy.

The purpose of this study was to determine the interactions between bombesin and substance P at the feline lower esophageal sphincter (LES). Intraluminal pressures were recorded using a fixed, perfused catheter assembly. Myoelectrical activity was recorded using bipolar Ag-AgCl serosal electrodes. Bombesin, i.v., gave a dose-dependent increase in LES pressure and electronically counted spike activity. The threshold dose was 10(-7) g/kg, while the maximal dose, 10(-5) g/kg, increased LES pressure by 65.5 +/- 14.8 mmHg. The neuroantagonist, tetrodotoxin, decreased the LES response to bombesin by 74.1% +/- 7.9% (P less than 0.05), but had no significant effect on the LES response to substance P. The sphincteric response to bombesin was not inhibited by bilateral cervical vagotomy, atropine, propranolol, or phentolamine (P less than 0.10). Bombesin tachyphylaxis abolished the LES response to bombesin but had no effect on the response to substance P. Conversely, substance P tachyphylaxis completely abolished the LES response to bombesin (P less than 0.001). The substance P antagonist [D-Pro2, D-Trp7,9]substance P also significantly inhibited the LES response to bombesin (P less than 0.05). Acidification of the distal esophagus with 2.0 ml of 0.1 N HCl increased LES pressure by 32.5 +/- 5.2 mmHg (P less than 0.02). The LES response to acid was inhibited by bombesin tachyphylaxis (maximal pressure response, 4.7 +/- 2.1 mmHg, P less than 0.01 compared with control acid response). The tachyphylaxis techniques were specific for the peptides giving no effect on the LES responses to phenylephrine, bethanechol, or pentagastrin. We drew the following conclusions: (a) bombesin increased feline LES pressure via nonvagal neural pathways that were insensitive to adrenergic or cholinergic antagonists; (b) bombesin may be involved in the enteric pathways that mediate the feline LES response to distal esophageal acidification; and (c) substance P mediates the effect of bombesin at the LES and is a neurotransmitter in the LES response to acidification.

Both calcitonin and gastrin have been found in the mammalian central nervous system, including the pituitary. Following a pentagastrin infusion in several patients with medullary carcinoma of the thyroid, we noted a coincident increase in plasma calcitonin and prolactin (PRL) levels. In order to evaluate further the influence of pentagastrin on human PRL release, a pentagastrin infusion was administered to 13 patients with active medullary carcinoma of the thyroid (MTC), eight subjects with inactive MTC, eight family members without MTC, and ten normal subjects. Plasma mean +/- SE PRL levels were significantly (P less than 0.01) increased in the active MTC patients from 7.6 +/- 0.5 to 12 +/- 1.4 ng/mL by 15 minutes post pentagastrin. Plasma mean +/- SE calcitonin levels increased in parallel with the plasma PRL levels from 0.28 +/- 0.1 to a peak of 1.9 +/- 0.9 ng/mL at 5 minutes post pentagastrin. A significant (P less than 0.05) correlation was found between the percentage increase in plasma calcitonin concentrations and plasma PRL levels at five and ten minutes post pentagastrin stimulation in this group of active MTC patients. Significant increases in serum calcitonin levels in the other groups post pentagastrin were of lesser magnitude and were not associated with a significant increase in PRL release. This latter observation suggested that neither the stress of the infusion nor the multiple endocrine neoplasia type 2 nor the pentagastrin was responsible for the observed increase in plasma PRL levels in the active MTC patients. These findings suggest, but do not prove, that calcitonin is a PRL-releasing factor in humans.

Objective To identify factors that influence the rate of healing of duodenal ulcers. Design A stepwise multivariable statistical analysis of patients with duodenal ulcer in a multicenter, prospective, open-label study. Healing was assessed by endoscopy at 4 or 8 weeks. Antacid use and symptoms were recorded in a daily diary. Subjects Of 135 patients, ages 19 to 86, 50% had a previous duodenal ulcer, 46.7% smoked, and 34.8% had melena or hematemesis. Interventions Famotidine, 40 mg orally, at bedtime for 4 or 8 weeks depending on endoscopic evaluation of ulcer healing. Limited antacid use was permitted. Setting Office practices, hospital practices, and university-based medical centers. Measurements and main results Multivariable analysis identified five independent predictors present at the time of diagnosis that influenced ulcer healing. The odds of not healing for each risk factor after simultaneous adjustment of the other risk factors were as follows: alcohol use, 6.5 (CI, 2.0 to 20.7, P less than 0.002); ulcer size greater than 10 mm, 4.2 (CI, 1.5 to 11.6, P less than 0.005), bleeding symptoms. 3.5 (CI, 1.2 to 10.2, P less than 0.03); and a previous duodenal ulcer, 3.1 (CI, 1.05 to 9.0, P less than 0.04). The use of salicylates or nonsteroidal anti-inflammatory drugs before treatment was associated with an improved odds of healing (adjusted odds ratio, 0.2; CI, 0.1 to 0.9, P less than 0.04). The percentage of patients achieving complete ulcer healing after 4 weeks of famotidine decreased inversely with the number of risk factors present, ulcer size, and the quantity of daily alcohol use (P less than 0.001). Fewer than half of those patients who still had severe pain at day 7 achieved healing at 4 weeks (P less than 0.001). In contrast, smoking and 23 other factors had no statistically discernible effect on ulcer healing with famotidine. Conclusions Five variables present at the time of diagnosis independently influenced the rate of ulcer healing at 4 weeks: alcohol use, ulcer size, bleeding symptoms, a previous duodenal ulcer, and previous use of salicylates or nonsteroidal anti-inflammatory drugs.

To evaluate the role of gastric inhibitory polypeptide (GIP) in the augmented insulin response to sucrose, seven normal volunteers ingested four separate meals of 100 g sucrose (S), 50 g glucose (G), 50 g fructose (F), and 50 g glucose + 50 g fructose (G + F). Serum insulin, glucose, and GIP were measured. In each of the 3 h after sugar ingestion the integrated insulin response to (S) was greater than to (G) with the 3-h total being 104% greater. The integrated glucose response to (S) was slightly greater than to (G) in the first and second hours but the differences were not significant. Integrated GIP response to (S) was greater than to (G) in hours 2 and 3. Although significant insulin and glucose responses to (F) occurred in hour 1, G + F led to insulin and glucose responses similar to G. G + F led to greater GIP levels than G in hour 3. These studies show that GIP may play a role in the augmented insulin response to S in hours 2 and 3. This may result from delayed gastric emptying and glucose absorption. The augmentation of insulin to S in the first hour may result from fructose, extra glucose equivalent of the sucrose test solution, or from endocrine mechanisms other than those subserved by GIP.