Toll-like receptors: exploring their potential connection with post-operative infectious complications and cancer recurrence.

Cancer is the leading cause of death in North America. Despite modern advances in cancer therapy, many patients will ultimately develop cancer metastasis resulting in mortality. Surgery to resect early stage solid malignancies remains the cornerstone of cancer treatment. However, surgery places patients at risk of developing post-operative infectious complications that are linked to earlier cancer metastatic recurrence and cancer mortality. Toll-like receptors (TLRs) are evolutionarily-conserved sentinel receptors of the innate immune system that are activated by microbial products present during infection, leading to activation of innate immunity. Numerous types of solid cancer cells also express TLRs, with their activation augmenting their ability to metastasize. Similarly, healthy host-tissue TLRs activated during infection induce a prometastatic environment in the host. Cancer cells additionally secrete TLR activating ligands that activate both cancer TLRs and host TLRs to promote metastasis. Consequently, TLRs are an attractive therapeutic candidate to target infection-induced cancer metastasis and progression.

Diagnostic criteria and symptom grading for delayed gastric conduit emptying after esophagectomy for cancer: international expert consensus based on a modified Delphi process.

Delayed gastric conduit emptying (DGCE) after esophagectomy for cancer is associated with adverse outcomes and troubling symptoms. Widely accepted diagnostic criteria and a symptom grading tool for DGCE are missing. This hampers the interpretation and comparison of studies. A modified Delphi process, using repeated web-based questionnaires, combined with live interim group discussions was conducted by 33 experts within the field, from Europe, North America, and Asia. DGCE was divided into early DGCE if present within 14 days of surgery and late if present later than 14 days after surgery. The final criteria for early DGCE, accepted by 25 of 27 (93%) experts, were as follows: >500 mL diurnal nasogastric tube output measured on the morning of postoperative day 5 or later or >100% increased gastric tube width on frontal chest x-ray projection together with the presence of an air-fluid level. The final criteria for late DGCE accepted by 89% of the experts were as follows: the patient should have 'quite a bit' or 'very much' of at least two of the following symptoms; early satiety/fullness, vomiting, nausea, regurgitation or inability to meet caloric need by oral intake and delayed contrast passage on upper gastrointestinal water-soluble contrast radiogram or on timed barium swallow. A symptom grading tool for late DGCE was constructed grading each symptom as: 'not at all', 'a little', 'quite a bit', or 'very much', generating 0, 1, 2, or 3 points, respectively. For the five symptoms retained in the diagnostic criteria for late DGCE, the minimum score would be 0, and the maximum score would be 15. The final symptom grading tool for late DGCE was accepted by 27 of 31 (87%) experts. For the first time, diagnostic criteria for early and late DGCE and a symptom grading tool for late DGCE are available, based on an international expert consensus process.

Multivisceral Resection for Locally Advanced Gastric and Gastroesophageal Junction Cancers-11-Year Experience at a High-Volume North American Center.

INTRODUCTION: The oncologic benefit of multivisceral en bloc resections for T4 gastroesophageal tumors has been questioned, given the increased morbidity associated. We thus sought to investigate the surgical and oncologic outcomes of curative-intent en bloc multivisceral resections for T4 gastroesophageal carcinomas. METHODS: Between 2005 and 2016, 35 of the 525 patients who had gastric or EGJ carcinomas underwent curative-intent multivisceral resections for direct invasion or adhesion to adjacent organs. RESULTS: Postoperative complications occurred in 16(46%), 10 of which were Clavien-Dindo ≥ 3 (29%). Ninety-day mortality was 3%. The R0 resection rate was 94% (33). Direct organ invasion (pT4b) was confirmed on pathological analysis in 14 (40%) and did not affect survival. The majority (28, 80%) had lymph node involvement with a high nodal disease burden and was associated with decreased survival. Overall 5-year survival rate was 34%, and the vast majority of recurrences were distant/peritoneal (81%). On multivariate analysis, positive lymph nodes (H.R. 21.2; 95%CI 2.34-192) and R1 resection (H.R. 5.6; 95%CI 1.02-30.9) were predictors of survival. CONCLUSION: Multivisceral resections for T4 gastric and GEJ adenocarcinomas, in combination with effective systemic therapy, result in prolonged long-term survival with acceptable morbidity. Complete resection to negative margins should remain a mainstay of curative-intent treatment in carefully selected patients.

Management of Dysphagia in Esophageal Adenocarcinoma Patients Undergoing Neoadjuvant Chemotherapy: Can Invasive Tube Feeding be Avoided?

BACKGROUND: Neoadjuvant chemotherapy is an accepted standard for locally advanced esophagogastric junction adenocarcinoma. However, the dysphagia frequently associated with this condition may interfere with patient tolerance of this treatment. In many centers, invasive tube feeding, placed either endoscopically, radiographically, or surgically, is used to address this issue, but it can cause significant morbidity. We sought to determine if an approach of goal-directed dietary counseling and appropriately timed neoadjuvant chemotherapy could obviate the need for invasive tube feeding. METHODS: Patients with locally advanced (cT3 or N+) esophageal and esophagogastric junction adenocarcinoma undergoing neoadjuvant TCF [Taxotere, cisplatin 5-fluorouracil (5-FU)], ECF (epirubicin, cisplatin, 5-FU), or FLOT (docetaxel, oxaliplatin, leucovorin, and 5-FU) at the McGill University Health Center from March 2007 to September 2012 were identified from a prospective database. All received individualized goal-directed dietary counseling, were monitored for signs/symptoms of malnutrition with serial (baseline/presurgery) body mass index, albumin, and completed serial symptom scores (dysphagia), and quality-of-life questionnaires (Functional Assessment in Cancer Therapy with the esophageal subset, FACT-E). We assessed the response of dysphagia and nutritional status to neoadjuvant chemotherapy and the need for invasive tube feeding. RESULTS: Of 130 patients undergoing neoadjuvant chemotherapy, 78 had severe dysphagia (defined as dysphagia score ≥2 on a 5-point Likert scale), most of whom received TCF (91 %). Overall dysphagia scores improved in 75 (96 %) of 78 patients from a dysphagia score of 3-0, most of which improved after the first cycle of therapy. This was associated with an increase in quality of life (FACT-E scores 117 ± 23 to 140 ± 20). With maintenance of weight (70 ± 22 to 69 ± 24 kg), body mass index (24.5 ± 8 to 23.9 ± 7 kg/m(2)), and serum albumin (40 ± 5 to 37 ± 4 g/L). Only one patient required a stent, and none required jejunostomy or gastrostomy. CONCLUSIONS: Appropriately timed neoadjuvant chemotherapy with a highly effective regimen rapidly restores normal swallowing, maintains nutritional status, and obviates the need for invasive tube feeding in patients with significant dysphagia from esophageal adenocarcinoma.

Economic impact of an enhanced recovery pathway for oesophagectomy.

BACKGROUND: Data are lacking to support the cost-effectiveness of enhanced recovery pathways (ERP) for oesophagectomy. The aim of this study was to investigate the impact of an ERP on medical costs for oesophagectomy. METHODS: This study investigated all patients undergoing elective oesophagectomy between June 2009 and December 2011 at a single high-volume university hospital. From June 2010, all patients were enrolled in an ERP. Clinical outcomes were recorded for up to 30 days. Deviation-based cost modelling was used to compare costs between the traditional care and ERP groups. RESULTS: A total of 106 patients were included (47 traditional care, 59 ERP). There were no differences in patient, pathological and operative characteristics between the groups. Median length of hospital stay (LOS) was lower in the ERP group (8 (interquartile range 7-18) days versus 10 (9-18) days with traditional care; P = 0·019). There was no difference in 30-day complication rates (59 per cent with ERP versus 62 per cent with traditional care; P = 0·803), and the 30-day or in-hospital mortality rate was low (3·8 per cent, 4 of 106). Costs in the on-course and minor-deviation groups were significantly lower after implementation of the ERP. The pathway-dependent cost saving per patient was €1055 and the overall cost saving per patient was €2013. One-way sensitivity analysis demonstrated that the ERP was cost-neutral or more costly only at extreme values of ward, operating and intensive care costs. CONCLUSION: A multidisciplinary ERP for oesophagectomy was associated with cost savings, with no increase in morbidity or mortality.

Perioperative DCF chemotherapy protocol for patients with gastroesophageal adenocarcinoma: correlation between response to treatment and outcome.

To determine whether metabolic or pathological response to preoperative chemotherapy can predict the relapse-free survival of gastroesophageal adenocarcinoma patients treated on a perioperative chemotherapy protocol. The prospectively collected data of a recently reported phase II trial of perioperative DCF chemotherapy (docetaxel/cisplatin/5-fluorouracil) were analyzed. Median relapse-free survival (RFS) was compared with the Wilcoxon rank-sum test between responders and non-responders according to defined metabolic (reduction in maximum standard uptake value of at least 35 %) and pathological (greater than 50 % tumor regression or ypN(0) status) criteria. A double-sided p value equal or inferior to 0.05 was considered significant. Patients were followed for a median of 807 days (95 % CI: 607-896). RFS was 576 days in metabolic non-responders versus not reached in metabolic responders (p 0.009) and 562 days in ypN+ versus not reached in ypN(0) patients (p 0.045). No statistically significant RFS difference was seen between low and high pathologic responders classified according to tumor regression criteria, although a trend was observed in favor of high pathologic responders. Simple metabolic and pathologic criteria used for the assessment of response to the preoperative part of perioperative chemotherapy can help to estimate the outcome of gastroesophageal adenocarcinoma patients.

Pattern of esophageal eosinophilic infiltration in patients with achalasia and response to Heller myotomy and Dor fundoplication.

Eosinophilic esophagitis (EoE) is now recognized as a common cause of dysphagia. Eosinophilic infiltration of the esophagus has also been associated with other conditions, such as gastroesophageal reflux disease (GERD); however, the incidence, pattern, and clinical significance of eosinophilic infiltration in achalasia are poorly documented. We sought to characterize this histological finding in patients undergoing Heller myotomy (HM) for achalasia. Ninety-six patients undergoing laparoscopic HM for primary achalasia between 1999 and 2008 were identified from a prospective database. Serial mid and distal per-endoscopic esophageal biopsies taken from patients before and after surgery were assessed for the presence of elevated intraepithelial eosinophils (EIEs). Slides from patients with reports suggestive of EIE were reviewed independently by two pathologists, and the highest eosinophil count/high-power field (eos/hpf) was recorded. Dysphagia scores (0 = none to 5 = severe dysphagia), GERD health-related quality of life scores (0 = best to 45 = worst), and 24-hour pH results were compared before and 3 months after surgery. We related the highest eos to the symptoms and response to HM. Data are presented as median (range). Paired t-test and Wilcoxon signed-rank test determined significance, *P < 0.05. Of 96 patients with achalasia, 50 had undergone pre-HM biopsies revealing EIE in 17/50 (34%), with a median of 3 eos/hpf (1-21). Two patients were found to have superimposed esophageal candidiasis. One patient met the pathologic criteria for EoE. Twenty-five of 50 (50%) postoperative biopsies demonstrated a median of 5 eos/hpf (1-62) for a total of 28/50 patients (56%) with EIE in either the preoperative or postoperative period. Four patients (8%) met the pathologic criteria for EoE, and two demonstrated persistent esophageal candidiasis. A decrease in eosinophils was found in 6/28 patients (21%) from 3/hpf (1-21) to 0.5/hpf (0-4). Increase in eosinophils was found in 22/28 patients (79%) from 0.5/hpf (0-8) to 5/hpf (1-62). Preoperative and postoperative dysphagia scores were available in 23 patients. Dysphagia scores improved in 22/23 patients. (3 [0-5] to 0 [0-2])*. Preoperative and postoperative GERD scores were available in 21 patients. GERD scores improved in 20/21 patients (10 [3-38] to 2 [2-14])*. Four of 13 patients (30.7%) demonstrated significant reflux in the postoperative period. No difference in clinical response to HM was detected between patients with preoperative EIE compared with patients with no EIE. No correlation between postoperative esophageal pH and eos was observed. A significant number of patients with achalasia demonstrate esophageal eosinophilic infiltration even at numbers demonstrable in patients with EoE (8% 4/50). While the interaction between achalasia and esophageal eosinophilic infiltration needs further investigation, this does not represent a distinct clinical entity. Thus, the presence of esophageal eosinophils in patients presenting with dysphagia should not preclude further work-up for other etiologies, including achalasia.

What is the optimal management of dysphagia in metastatic esophageal cancer?

BACKGROUND: The palliation of dysphagia in metastatic esophageal cancer remains a challenge, and the optimal approach for this difficult clinical scenario is not clear. We therefore sought to define and determine the efficacy of various treatment options used at our institution for this condition. METHODS: We reviewed a prospective database for all patients managed in an esophageal cancer referral centre over a 5-year period. All patients receiving palliation of malignant dysphagia were reviewed for demographics, palliative treatment modalities, complications, and dysphagia scores (0 = none to 4 = complete). The Wilcoxon signed rank test was used to determine significance (p < 0.05). RESULTS: During 2004-2009, 63 patients with inoperable esophageal cancer were treated for palliation of dysphagia. The primary treatment was radiotherapy in 79% (brachytherapy in 18 of 50; external-beam in 10 of 50; both types in 22 of 50), and stenting in 21%. Mean wait time from diagnosis to treatment was 22 days in the stent group and 54 days in the radiotherapy group (p = 0.003). Mean duration of treatment was 1 day in the stent group and 40 days in the radiotherapy group (p = 0.001). In patients treated initially by stenting, dysphagia improved within 2 weeks of treatment in 85% of patients (dysphagia score of 0 or 1). However, 20% of patients presented with recurrence of dysphagia at 10 weeks of treatment. In the radiotherapy group, the onset of palliation was slower, with only 50% of patients palliated at 2 weeks (dysphagia score of 0 or 1). However, long-term palliation was more satisfactory, with 90% of patients remaining palliated after 10 weeks of treatment. CONCLUSIONS: In inoperable esophageal cancer at our centre, radiation treatment provided durable long-term relief, but came at a high price of a long wait time for initiation of treatment and a long lag time between initiation of treatment and relief of symptoms. On the other hand, endoluminal stenting provided more rapid and effective early relief from symptoms, but was affected by recurrence of dysphagia in the long-term. It is now time for a prospective randomized trial to assess the safety and efficacy of combined-modality treatment with both endoluminal stenting and radiation therapy compared with either treatment alone.

Perioperative docetaxel, cisplatin, and 5-fluorouracil (DCF) for locally advanced esophageal and gastric adenocarcinoma: a multicenter phase II trial.

BACKGROUND: Although perioperative chemotherapy for esophagogastric adenocarcinoma (ADC) improves survival, the overall poor prognosis suggests that further refinement of treatment is required. Docetaxel, cisplatin, and 5-fluorouracil (5-FU) (DCF) is effective for metastatic ADC of the upper gastrointestinal (GI) tract; we thus sought to investigate the efficacy of this regimen in patients with resectable disease. PATIENTS AND METHODS: Patients with resectable ADC of the upper GI tract received DCF [docetaxel (Taxotere) 75 mg/m(2) I.V. day 1, cisplatin 75 mg/m(2) I.V. day 1, 5-FU 750 mg/m(2) continuous infusion for 120 h, every 3 weeks] for three cycles before and after resection. Primary end point was complete resection; secondary end points were response, toxicity, surgical morbidity, and overall survival. RESULTS: Forty-three patients with ADC of the esophagus (11), gastroesophageal junction (25), or stomach (7) started treatment and 86% completed all preoperative cycles with grade 3-4 toxicity arising in 47%. Metabolic response to chemotherapy (reduction in maximal standard uptake value >35%) was achieved in 25/33 (76%) patients. Surgery was carried out in 41/43 and complete resection was achieved in all 41 patients with pathologic complete response in 4/41. Postoperative chemotherapy was started in 29 patients and completed in 24. Three-year overall survival was 60%. CONCLUSION: Perioperative DCF is a tolerable and highly effective regimen for the treatment of esophagogastric ADC.

Clinical predictors of achalasia.

Limited access to esophageal manometry (EM) may delay identification and treatment of patients with achalasia. In order to assess predictors to fast-track patients for manometric confirmation of achalasia, we compared the clinical, radiographic, and endoscopic characteristics of achalasia patients to patients with functional dysphagia without manometric features of achalasia (controls). Patients referred for esophageal manometry to assess functional dysphagia prospectively identified over a 12-month period were asked to participate in this study. The Achalasia Symptom Questionnaire (ASQ), a structured 11-question survey (score: 0-best, 67-worst), was completed by all consenting patients. ASQ scores, esophago-gastro-duodenoscopy and upper gastro-intestinal (UGI) contrast study findings were compared between patents with subsequently confirmed achalasia and those in whom achalasia was excluded by EM. Univariate logistic regression identified predictors that were tested by multivariate logistic regression to generate the model. Of the 803 EM performed over this 12-month period, 95 patients were referred specifically to assess functional dysphagia. Of these, 50 were confirmed to have achalasia, and 45 had dysphagia without manometric evidence for achalasia and hence comprised the control group. ASQ scores were higher in achalasia patients (37+/-13 versus 23+/-10). Endoscopy and/or contrast esophagogram reports were available in 92% achalasia patients and 80% controls. Significant predictors for achalasia identified on univariate logistic regression included ASQ score, abnormal findings on endoscopy, and contrast UGI study. Using multivariate logistic regression, we were able to accurately predict the probability of achalasia to be P where P=ey/(1+ey) and y=5.6+(0.089xASQ)+(2.088xEGD)+(3.083xUGI), e=exponential constant 2.7182, esophagogastroduodenoscopy (EGD) and UGI=0 if normal and 1 if abnormal. Dropping the predictor ASQ, the formula changes to y=-2.7+(1.987xEGD)+(2.861xUGI). Using only noninvasive investigations (i.e. eliminating EGD), the formula changes to y=-4.9653+(0.0951xASQ)+(3.4312xUGI). The probability of achalasia can be calculated in patients with functional dysphagia based on clinical, endoscopic, and radiographic findings allowing for a prioritization of EM studies.

A type IV paraesophageal hernia containing a volvulized sigmoid colon.

A type IV paraesophageal hernia is a rare complication in esophageal hiatus and is an uncommon presentation of hiatal hernia. We report herein a 71-year-old man who presented with abdominal pain, nausea and constipation that was attributed to a sigmoid volvulus. At laparotomy, the sigmoid volvulus was identified as strangulated and involved in a type IV paraesophageal hernia in which the esophageal junction was located in its normal anatomic position. The esophageal hiatus was impressively dilated and there was no evidence suggesting previous mechanical disruption of the esophageal hiatus.

Should laparoscopic paraesophageal hernia repair be abandoned in favor of the open approach?

BACKGROUND: The most appropriate approach to the repair of large paraesophageal hernias remains controversial. Despite early results of excellent outcomes after laparoscopic repair, recent reports of high recurrence require that this approach be reevaluated. METHODS: For this study, 60 primary paraesophageal hernias consecutively repaired at one institution from 1990 to 2002 were reviewed. These 25 open transabdominal and 35 laparoscopic repairs were compared for operative, short-, and long-term outcomes on the basis of quality-of -life questionnaires and radiographs. RESULTS: No difference in patient characteristics was detected. Laparoscopic repair resulted in lower blood loss, fewer intraoperative complications, and a shorter length of hospital stay. No difference in general or disease-specific quality-of-life was documented. Radiographic follow-up was available for 78% open and 91% laparoscopic repairs, showing anatomic recurrence rates of 44% and 23%, respectively (p = 0.11). CONCLUSIONS: Laparoscopic repair should remain in the forefront for the management of paraesophageal hernias. However, there is considerable room for improvement in reducing the incidence of recurrence.

Soluble L-selectin at levels present in septic patients diminishes leukocyte-endothelial cell interactions in mice in vivo: a mechanism for decreased leukocyte delivery to remote sites in sepsis.

OBJECTIVE: Recent in vivo studies of both septic humans and animals demonstrate that leukocyte delivery is attenuated to sites remote from the primary infection. The mechanisms for this are not entirely clear. L-selectin is integral to rolling, the first step in leukocyte recruitment to an inflammatory site. L-selectin is shed from leukocytes in sepsis, resulting in increased levels of soluble L-selectin in plasma (2.33 microg/mL). This study investigates the effects of soluble L-selectin at levels found in sepsis on leukocyte trafficking in vivo. DESIGN: Prospective, controlled trial. SETTING: Surgical research laboratory in a university hospital. SUBJECTS: Swiss white male mice of 25-35 g. INTERVENTIONS: Mice were randomized to one of three study groups: soluble L-selectin 2.33, soluble L-selectin 8.0, or albumin. Intravital microscopy was performed on postcapillary venules of 20-40 microm in diameter in the cremaster muscle of mice. Leukocyte-endothelial cell interactions (rolling, adherence, and rolling velocity) were measured pre- and post- (1, 15, 30, and 45 mins) intravenous infusion of human recombinant soluble L-selectin (2.33 and 8.0 microg/mL) or human albumin (8.0 microg/mL). MEASUREMENTS AND MAIN RESULTS: The intravenous administration of soluble L-selectin to a systemic concentration of 2.33 microg/mL diminished rolling significantly. Soluble L-selectin at 8.0 microg/mL decreased rolling and increased rolling velocity to a greater degree. Injection of albumin did not alter leukocyte-endothelial cell interactions at any time point. No difference between groups in blood pressure, shear rate, or leukocyte counts was detected. CONCLUSIONS: Soluble L-selectin diminishes leukocyte rolling at levels present in sepsis (2.33 microg/mL). This effect is dose dependent, and could not be explained by differences in blood pressure, shear rate, or leukocyte counts. These findings identify increased soluble L-selectin levels as one of the mechanisms for decreased leukocyte delivery and exudation to remote sites in septic patients.

Hemorrhagic shock resuscitation with a low molecular weight starch reduces neutrophil-endothelial interactions and vessel leakage in vivo.

BACKGROUND: The polymorphonuclear neutrophil (PMN) has been implicated in the pathogenesis of endothelial cell (EC) damage and organ injury following hemorrhagic shock. Pentastarch (PTS), a low substituted medium molecular weight (MW) colloid, improves hemodynamics in hypovolemic shock and cardiac surgery. No data exist comparing the immunomodulation of PTS and Ringer's lactate (RL) on the activation of PMN in hemorrhagic shock in vivo. METHODS: Using an in vivo murine hemorrhagic shock model (blood withdrawal to maintain 50 mmHg x 45 min), circulating PMN were observed every 15 minutes using intravital microscopy on cremaster muscle. EC-PMN interactions (videorecorded and subsequently analyzed blindly), vessel leakage (live epifluorescence after injection of 50 mg/kg fluorescent albumin) and PMN expression of L-selectin (immunofluorescent monoclonal antibodies and flow cytometry) were evaluated in three resuscitation groups: PTS (7.14 mL/kg 10% pentastarch/0.9% NaCl + shed blood, n = 13), RL (RL [2 x shed blood volume] + shed blood, n = 13) and SHAM (0 hemorrhage, 0 resuscitation, n = 9). Significance was evaluated by ANOVA with Bonferroni correction. RESULTS: PMN rolling was significantly diminished in PTS and SHAM as compared to RL animals at all time points. Similar differences were found in PMN adherence to EC at most time points onwards from 15 minutes following resuscitation. In vivo vessel permeability was lowest in SHAM and PTS animals (mean 0.274 +/- 0.07 and 0.356 +/- 0.15, respectively, p > 0.05) and highest in RL animals (0.667 +/- 0.09, p < 0.001 vs PTS or SHAM). PMN L-selectin expression tended to be higher in the RL group than either SHAM and PTS groups. There were no flow-mechanics differences between groups (vessel diameter, mean red cell velocity, shear stress, shear rate). CONCLUSIONS: 10% pentastarch reduces RL-associated EC-PMN interactions and vessel leakage following hemorrhagic shock. These results support the use of low MW starches to resuscitate hemorrhagic shock, potentially reducing PMN-mediated tissue injury.