Feasibility RCT of definitive chemoradiotherapy or chemotherapy and surgery for oesophageal squamous cell cancer.

BACKGROUND: The optimal treatment for localised oesophageal squamous cell carcinoma (SCC) is uncertain. We assessed the feasibility of an RCT comparing neoadjuvant treatment and surgery with definitive chemoradiotherapy. METHODS: A feasibility RCT in three centres examined incident patients and reasons for ineligibility using multi-disciplinary team meeting records. Eligible patients were offered participation in the RCT with integrated qualitative research involving audio-recorded recruitment appointments and interviews with patients to inform recruitment training for staff. RESULTS: Of 375 patients with oesophageal SCC, 42 (11.2%) were eligible. Reasons for eligibility varied between centres, with significantly differing proportions of patients excluded because of total tumour length (P=0.002). Analyses of audio-recordings and patient interviews showed that recruiters had challenges articulating the trial design in simple terms, balancing treatment arms and explaining the need for randomisation. Before analyses of the qualitative data and recruiter training no patients were randomised. Following training in one centre 5 of 16 eligible patients were randomised. CONCLUSIONS: An RCT of surgical vs non-surgical treatment for SCC of the oesophagus is not feasible in the UK alone because of the low number of incident eligible patients. A trial comparing diverse treatment approaches may be possible with investment to support the recruitment process.

Assessment and comparison of recovery after open and minimally invasive esophagectomy for cancer: an exploratory study in two centers.

BACKGROUND: Minimally invasive esophagectomy (MIE) may lead to early restoration of health-related quality of life, but few prospective comparative studies have been performed. This exploratory study compared recovery between totally minimally invasive esophagectomy (MIE), laparoscopically assisted esophagectomy (LAE) and open surgery (OE). METHODS: A prospective study in 2 specialist centers recruited consecutive patients undergoing OE, LAE, or MIE for high-grade dysplasia or cancer. Patients completed validated questionnaires, the Multi-Dimensional Fatigue Inventory (MFI-20), modified Katz Scale, and modified Lawton and Brody Scale (assessing activities of daily living) before and 6 weeks and 3 and 6 months after surgery. RESULTS: A total of 97 patients (26 women; median age 64 years) were scheduled for surgery that was abandoned in 11 due to occult low-volume metastatic disease. In the remaining 86 (OE = 19, LAE = 31, and MIE = 36), there were 4 in-hospital deaths (4 %), and 54 postoperative complications (OE = 12, LAE = 19, and MIE = 23). Overall questionnaire compliance was high (77 %) and baseline scores similar in all groups, although clinical differences between groups were observed with earlier tumors and more squamous cell cancers selected for MIE. Following surgery fatigue levels increased dramatically and activity levels reduced in all groups. These gradually recovered to baseline following MIE and LAE within 6 months, but the ability to perform activities of daily living and most parameters of fatigue had not returned to baseline levels in the OE group. CONCLUSIONS: This exploratory prospective nonrandomized study of recovery after different types of surgery for esophageal cancer showed possible small benefits to MIE. A much larger study is needed to confirm these findings.

Centralisation of upper-GI cancer services: is the hub quicker than the spoke?

BACKGROUND: The aim of this study was to assess whether patients diagnosed with oesophageal or gastric cancer at a local district general hospital (the "spoke") have a similar temporal pathway through the decision-making and treatment process compared to those patients presenting at the centralised, tertiary hospital (the "hub"). METHODS: Between April 2010 and April 2011, patients with a new diagnosis of oesophagogastric cancer from both hub and spoke hospitals were analysed. Data regarding diagnosis, time from diagnosis to multidisciplinary meeting (MDM) discussion, and time from MDM decision to first treatment were all recorded. Statistical analysis was performed using parametric two-tailed t test to assess significance. RESULTS: There was a statistically significant increase in the time from diagnosis to MDM discussion at the spoke hospital compared to the hub (13.3 days vs. 25.67 days; p = 0.001). However, time to first treatment (surgery, palliative therapy, neoadjuvant therapy, or best supportive care) was significantly increased in the hub hospital compared to the spoke (43.4 days vs. 25.5 days; p = 0.023). CONCLUSIONS: Notwithstanding its limitations, this study is the first of its kind to show that there is a disparity in the management pathways of patients who first present to a regional hospital rather than the tertiary centre. Patients at the spoke hospital have a longer lead time into the MDM but nonoperative treatment appears to be delivered more quickly locally.

Lazaroids prevent acute cyclosporine-induced renal vasoconstriction.

BACKGROUND: Cyclosporine (CsA)-induced nephrotoxicity may be due to intrarenal vasoconstriction and glomerular hypoperfusion. Several factors, including endothelin and prostanoids, are suggested mediators of this response. Recent evidence suggests that CsA leads to increased oxygen-derived free radical (ODFR) production and lipid peroxidation in renal tissue. Whether this leads to alterations in renal vessel reactivity is unclear. Lazaroids, such as U74389G, are radical-quenching antioxidants that inhibit ODFR-induced lipid peroxidation and may improve renal function after ischemia and reperfusion. We hypothesized that ODFRs contribute to CsA-induced alterations of the renal microcirculation. METHODS: Rat hydronephrotic kidneys were studied by video microscopy. Interlobular arteriolar diameter and flow, afferent and efferent arteriolar diameters, and cardiac output were measured at 15-min intervals for 120 min. U74389G or its vehicle was infused 15 min before topical application of CsA to the kidney. The results were compared with U74389G alone and normal saline. RESULTS: CsA administration caused renal microvascular vasoconstriction (10-25% below baseline) and hypoperfusion (35% below baseline). Both vasoconstriction and hypoperfusion were significantly attenuated by U74389G (5-8% and 20% below baseline, respectively). CONCLUSIONS: Inhibition of lipid peroxidation by U74389G maintained renal blood flow during acute CsA administration. These data suggest that ODFRs are involved in the renal microvascular response to CsA. Inhibition of ODFR-induced lipid peroxidation may help prevent CsA-induced glomerular hypoperfusion. Lazaroids may prove an effective adjunct in reducing CsA-induced nephrotoxicity.

Free radical scavenging by lazaroids improves renal blood flow during sepsis.

BACKGROUND: Acute kidney failure in surgical patients is often related to severe infection. Renal vasoconstriction is a major factor in the genesis of kidney failure. Reactive oxygen species (ROS) are known to mediate kidney injury after ischemia-reperfusion and are increased during sepsis. The role of ROS as mediators of intrarenal vasoconstriction and renal dysfunction during sepsis is unclear. Lazaroids such as U74389G are radical quenching antioxidants that inhibit ROS-induced lipid peroxidation. We sought to determine whether radical scavenging affected the renal microvascular response to a septic challenge. METHODS: In vivo videomicroscopy was used to study the rat hydronephrotic kidney. Interlobular artery (ILA) diameter and flow, afferent and efferent arteriolar diameters, and cardiac output were measured. U74389G or vehicle was infused before a bolus injection of live Escherichia coli or normal saline solution. RESULTS: U74389G alone had no effect on the renal vessels or hemodynamics. E. coli caused preglomerular vasoconstriction (ILA, -32%; afferent, -30% of baseline) and hypoperfusion (-66%) despite increased cardiac output (+54%). U74389G significantly attenuated both the constriction (ILA, -16%; afferent, -9%) and hypoperfusion (-38%) but not increased cardiac output (+41%). CONCLUSIONS: E. coli bacteremia led to preglomerular vasoconstriction and hypoperfusion. Inhibition of lipid peroxidation with the radical scavenger U74389G reduced this effect without altering central hemodynamic responses. Free radicals have a deleterious effect on the renal microcirculation during bacteremia, and these data suggest that antioxidants may be of value in preventing sepsis-associated kidney failure.

Pneumothorax during laparoscopy.

BACKGROUND: Pneumothorax is a known complication of laparoscopy, with most pneumothoraces diagnosed postoperatively with conventional chest x-ray. Electrocardiogram (ECG) conduction changes are associated with pneumothorax. In a sheep model, ECG changes were evaluated as a potential indicator of intraoperative pneumothorax. Additionally, resolution rates of helium (He) and carbon dioxide (CO2) pneumothorax were also evaluated in this model. METHODS: Under general anesthesia, 10 sheep had known volumes (20-100 cc) of either He or CO2 introduced into the left hemithorax. A 12-lead ECG recorded changes associated with the induced pneumothorax. After changes in the ECG plateaued, the gas volume in the hemithorax was increased to 2 L and the resultant pneumothorax was followed for a 2-h period using fluoroscopy to determine resolution rates for the different gas pneumothoraces. Gas volumes were aspirated after 2 h and ECGs were again recorded. RESULTS: Pneumothorax volumes as low as 20 cc produced consistent ECG changes. The amplitude of the precordial QRS complex was seen to diminish, and this lowering of the QRS amplitude continued as pneumothorax volume increased up to 100 cc. The ECG returned to prepneumothorax patterns with aspiration of the left chest. For different gas pneumothoraces, CO(2) pneumothorax showed almost complete resolution in the 2-h period, whereas He pneumothorax was unchanged. CONCLUSIONS: Precordial ECG changes appear to be a very sensitive indicator of pneumothorax, with very small pneumothorax (<100 cc) consistently being detected by reduction of the QRS complex amplitude. Intraoperative use of precordial ECG leads could result in rapid identification of pneumothorax during laparoscopic surgery. Carbon dioxide pneumothorax shows near 100% resolution in a 2-h period. This supports recommendations of expectant management in asymptomatic patients with CO(2) pneumothorax. However, He pneumothorax does not resolve spontaneously quickly and may require aspiration even in asymptomatic patients.

A further modification of fundoplication. 90 degrees anterior fundoplication.

BACKGROUND: Laparoscopic Nissen fundoplication is the most widely applied procedure for the surgical treatment of gastroesophageal reflux. However, it can be followed by adverse outcomes, including dysphagia and "wind-related" problems. To reduce the likelihood of side effects, we have progressively modified this procedure to an anterior 90 degrees partial fundoplication. METHODS: The procedure entails posterior hiatal repair, posterior esophagopexy, accentuation of the angle of His, and construction of a 90 degrees anterior partial fundoplication. Clinical follow-up was performed prospectively using a standardized questionnaire. RESULTS: From February 1999 to June 2001, 83 patients underwent 90 degrees anterior fundoplication for gastroesophageal reflux disease. In 45 the procedure was chosen because of specific patient or surgeon preference, and in 38 it was performed within the context of an ongoing randomized trial. Operating time ranged from 20 to 140 minutes (median, 52 min), and all but one of the procedures were completed laparoscopically. One patient experienced a major postoperative complication--small bowel injury from Veress needle. Follow-up extends up to 2 years (median, 1 year). Two patients have undergone further surgery, both for recurrent reflux. Control of reflux has been acceptable, with a reduction in heartburn symptom scores and high overall satisfaction. Postoperative dysphagia measured using a visual analog scale was less following surgery compared with preoperative scores. Eighty-two percent of patients could belch normally 3 and 12 months after surgery. CONCLUSIONS: Ninety-degree anterior fundoplication achieves good control of reflux and a low incidence of side effects. To further evaluate its potential, we are currently undertaking a prospective randomized trial.

Blood patch treatment of chylothorax following transthoracic oesophagogastrectomy: a novel technique to aid surgical management.

Chylothorax is a well-recognised complication of oesophagectomy, occurring in around 3% of cases. If managed conservatively, the mortality rate can be over 50%. We describe our experience of managing a patient with a chylothorax following oesophagectomy, and the use of a blood patch (a novel technique) to overcome persistent leakage following re-operation. The authors feel that this technique has the potential for a wider application in the treatment of chyle leak, especially if combined with minimally invasive or radiological techniques.

Lazaroid and pentoxifylline suppress sepsis-induced increases in renal vascular resistance via altered arachidonic acid metabolism.

Early sepsis leads to renal hypoperfusion, despite a hyperdynamic systemic circulation. It is thought that failure of local control of the renal microcirculation leads to hypoperfusion and organ dysfunction. Of the many mediators implicated in the pathogenesis of microvascular vasoconstriction, arachidonic acid metabolites are thought to be important. Vasoconstriction may be due to excess production of vasoconstrictors or loss of vasodilators. Using the isolated perfused kidney model, we describe a sepsis-induced rise in renal vascular resistance and increased production of key arachidonic acid metabolites, both vasoconstrictors and vasodilators, suggesting excessive production of vasoconstrictors as a cause for microcirculatory hypoperfusion. There is evidence of increased enzymatic production of arachidonic acid metabolites as well as nonenzymatic, free radical, catalyzed conversion of arachidonic acid. Pentoxifylline (a phosphodiesterase inhibitor) and U74389G (an antioxidant) both have a protective effect on the renal microcirculation during sepsis. Both drugs appear to alter the renal microvascular response to sepsis by altering renal arachidonic acid metabolism. This study demonstrates that sepsis leads to increased renal vascular resistance. This response is in part mediated by metabolites produced by metabolism of arachidonic acid within the kidney. The ability of drugs to modulate arachidonic acid metabolism and so alter the renal response to sepsis suggests a possible role for these agents in protecting the renal microcirculation during sepsis.

Vasomotor response to pentoxifylline mediates improved renal blood flow to bacteremia.

Bacteremia leads to rapid intrarenal vasoconstriction, mediated by endogenous vasoconstrictors such as TXA2 and endothelin. These changes occur before the onset of neutrophil adherence, platelet aggregation, or increases in proinflammatory cytokines. Pentoxifylline (PTX) increases red cell deformability, reduces neutrophil adhesion, abrogates rises in TNFalpha, and lessens the deleterious effects of other cytokines during prolonged sepsis. PTX also improves renal function in models of established sepsis, but the specific mechanisms of this effect are unclear. Because PTX is a relatively selective visceral vasodilator we sought to determine whether PTX improves renal microvascular hypoperfusion during bacteremia and whether the mechanism involves altered vascular reactivity. Rat hydronephrotic kidneys were studied by videomicroscopy. Interlobular (ILA) arteriolar diameter and flow, afferent (AFF) and efferent (EFF) arteriolar diameters, and cardiac output (CO) were measured at 15-min intervals for 120 min. PTX was infused alone or prior to a bolus injection of live Escherichia coli. The responses were compared to controls infused with equivalent volumes of normal saline alone. PTX led to improved renal blood flow and to pre- and postglomerular vasodilatation. This improvement remained significant compared to bacteremic animals throughout the period of observation. We conclude that PTX improves renal blood flow during bacteremia due to pre- and postglomerular vasodilation. These responses may be a consequence of increased intracellular cAMP and release of vasodilator prostanoids.

Differential intestinal microvascular dysfunction occurs during bacteremia.

Altered vascular responsiveness is the hallmark of septic shock. Recently, these changes have frequently been attributed to increased production of nitric oxide (NO). Continued exposure to high levels of NO may alter both endothelial and vascular smooth muscle cell function. Although ex vivo studies demonstrate hyporeactivity of large conduit arteries during established sepsis, it is unclear if the same phenomena exist during early sepsis. This is especially true in the small resistance arterioles of the viscera. We used in vivo microscopy of the rat small intestine to assess (1) endothelial-dependent relaxation and vasomotion (periodic contraction and relaxation of blood vessels) in response to acetylcholine (ACH; 10(-8) to 10(-5) M), (2) endothelial-independent relaxation to nitroprusside (NTP; 10(-5) M), and (3) vascular smooth muscle response to norepinephrine (NE; 10(-10) to 10(-7) M) in normal and bacteremic rats (Escherichia coli). There were no alterations in endothelial-dependent or -independent relaxation during bacteremia as measured by mean diameters. However, acute E. coli bacteremia severely impaired vasomotion in A1 (inflow) and A3 (premucosal) arterioles. Vasomotion was returned to baseline levels in A1 with low-dose ACH (10(-8) M) but only partially improved in A3 arterioles (P < 0.05). A1 response to NE was impaired, while A3 were minimally altered despite being more sensitive to E. coli-induced vasoconstriction. These data suggest that bacteremia causes a rapid, differential impairment of both endothelial-dependent (A3 vasomotion) and vascular smooth muscle cell (A1 constriction) functions. These microvascular impairments occur much earlier than previously described and may contribute to sepsis-induced mucosal ischemia of the intestines.

Heparan preserves intestinal perfusion after hemorrhage and resuscitation.

BACKGROUND: Multiple system organ failure (MOF) remains a major source of morbidity and mortality in trauma patients. Despite restoration of central hemodynamics, intestinal hypoperfusion can persist. Mucosal ischemia and barrier breakdown are factors in the genesis of MOF. Heparan sulfate is a gycosaminoglycan similar to heparin, but with minimal anticoagulant properties. As an adjunct to resuscitation, it improves immunologic function and restores mucosal oxygenation and function. We hypothesized that resuscitation with heparan following hemorrhage wound prevents intestinal hypoperfusion. MATERIALS AND METHODS: In vivo videomicroscopy was used to study small intestine microcirculation in rats. Animals were hemorrhaged to 50% of baseline mean arterial pressure (MAP) and maintained there. Resuscitation was initiated when the return of 10% shed blood was required to keep MAP at 50%. Animals received either heparan (7 mg/kg/1 ml saline) or saline (1 ml) followed by the remaining shed blood and an equal volume of saline. MAP, cardiac output (CO), A1 arteriole diameters, and flow were determined. RESULTS: Resuscitation of the saline control group resulted in normal MAP with elevation of CO to 25-40% above baseline. The heparan group had return of MAP but only a moderate increase in CO (7-15%). Saline resuscitation led to progressive deterioration in A1 diameters and flow. The addition of heparan prevented delayed A1 constriction and significantly improved perfusion. CONCLUSIONS: Heparan prior to resuscitation improved intestinal perfusion, despite a relative reduction in CO. Improvement in nutrient blood flow may protect the mucosal barrier, reducing the incidence of MOF, and suggests that heparan may be useful in resuscitation of trauma patients.

Lazaroid improves intestinal blood flow in the rat during hyperdynamic bacteraemia.

BACKGROUND: Intestinal mucosal hypoperfusion and loss of barrier function during sepsis may contribute to maintaining the septic state. Free radicals are produced during sepsis and antioxidants improve survival from experimental sepsis. It is unclear whether endothelial cell injury from free radicals results in altered microvascular reactivity. Lazaroids are antioxidants which scavenge radicals and block lipid radical chain reactions. The authors sought to determine whether lazaroids altered the intestinal microvascular responses to sepsis. METHODS: In vivo video microscopy was used to study the ileal microcirculation of the rat. A1 (inflow) arteriolar diameter and flow, A3 (premucosal) arteriolar diameters, and cardiac output were measured. Lazaroid or vehicle was infused before a bolus injection of live Escherichia coli or saline. RESULTS: Lazaroid alone had no effect on the intestinal vessels or haemodynamics. E. coli caused vasoconstriction (A1, -21 per cent, A3, -19 per cent of baseline) and hypoperfusion (-36 per cent) despite increased cardiac output (+31 per cent). Lazaroid significantly attenuated both constriction (A1, -11 per cent; A3, 10 to -1 per cent) and hypoperfusion (-15 per cent), but did not increase cardiac output (30 per cent). CONCLUSION: E. coli bacteraemia led to intestinal vasoconstriction and hypoperfusion. Lazaroid reduced this effect without altering central haemodynamic responses, suggesting that free radicals have a deleterious effect on the intestinal microcirculation during bacteraemia.