The impact of progesterone receptor negativity on oncological outcomes in oestrogen-receptor-positive breast cancer.

BACKGROUND: Oestrogen receptor (ER) status provides invaluable prognostic and therapeutic information in breast cancer (BC). When clinical decision making is driven by ER status, the value of progesterone receptor (PgR) status is less certain. The aim of this study was to describe clinicopathological features of ER-positive (ER+)/PgR-negative (PgR-) BC and to determine the effect of PgR negativity in ER+ disease. METHODS: Consecutive female patients with ER+ BC from a single institution were included. Factors associated with PgR- disease were assessed using binary logistic regression. Oncological outcome was assessed using Kaplan-Meier and Cox regression analysis. RESULTS: In total, 2660 patients were included with a mean(s.d.) age of 59.6(13.3) years (range 21-99 years). Median follow-up was 97.2 months (range 3.0-181.2). Some 2208 cases were PgR+ (83.0 per cent) and 452 were PgR- (17.0 per cent). Being postmenopausal (odds ratio (OR) 1.66, 95 per cent c.i. 1.25 to 2.20, P < 0.001), presenting with symptoms (OR 1.71, 95 per cent c.i. 1.30 to 2.25, P < 0.001), ductal subtype (OR 1.51, 95 per cent c.i. 1.17 to 1.97, P = 0.002) and grade 3 tumours (OR 2.20, 95 per cent c.i. 1.68 to 2.87, P < 0.001) were all associated with PgR negativity. In those receiving neoadjuvant chemotherapy (308 patients), pathological complete response rates were 10.1 per cent (25 of 247 patients) in patients with PgR+ disease versus 18.0 per cent in PgR- disease (11 of 61) (P = 0.050). PgR negativity independently predicted worse disease-free (hazard ratio (HR) 1.632, 95 per cent c.i. 1.209 to 2.204, P = 0.001) and overall survival (HR 1.774, 95 per cent c.i. 1.324 to 2.375, P < 0.001), as well as worse overall survival in ER+/HER2- disease (P = 0.004). CONCLUSIONS: In ER+ disease, PgR- tumours have more aggressive clinicopathological features and worse oncological outcomes. Neoadjuvant and adjuvant therapeutic strategies should be tailored according to PgR status.

Clinical utility of the 21-gene assay in predicting response to neoadjuvant endocrine therapy in breast cancer: A systematic review and meta-analysis.

INTRODUCTION: OncotypeDX© Recurrence Score (RS) is a multigene panel used to aid therapeutic decision making in early-stage, estrogen receptor positive (ER+)/human epidermal growth factor receptor-2 negative (HER2-) breast cancer. AIM: To compare responses to neoadjuvant endocrine therapy (NET) in patients with ER+/HER2-breast cancer following substratification by RS testing. METHODS: This systematic review was performed in accordance to the PRISMA guidelines. Studies evaluating pathological complete response (pCR), partial response (PR), and successful conversion to breast conservation surgery (BCS) rates following NET guided by RS were retrieved. Dichotomous outcomes were reported as odds ratios (ORs) with 95% confidence intervals (CIs) following estimation by Mantel-Haenszel method. RESULTS: Eight prospective studies involving 691 patients were included. The mean age was 62.6 years (range 25-85) and the mean RS was 14.5 (range 0-68). Patients with RS < 25 (OR: 4.60, 95% CI: 2.53-8.37, P < 0.001) and RS < 30 (OR: 3.40, 95% CI: 1.96-5.91, P < 0.001) were more likely to achieve PR than their counterparts. NET prescription failed to increase BCS conversion rates for patients with RS < 18 (OR: 0.23, 95% CI: 0.04-1.47, P = 0.120) and RS > 30 (OR: 1.27, 95% CI: 0.64-2.49, P = 0.490) respectively. Only 22 patients achieved pCR (2.8%) and RS group failed to predict pCR following NET (P = 0.850). CONCLUSION: Estimations from this analysis indicate that those with low-intermediate RS on core biopsy are four times more likely to respond to NET than those with high-risk RS. Performing RS testing on diagnostic biopsy may be useful in guiding NET prescription.

Disease recurrence and oncological outcome of patients treated surgically with curative intent for estrogen receptor positive, lymph node negative breast cancer.

BACKGROUND: The molecular era has identified four breast cancer subtypes. Luminal A breast cancer (LABC) is defined by estrogen-receptor positive (ER+), progesterone-receptor positive (PgR+) and human epidermal growth factor receptor-2 negative (HER2-) tumours; these cancers are the most common and carry favourable prognoses. AIMS: To describe clinicopathologic features, oncological outcome and relapse patterns in LABC. METHODS: Consecutive female patients diagnosed with ER/PgR+/HER2-, lymph node negative (LN-) breast cancer between 2005 and 2015 were included. Clinicopathological and recurrence data was recorded using descriptive statistics. Oncological outcome was determined using Kaplan-Meier and Cox-regression analyses. RESULTS: Analysis was performed for 849 patients with median follow-up of 102.1 months. Mean disease-free (DFS) and overall survival (OS) were 85.8% and 91.8%. Seventy patients died during this study (8.2%), while 58 patients had recurrence; 7 had local recurrence (0.8%) and 51 had distant recurrence (DDR) (6.0%). Patients developing DDR were likely to be postmenopausal (P = 0.028), present symptomatically (P < 0.001) and have larger tumours (P < 0.001). The mean time to DDR was 65.7 months, with fatal recurrence occurring in 66.6% of patients with DDR (34/51). Systemic chemotherapy prescription did not influence DDR (P = 0.053). Age >65 (hazards ratio (HR):1.66, 95% Confidence Interval (CI):1.07-2.55, P = 0.022), presenting symptomatically (HR:2.28, 95%CI:1.21-4.29, P = 0.011) and tumour size >20 mm (HR:1.81, 95%CI:1.25-2.62, P = 0.002) predicted DFS, while age>65 (HR:2.60, 95%CI:1.49-4.53, P = 0.001) and being postmenopausal at diagnosis (HR:3.13, 95%CI:1.19-8.22, P = 0.020) predicted OS. CONCLUSION: Our series demonstrated excellent survival outcomes for patients diagnosed with LN- LABC after almost a decade of follow-up. However, following DDR, fatal progression is often imminent.

Mesenteric venous thrombosis secondary to an unsuspected JAK2 V617F-positive myeloproliferative disorder.

BACKGROUND: Mesenteric venous thrombosis (MVT) is a rare but potentially fatal cause of mesenteric ischaemia. It presents insidiously and often diagnosis is made at emergency surgery. In half of the cases MVT develops without a causative factor, while in cases in which a pro-thrombotic state is found to exist MVT may be the first clinically detected consequence of that state. The myeloproliferative disorders (MPD) are known to contribute to the development of pro-thrombotic states. Recently, the JAK2 V617F mutation has been associated with the MPDs. CONCLUSION: We describe a case of MVT occurring secondary to an unsuspected MPD, in which the patient was subsequently found to carry this mutation. We highlight the necessity to screen for this mutation in cases of intra-abdominal thromboses so that appropriate systemic anticoagulation may be instituted, and the patient may be followed so as to detect the development of an overt MPD.

Pancreas regeneration after resection: does it occur in humans?

Although pancreatic regeneration after partial resection or pancreatic injury (restitutio ad integrum) has been demonstrated in animal models, whether regeneration occurs in the human pancreas is unknown. Our aim was to determine whether the human pancreas regenerates after subtotal resection. We reviewed pre- and postoperative computerized tomograms (CTs) of 21 patients after proximal pancreatectomy (50-60% resection) for malignancy with no recurrent disease during follow-up of pancreatic parenchymal abnormalities. Three fixed anatomic measurements (pancreatic body width, tail width, and length) were compared with the same region 10 and 21 months after surgery. Data are expressed as mean +/- SEM. Pancreatic measurements before and 10 months after resection did not differ for body width (2.0+/-0.1 cm vs. 1.8+/-0.1 cm), tail width (2.2+/-0.2 cm vs. 1.8+/-0.2 cm) or length (8.2+/-0.3 vs. 7.4+/-0.4 cm) (p> or =0.1 each). At 21 months after resection, measurements were less for body width and tail width (2.2+/-0.2 cm vs. 1.5+/-0.2 cm and 2.2+/-0.1 cm vs. 1.5+/-0.2 cm, respectively; p = 0.01) and unchanged for length (8.1+/-0.4 cm vs. 8.1+/-0.4 cm; p = 0.9). We conclude that the human pancreas does not regenerate after partial anatomic (50%) resection.

A peritrophin-like protein expressed in the embryonic tracheae of Drosophila melanogaster.

We have cloned and sequenced a cDNA from Drosophila melanogaster that encodes a protein homologous to the peritrophins, a family of chitin-binding proteins from the peritrophic matrix of insects. Unexpectedly, the gene, Gasp, is expressed in the embryonic tracheae. We suggest that this family of proteins may be present in other tissues than the peritrophic matrix, particularly where nutrient or gas exchange are important, and/or where invasion by parasites or viruses is possible. We have also mapped two similar genes that had been sequenced by the Berkeley Drosophila Genome Project, and find that these three very similar genes are not clustered, but are located on three different chromosomes.

Defunctioning loop ileostomy: a prospective audit.

BACKGROUND: Defunctioning loop ileostomies are uncommonly used forms of fecal diversion. The aim of this study was to determine the morbidity associated with both construction and reversal of loop ileostomies. STUDY DESIGN: An analysis was performed of all patients who underwent loop ileostomy construction or reversal between 1990 and 1997, with data being collected prospectively. RESULTS: One-hundred-two patients, (43 male, 59 female) with a mean age of 38 years (range 13 to 81 years) had loop ileostomies constructed. Indications for ileostomy construction included inflammatory bowel disease (76 patients), ultralow anterior resection for carcinoma (16 patients), or miscellaneous reasons (10 patients). Nine patients (9%) had complications arising from ileostomy construction including 4 parastomal infections, 3 high output ileostomies, 1 small-bowel obstruction, and 1 ileostomy stenosis in the early postoperative period. Only the stricture required surgical intervention. All other complications improved with conservative management. Mean time to ileostomy reversal was 120 days. Three patients (4%) had complications associated with reversal. All of these complications required surgical intervention, 2 for small bowel obstruction, and 1 for small bowel perforation. Currently 84 patients have had their ileostomy reversed, and 12 patients have had their loop ileostomy converted to a permanent stoma for reasons not related to the loop ileostomy itself. CONCLUSIONS: Defunctioning loop ileostomy is associated with low morbidity. We recommend a defunctioning ileostomy as the procedure of choice for temporary fecal diversion.

Transabdominal preperitoneal laparoscopic inguinal herniorrhaphy: assessment of initial experience.

OBJECTIVE: To evaluate our initial experience with laparoscopic inguinal herniorrhaphy. DESIGN: We retrospectively studied a consecutive series of patients selectively chosen for laparoscopic repair of inguinal hernia. MATERIAL AND METHODS: The study cohort consisted of 173 patients treated by a single surgeon between 1992 and 1995. For all operations, a transabdominal approach was used. Follow-up was obtained by telephone contact or letter. RESULTS: The study group consisted of 167 male and 6 female patients with a mean age at operation of 55 years (range, 15 to 81). During the study period, 206 laparoscopic inguinal hernia repairs were performed in the 173 patients. Only one patient (0.6%) required conversion to laparotomy. Bilateral hernia repair was done in 31 patients (18%). Of the 206 procedures, 63 repairs (31%) were performed for recurrent hernias. In 69% of the patients, the procedure was completed on an outpatient basis. Early postoperative complications necessitating surgical intervention occurred in four patients. The median time to return to work or normal physical activity was 7 days for unilateral and 12 days for bilateral hernia repair (P = 0.18). A mean follow-up of 29 months was obtained for 171 patients (99%). In six patients (3%), a recurrent hernia developed. Four of these six patients had previously undergone an open surgical procedure on the side of the recurrence. CONCLUSION: Laparoscopic inguinal herniorrhaphy is a feasible alternative to open hernia repair. This operation, however, should be reserved for selected patients. Longer follow-up and controlled trials comparing laparoscopic and tension-free open herniorrhaphy are necessary for assessment of the relative benefits of this procedure.

Surgical management of intrahepatic cholangiocarcinoma: a 31-year experience.

Intrahepatic cholangiocarcinoma (ICC) is the second most common malignant primary tumor of the liver. It is, though, a rare tumor and little is known regarding its natural history, clinicopathologic characteristics, or the outcomes of surgical therapy. We reviewed the experience of 61 patients with ICC seen by the surgical service at the Mayo Clinic over a 31-year period. Patient demographic and clinical data were recorded, as were survival statistics. Pathologic data were also obtained and patients stratified according to the TNM classification. Twenty-eight patients were resected for cure. Overall, 45 patients died of ICC. Of the patients resected for cure, survival at 3 years was 60%. No pathologic condition was found to be associated with the development of ICC. Overall survival correlated with stage of the tumor. Among patients resected for cure, stage did not correlate with survival. Prognosis for patients with ICC remains poor; resection, though, appears to prolong survival.

Can adrenal incidentalomas be safely observed?

We currently recommend excision of adrenal incidentalomas > or = 4 cm in size and all hormonally active tumors. The optimal management and follow-up of smaller nonfunctioning tumors are controversial. The aim of this study was to determine the clinical outcome of a well defined population of patients with incidentalomas followed without operative intervention. The study group comprised 231 patients, identified from the records of abdominal or thoracic computed tomographic (CT) scans performed between 1985 and 1989. The primary outcome variable analyzed was survival. Follow-up was obtained by office records, telephone contact, or letter. There were 101 male and 130 female patients with a mean age at diagnosis of 64 years (range 5-86 years). Most adrenal tumors were unilateral (right 113; left 98); 20 were bilateral. Mean tumor size was 2 cm (range 1-6 cm). In nine (4%) patients the tumor was > or = 4 cm. Follow-up [mean 7 years; range 1 month (patient died) to 11.7 years] was complete in 224 (97%) patients. Ninety-one (39%) patients had one or more additional CT scans performed during the follow-up period, with only four patients demonstrating a > 1 cm increase in the size of the adrenal mass. Surgical excision of these four lesions identified benign pathology. Eighty-one (35%) patients died of conditions unrelated to adrenal pathology. No patient developed subsequent adrenal hyperfunction or adrenal malignancy. Within the context of our guidelines, conservative management of adrenal incidentalomas considered benign or nonfunctioning at diagnosis is appropriate. Additional information provided by repeat CT scanning appears to confer limited benefit. This study does not support laparoscopic removal of small, nonfunctional adrenal tumors, as has been suggested.

Audit of colorectal cancer surgery by non-specialist surgeons.

BACKGROUND: Some authorities recommend that colorectal cancer should be treated in specialist units but evidence that non-specialist units demonstrate comparatively poor results may be lacking. METHODS: Between 1987 and 1991, 267 patients were operated on by four general surgeons, none of whom was a specialist in colorectal surgery. Procedure-related complications, postoperative mortality and disease-related survival rates were analysed. RESULTS: There were four cases of intraperitoneal sepsis (1 per cent) and five of 189 patients (3 per cent) had clinical anastomotic dehiscence; there was no case of wound dehiscence. The postoperative mortality rate after elective and emergency surgery was 2 and 13 per cent respectively. The 5-year disease-related survival rate for curative and palliative surgery was 67 and 9 per cent respectively. There were no significant differences between the surgeons. CONCLUSION: Disease-related variables such as early-stage disease and fewer patients presenting as emergencies may have a greater favourable influence on ultimate survival than surgeon-related variables.

Is familial hyperparathyroidism a unique disease?

BACKGROUND: Familial hyperparathyroidism is a rare condition reported to behave more aggressively than sporadic hyperparathyroidism. METHODS: A retrospective (1975 to 1995) analysis was performed on 30 such patients. All patients had at least one first-degree relative with surgically treated hyperparathyroidism and no personal or family history of multiple endocrine neoplasia. RESULTS: There were 19 women and 11 men with a mean age of 39 years (range, 13 to 78 years). Fourteen patients (47%) had nephrolithiasis. The mean serum calcium level was 11.6 mg/dl (range, 10.5 to 15.3 mg/dl). Twenty-three primary and 15 repeat explorations (eight recurrent and seven persistent disease) were performed during the study period. Follow-up was obtained on all patients and ranged from 1 to 21 years (mean, 12 years). At the conclusion of the study, hypercalcemia (five recurrent and one persistent) was present in six patients (20%). CONCLUSIONS: Familial hyperparathyroidism is a distinct and unique entity. Patients are diagnosed at a young age and have a high incidence of nephrolithiasis. Long-term follow-up is mandatory because of the high incidence of both recurrent and persistent hyperparathyroidism. Surgical treatment should include subtotal parathyroidectomy and routine transcervical thymectomy performed in centers with experience in the management of multiple-gland parathyroid disease.

Laparoscopic oophorectomy: a prospective evaluation in pre-menopausal breast cancer with particular reference to incidence and severity of menopausal symptoms.

Laparoscopic oophorectomy offers potential advantages over other methods of ovarian ablation. In this prospective study the technique, complications and side-effects have been assessed in 69 consecutive patients. Menopausal symptoms were assessed using two scoring systems - the Kupperman index and the Women's Health Questionnaire. The serum beta oestradiol levels fell rapidly post-operatively (from 540 pmol/l to 25 pmol/l within 1 month). Menopausal symptoms were mild in 75% of patients and severe in none. Complications occurred in three patients. Laparoscopic oophorectomy has an important role to play in the management of pre-menopausal breast cancer and this study confirms that is well tolerated and gives good short-term results.

Methods of renal blood flow measurement.

Variations in regional renal blood flow have been implicated in a variety of disease states. Many techniques have been developed in an attempt to accurately assess these changes. The microsphere technique is the most widely used method at the present time. This technique allows focal measurements to be performed, but there is a conflict between the resolution of the method and the number of microspheres necessary in each sample. New imaging techniques such as tomography and autoradiography enable visual assessment of renal blood flow. Though there is no ideal method, these techniques have opened up new possibilities in the quantification of regional renal blood flow.

Cholinergic agents modulate transport in the isolated, perfused ileum.

The mammalian small intestine is extensively innervated by cholinergic nerve fibers, including projections to the muscular and submucosal layers. This study tested the hypothesis that cholinergic agents modulate ileal transport independent of alterations in intestinal vascular resistance and motility. Ten-centimeter segments of rabbit ileum (n = 32) were vascularly perfused ex vivo with a physiologic electrolyte solution containing red cells. The lumen was perfused with an electrolyte solution containing [14C]polyethylene glycol. Net fluxes of water, sodium, and chloride were calculated during three 20-min periods: basal, drug infusion, and recovery. Agents infused at a final arterial concentration of 10(-5) mole/liter included acetylcholine, atropine, and hexamethonium. Measured perfusion pressure reflected changes in vascular resistance. Recovery calculations controlled for motility effects. Acetylcholine caused significant secretion of water, sodium, and chloride (P < 0.05). The infusion of atropine or hexamethonium alone had no effect. Atropine but not hexamethonium prevented the prosecretory effect of acetylcholine. There were no significant changes in perfusion pressure or 14C recovery for any infused agent. Acetylcholine-induced ileal secretion is (1) mediated via atropine-sensitive muscarinic cholinergic receptors, (2) independent of extraintestinal neural pathways, and (3) independent of changes in vascular resistance or motility. These data support the hypothesis that acetylcholine influences ileal transport directly, independent of alterations in vascular resistance and motility.

A prospective study of acid reflux and globus pharyngeus using a modified symptom index.

Previous authors have demonstrated an association between gastro-oesophageal reflux and globus pharyngeus. With the advent of 24-h pH monitoring the strength of this association has been questioned. A prospective study was performed using a 'Symptom Index' of acid reflux. A positive result was recorded when one out of two globus sensations occurred with acid reflux. The symptom index was assessed prospectively in 21 patients with a history of globus pharyngeus. In eight patients with significant acid reflux as defined by standard pH criteria the symptom index was positive in all cases. The remaining 13 patients had no objective evidence of significant reflux and the symptom index was negative. The symptom index is a useful additional marker to determine the significance of acid reflux in the pathogenesis of globus pharyngeus.

Luminal dopamine modulates canine ileal water and electrolyte transport.

Previous studies have suggested that dopamine stimulates active ileal ion absorption via alpha 2-adrenergic or dopaminergic receptor activation. Identification of a dopamine 1a receptor on rat enterocytes located in intestinal crypts prompted this investigation of the effect of luminally administered dopamine on water and ion transport in the canine ileum. Absorption studies (n = 27) were performed in dogs with 25-cm ileal Thiry-Vella fistulas. Perfusion with [14C] PEG was used to calculate absorption of water and electrolytes from the Thiry-Vella fistula. Experiments consisted of three 1-hr periods: basal, luminal drug infusion at 10(-4) M, and recovery. Agonists used included dopamine (DOP: alpha-adrenergic, D1 and D2 receptor) and SKF 38393 (D1 receptor). Antagonists used included terazosin (TZ: alpha 1) and yohimbine (YOH: alpha 2). DOP caused significant increases in water and electrolyte absorption. TZ and YOH prevented the dopamine-induced proabsorptive response. Luminal DOP may serve as a proabsorptive modulator of ileal transport, acting via alpha 1, alpha 2, and dopaminergic receptors. The development of more potent proabsorptive dopamine analogs, which maintain the ability to broadly activate mucosal receptors, may be useful in such clinical situations as diabetic diarrhea, short gut syndrome, or following small bowel transplantation.

Neural mechanisms in basal and meal-stimulated ileal absorption.

The ingestion of a meal stimulates absorption from the jejunal lumen and is dependent on intact neural pathways. Few studies of ileal absorptive responses to a meal have been performed. This study tested two hypotheses: (1) a meal stimulates ileal glucose, water, and ion absorption, and (2) intact intestinal neurotransmission is necessary to maintain the basal and meal-stimulated absorptive states in the ileum. Absorption studies (n = 50) using 14C-labeled PEG were performed on six dogs with 25-cm ileal Thiry-Vella fistulas (TVF). Four groups were randomly studied over 4 hr. Intraluminal oxethazaine (2 mg/dl) was administered to the TVF in Groups 2 and 4 after the 1st hour to produce neural blockade. A control volume of water was administered to the TVF in Groups 1 and 3 after the 1st hour. A 480 kcal meal was ingested at the end of the 2nd hour in groups 3 and 4. Ileal water, ion, and glucose absorption were increased significantly (P < 0.05) by the ingestion of a meal. TVF oxethazaine significantly reduced (P < 0.05) basal water and ion absorption but had no effect on meal-stimulated absorption. Ileal absorption of water, ions, and glucose is significantly increased by the ingestion of a meal. Basal ileal absorption appears to be partly dependent upon intact neurotransmission. Postprandial ileal absorption appears to be independent of neural blockade, implicating circulating hormones, paracrine mediators, or neurotransmission within the myenteric plexus of the enteric nervous system as the primary modulators of meal-stimulated ileal absorption.

Effect of alpha 1-adrenergic blockade on canine ileal water, electrolyte, and glucose absorption.

Meal ingestion stimulates an increase in small intestinal water and electrolyte absorption. Endogenous norepinephrine may at least partially mediate this meal-stimulated proabsorptive response. Luminally administered alpha 1-adrenergic agonists such as norepinephrine and phenylephrine cause significant small bowel absorption, which can be prevented by the selective alpha 1-adrenergic antagonist terazosin. This study tested two hypotheses: (1) a meal stimulates ileal water, electrolyte, and glucose absorption; and (2) meal-stimulated ileal absorption is mediated via alpha 1-adrenergic receptor activation. Absorption studies (N = 27) were performed on dogs with 25-cm ileal Thirty-Vella fistulas (TVF). Perfusion with [14C]PEG was used to calculate absorption of water, electrolytes, and glucose from the TVF. Three groups were randomly studied over 4 hr: (1) terazosin alone, (2) meal alone, and (3) terazosin plus meal. Terazosin (10(-4) M) was administered to the TVF in groups 1 and 3 following the first hour. A 480-kcal mixed canine meal was ingested at the end of the second hour in groups 2 and 3. Ileal water, electrolyte, and glucose absorption increased significantly in response to meal ingestion (P < 0.05). Luminal terazosin did not significantly alter basal or meal-stimulated ileal absorption. In conclusion, meal ingestion stimulates ileal absorption of water, electrolytes, and glucose. Neither basal nor meal-stimulated ileal absorption is altered by alpha 1-adrenergic receptor blockade. These data suggest that nonadrenergic neural pathways or humoral factors are the likely mediators of meal-induced intestinal absorption.

Nitric oxide modulates water and electrolyte transport in the ileum.

OBJECTIVE: To test the hypothesis that nitric oxide is a modulator of ileal water and ion transport. SUMMARY BACKGROUND DATA: Nitric oxide is produced in the vascular endothelium and enteric neural plexuses of the intestine and is involved in gastrointestinal motility and smooth muscle contractility. Little is known about the role of nitric oxide in intestinal epithelial transport. METHODS: Ten-centimeter rabbit ileal segments (n = 50) were vascularly perfused with an electrolyte solution containing red cells. The lumen was perfused with a solution containing 14C-PEG. Net fluxes of water and ions were calculated during three 20-minute periods: basal, drug infusion, and recovery. Perfusion pressure was recorded to document changes in vascular resistance. Agents infused included the nitric oxide synthase substrate L-arginine, the nitric oxide source sodium nitroprusside, the substrate control D-arginine, and the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester. RESULTS: L-arginine and sodium nitroprusside caused absorption of water and ions. NG-nitro-L-arginine methyl ester caused secretion of water and ions, which was prevented by synchronous infusion of L-arginine. Infusion of D-arginine had no effect. Both L-arginine and sodium nitroprusside caused mild vasodilation. CONCLUSIONS: Inhibition of endogenous nitric oxide synthesis by NG-nitro-L-arginine methyl ester causes secretion of water and ions. This secretion is reversed by administration of the nitric oxide synthase substrate L-arginine. These findings are consistent with the hypothesis that endogenous nitric oxide has a proabsorptive influence over the ileum in the basal state.