Oncological outcomes of standard versus prolonged time to surgery after neoadjuvant chemoradiotherapy for oesophageal cancer in the multicentre, randomised, controlled NeoRes II trial.

BACKGROUND: The optimal time to surgery (TTS) after neoadjuvant chemoradiotherapy (nCRT) for oesophageal cancer is unknown and has traditionally been 4-6 weeks in clinical practice. Observational studies have suggested better outcomes, especially in terms of histological response, after prolonged delay of up to 3 months after nCRT. The NeoRes II trial is the first randomised trial to compare standard to prolonged TTS after nCRT for oesophageal cancer. PATIENTS AND METHODS: Patients with resectable, locally advanced oesophageal cancer were randomly assigned to standard delay of surgery of 4-6 weeks or prolonged delay of 10-12 weeks after nCRT. The primary endpoint was complete histological response of the primary tumour in patients with adenocarcinoma (AC). Secondary endpoints included histological tumour response, resection margins, overall and progression-free survival in all patients and stratified by histologic type. RESULTS: Between February 2015 and March 2019, 249 patients from 10 participating centres in Sweden, Norway and Germany were randomised: 125 to standard and 124 to prolonged TTS. There was no significant difference in complete histological response between AC patients allocated to standard (21%) compared to prolonged (26%) TTS (P = 0.429). Tumour regression, resection margins and number of resected lymph nodes, total and metastatic, did not differ between the allocated interventions. The first quartile overall survival in patients allocated to standard TTS was 26.5 months compared to 14.2 months after prolonged TTS (P = 0.003) and the overall risk of death during follow-up was 35% higher after prolonged delay (hazard ratio 1.35, 95% confidence interval 0.94-1.95, P = 0.107). CONCLUSION: Prolonged TTS did not improve histological complete response or other pathological endpoints, while there was a strong trend towards worse survival, suggesting caution in routinely delaying surgery for >6 weeks after nCRT.

Effects of a Training Intervention for Enhancing Recovery after Ivor-Lewis Esophagus Surgery: A Randomized Controlled Trial.

BACKGROUND AND AIMS: There is a risk of decreased physical function, quality of life and persistent pain after open surgery for esophageal cancer. There are currently no studies that evaluate the effect of any postoperative intervention, including physical exercises, after this type of surgery. The aim of the study was therefore to evaluate the effect of a training intervention after Ivor-Lewis resection of the esophagus. MATERIAL AND METHODS: Patients scheduled for esophagus resection according to Ivor-Lewis were randomized to an intervention group or a control group. The training intervention started at discharge and lasted three months. Before discharge, patients were given three leaflets with exercises to increase range of motion in the affected area and exercises aiming to restore lung function and physical function. All exercises were described in detail and the patients carried out the ones in the first program under supervision. Before surgery and three months after discharge, the patients estimated their level of physical function, level of physical activity, and quality of life. They also underwent spirometry, measurements of range of motion in the rib cage, spine, and shoulders, and three functional tests. Comparisons of differences within and between the groups were made. RESULTS: A total of 43 of 64 randomized patients participated in the follow-up. Postoperatively, the patients in the intervention group had a significantly higher degree of physical function and less deteriorated range of motion in right shoulder flexion and thoracic left lateral flexion. There were no significant differences between the groups in lung function, pain, or quality of life. CONCLUSION: The results of the three-month intervention indicate that specific training can positively affect physical function and range of motion to preoperative values. The intervention was well tolerated, and no side effects were registered.

Hepatic fibrogenesis requires sympathetic neurotransmitters.

BACKGROUND AND AIMS: Hepatic stellate cells (HSC) are activated by liver injury to become proliferative fibrogenic myofibroblasts. This process may be regulated by the sympathetic nervous system (SNS) but the mechanisms involved are unclear. METHODS: We studied cultured HSC and intact mice with liver injury to test the hypothesis that HSC respond to and produce SNS neurotransmitters to promote fibrogenesis. RESULTS: HSC expressed adrenoceptors, catecholamine biosynthetic enzymes, released norepinephrine (NE), and were growth inhibited by alpha- and beta-adrenoceptor antagonists. HSC from dopamine beta-hydroxylase deficient (Dbh(-/-)) mice, which cannot make NE, grew poorly in culture and were rescued by NE. Inhibitor studies demonstrated that this effect was mediated via G protein coupled adrenoceptors, mitogen activated kinases, and phosphatidylinositol 3-kinase. Injury related fibrogenic responses were inhibited in Dbh(-/-) mice, as evidenced by reduced hepatic accumulation of alpha-smooth muscle actin(+ve) HSC and decreased induction of transforming growth factor beta1 (TGF-beta1) and collagen. Treatment with isoprenaline rescued HSC activation. HSC were also reduced in leptin deficient ob/ob mice which have reduced NE levels and are resistant to hepatic fibrosis. Treating ob/ob mice with NE induced HSC proliferation, upregulated hepatic TGF-beta1 and collagen, and increased liver fibrosis. CONCLUSIONS: HSC are hepatic neuroglia that produce and respond to SNS neurotransmitters to promote hepatic fibrosis.

Dual effects of somatostatin analog octreotide on gastric emptying during and after intragastric fill.

The effect of the somatostatin analog agonist octreotide (Oct) on gastric emptying of 12.5% glucose during and after intragastric fill was examined in nondeprived rats equipped with stainless steel gastric fistulas. The rate of intragastric infusion (1.0 ml/min) and the volumes delivered (6 or 12 ml) were within the ranges typically observed in rats normally ingesting the same stimulus. In experiment 1, a dose-related suppression of glucose emptying during 12-min infusions was obtained in response to Oct (0, 0.0014, 0.014, 0.14, and 1.4 nmol/kg sc) injected 60 min before the test. The highest dose tested yielded a 37% suppression of glucose solute emptying during fill. In experiment 2, the suppression of emptying during fill induced by Oct (1.4 nmol/kg) was reversed by 10 or 40 microgram/kg of the somatostatin antagonist cyclo(7-aminoheptanoyl-Phe-D-Trp-Lys-Thr[Bzl]). The antagonist did not by itself affect emptying. Experiment 3 showed that the suppression of emptying obtained with 0.14 and 1.4 nmol/kg Oct had disappeared when the gastric sample was withdrawn 36 min after the termination of 12-min glucose infusions. Experiment 4 showed that the Oct-induced reductions in emptying during 6- and 12-min infusions, in fact, were reversed within 6 min after infusion offset. The point of transition between suppressed and increased emptying did not depend on time from injection or from infusion onset but was linked to the offset of the intragastric infusion regardless of its duration. The present findings support the notion that separable mechanisms govern gastric emptying during vs. after gastric fill.

Corticotropin-releasing factor-induced suppression of gastric emptying in the rat is blocked by cyclo(7-aminoheptanoyl-phe-D-TRP-LYS-THR[BZL], an in vivo somatostatin antagonist.

Corticotropin-releasing factor (CRF) acts centrally to suppress gastric emptying and increase plasma levels of somatostatin in rats. The experiments were conducted to examine whether cyclo(7-aminoheptanoyl-phe-D-TRP-LYS-THR[BZL]), which acts as a somatostatin antagonist in vivo, blocks the effect of CRF on gastric emptying of glucose. Sprague-Dawley rats were implanted with chronic intragastric fistulas and guide cannulas for fourth intracerebroventricular (4th i.c.v.) delivery. The stomach was evacuated after the offset of a 12-min intragastric glucose infusion (12.5%, 1.0 ml/min). CRF, (1000 pmol) injected 4th i.c.v. suppressed solute emptying by 44% as compared to vehicle (P < 0.001). Pretreatment with cyclo(7-aminoheptanoyl-phe-D-TRP-LYS-THR[BZL]), 40 microg/kg, s.c., having no effect when delivered alone, blocked the effect of CRF on emptying. The results suggest that endogenously released somatostatin participates in CRF-induced suppression of gastric emptying during gastric fill.

Leptin injected into the fourth ventricle inhibits gastric emptying.

The effect of leptin on gastric emptying of glucose was studied in freely moving rats bearing intragastric fistulas. Leptin (0.39 microg and 3.9 microg) injected into the fourth ventricle inhibited gastric emptying significantly, whereas s.c. administration of leptin (10 microg/kg) had no effect. Leptin receptor immunoreactivity, revealed by an antiserum that recognizes all leptin receptor isoforms, was demonstrated in choline acetyltransferase (ChAT)-containing neurones of the dorsal motor nucleus of the vagus nerve (DMX). The data indicate that leptin acts centrally to suppress gastric emptying possibly via leptin receptors located on cholinergic DMX neurones.

Gastric branch vagotomy and gastric emptying during and after intragastric infusion of glucose.

The effect of gastric branch vagotomy (GVX) on the gastric emptying of glucose was evaluated during two phases of emptying control: as the stomach fills and in the postload period. GVX and control rats received a series of intragastric glucose infusions (1.0 ml/min) through indwelling gastric fistulas. In experiment 1, gastric samples were withdrawn either immediately after the offset of 9- or 18-min infusions of 12.5% glucose or at various times up to 36 min postinfusion. In experiment 2, samples were withdrawn either immediately or 30 min after termination of 12-min infusions of 12.5 or 25% glucose. After gastric fill, glucose solute emptying rate was stable over time not influenced by concentration doubling, and, surprisingly, not affected by GVX. During gastric fill, solute emptying rate doubled with concentration in both GVX and control rats. For each concentration, however, glucose emptied during fill at almost twice the rate in GVX compared with control rats. This accelerated emptying of glucose during fill in GVX rats is consistent with a gastric vagal contribution to inhibitory mechanisms (e.g., receptive relaxation) that operate as the stomach fills under normal conditions. The absence of a GVX effect on emptying after fill suggests either that gastric branch vagal efferents play little role in feedback inhibitory control of glucose emptying under normal conditions or that other systems compensate for the function previously served by vagal gastric branch efferents. Further work is required to address the possible role of the gastric vagus in feedback control of gastric emptying when nutritive fluids other than glucose are delivered.

The oxytocin receptor antagonist 1-deamino-2-D-Tyr-(OEt)-4-Thr-8-Orn-oxytocin inhibits effects of the 5-HT1A receptor agonist 8-OH-DPAT on plasma levels of insulin, cholecystokinin and somatostatin.

The aim of the present study was to investigate whether the 5-HT1A receptor agonist 8-OH-DPAT, which previously has been shown to release oxytocin, also influences plasma levels of gastrointestinal and pancreatic hormones, and if so, whether such an effect is mediated by an oxytocinergic mechanism. For this purpose 8-OH-DPAT (0.5 mg/kg s.c.) was injected to male rats pretreated with the oxytocin receptor antagonist 1-deamino-2-D-Tyr-(OEt)-4-Thr-8-Orn-oxytocin (1 mg/kg s.c.), or vehicle. Thirty min after injection of 8-OH-DPAT, plasma levels of oxytocin were significantly increased. 8-OH-DPAT also increased insulin and decreased CCK and somatostatin levels, effects that were blocked by pretreatment with the oxytocin antagonist. Taken together, these data suggest that the effect of 8-OH-DPAT on plasma levels of insulin, somatostatin and CCK may be mediated by oxytocin. In previous experiments, we have shown that following i.c.v. application of oxytocin, plasma levels of insulin are increased through a cholinergic mechanism. In this study, 2 ng of oxytocin decreased plasma levels of CCK, gastrin and somatostatin, effects that were blocked by pretreatment with atropine. Since oxytocinergic fibers which originate in the PVN project to the DMX, we suggest that the effect on the release of insulin, CCK and somatostatin induced by the 5 HT1A receptor agonist 8-OH-DPAT may be mediated by an oxytocinergic activation of a vagal mechanism.

Fourth ventricle injection of corticotropin-releasing factor and gastric emptying of glucose during gastric fill.

The effect of corticotropin-releasing factor (CRF) administered into the fourth ventricle on the gastric emptying of a 12-ml intragastric infusion of 12.5% D-glucose was examined in nondeprived male rats. All three CRF doses tested (10, 100, and 1,000 pmol) significantly reduced (by 28, 29, and 44%, respectively) the amount of glucose emptied from the stomach at the end of the 12-min (1.0 ml/min) gastric infusion interval. The 10 pmol effective dose is the lowest yet reported to influence gastric emptying. The receptor specificity of the exogenous CRF (1,000 pmol) effect was demonstrated by its complete blockade by preinjection of alpha-helical CRF-9-41 (10 nmol) into the fourth ventricle. Injection of the antagonist alone, however, did not affect glucose emptying, indicating little activation of the targeted receptors under the present nonstressful, baseline conditions. Our results suggest that of the central CRF receptor systems that influence gastric emptying, those in the caudal brain stem, targeted by fourth ventricular injection, may be of particular importance.

Role of vagal nerve activity during suckling. Effects on plasma levels of oxytocin, prolactin, VIP, somatostatin, insulin, glucagon, glucose and of milk secretion in lactating rats.

The aim of this study was to investigate the role of vagal nerve activity for the release of oxytocin, prolactin and gastrointestinal (GI) hormones during suckling as well as for the secretion of milk in lactating rats. We have therefore performed experiments on vagotomized lactating rats. The animals were decapitated and trunk blood was collected from nonsuckling rats and from suckling rats in connection with milk ejection. Oxytocin, prolactin, vasoactive intestinal polypeptide (VIP), somatostatin, insulin, glucagon and glucose levels in plasma were measured by RIA-technique. In addition, maternal weight as well as the weight of the litters were recorded 7 d after vagotomy. As expected, oxytocin and prolactin levels rose in response to suckling in sham-operated controls. In vagotomized animals the suckling-induced increase of oxytocin was blocked and prolactin levels were significantly decreased. VIP levels in plasma increased following suckling in sham-operated animals and failed to respond after vagotomy. In contrast, somatostatin levels that rose significantly in sham-operated rats were even more significantly raised in vagotomized animals. In addition, insulin but not glucagon levels were increased by suckling. The insulin response, however, persisted after vagotomy. Interestingly, suckling was followed by a lowering of blood-glucose levels in vagotomized, but not in sham-operated animals. The vagotomized rats ate as much and increased in weight as sham-operated rats during the 7 d of vagotomy. The litters of vagotomized rats, however, gained significantly less weight in comparison with control litters. In conclusion, this study shows that vagal nerve activity is of importance for the release of oxytocin, prolactin, vasoactive intestinal polypeptide and somatostatin during suckling.(ABSTRACT TRUNCATED AT 250 WORDS)

Intracerebroventricularly administered corticotropin-releasing factor releases somatostatin through a cholinergic, vagal pathway in freely fed rats.

The aim of this study was to investigate whether corticotropin-releasing factor influences the plasma levels of somatostatin, gastrin or cholecystokinin when administered intracerebroventricularly to rats, and if such an effect could be vagally mediated, and dependent on the animals feeding states. Anaesthetized, freely fed rats were given 5 microliters intracerebroventricular injections of corticotropin-releasing factor in four doses; 10 pmol-1.28 nmol. Immediately following death, trunk blood was collected for subsequent peptide analysis with radioimmunoassay (RIA). The three higher doses of corticotropin-releasing factor elevated the plasma levels of somatostatin (P < 0.01) after 20 min but left the plasma levels of gastrin and cholecystokinin unchanged. Intraperitoneal injections of 60 and 320 pmol of corticotropin-releasing factor did not influence the somatostatin levels. Further, intracerebroventricular injections of 60 pmol of corticotropin-releasing factor produced a peak increase in somatostatin after 20 min (P < 0.01). After 60 min the somatostatin levels were still increased (P < 0.05). Gastrin and cholecystokinin remained unaltered at these time-points. Intracerebroventricular administration of 10 nmol of alpha-helical corticotropin-releasing factor 9-41 attenuated the basal levels of somatostatin and blocked the corticotropin-releasing factor-induced rise in somatostatin. Bilateral truncal vagotomy, as well as pretreatment with atropine (0.05 mg kg-1, subcutaneously) abolished the effects of corticotropin-releasing factor on somatostatin. In animals which were food-deprived for 24 h, corticotropin-releasing factor did not influence somatostatin, gastrin or cholecystokinin. Pretreatment with cholecystokinin did not potentiate corticotropin-releasing factor-induced somatostatin release in food-deprived rats.(ABSTRACT TRUNCATED AT 250 WORDS)