Distinct classes of misfolded proteins differentially affect the growth of yeast compromised for proteasome function.

Maintenance of the proteome (proteostasis) is essential for cellular homeostasis and prevents cytotoxic stress responses that arise from protein misfolding. However, little is known about how different types of misfolded proteins impact homeostasis, especially when protein degradation pathways are compromised. We examined the effects of misfolded protein expression on yeast growth by characterizing a suite of substrates possessing the same aggregation-prone domain but engaging different quality control pathways. We discovered that treatment with a proteasome inhibitor was more toxic in yeast expressing misfolded membrane proteins, and this growth defect was mirrored in yeast lacking a proteasome-specific transcription factor, Rpn4p. These results highlight weaknesses in the proteostasis network's ability to handle the stress arising from an accumulation of misfolded membrane proteins.

Harmonizing Experimental Data with Modeling to Predict Membrane Protein Insertion in Yeast.

Membrane proteins must adopt their proper topologies within biological membranes, but achieving the correct topology is compromised by the presence of marginally hydrophobic transmembrane helices (TMHs). In this study, we report on a new model membrane protein in yeast that harbors two TMHs fused to an unstable nucleotide-binding domain. Because the second helix (TMH2) in this reporter has an unfavorable predicted free energy of insertion, we employed established methods to generate variants that alter TMH2 insertion free energy. We first found that altering TMH2 did not significantly affect the extent of protein degradation by the cellular quality control machinery. Next, we correlated predicted insertion free energies from a knowledge-based energy scale with the measured apparent free energies of TMH2 insertion. Although the predicted and apparent insertion energies showed a similar trend, the predicted free-energy changes spanned an unanticipated narrow range. By instead using a physics-based model, we obtained a broader range of free energies that agreed considerably better with the magnitude of the experimentally derived values. Nevertheless, some variants still inserted better in yeast than predicted from energy-based scales. Therefore, molecular dynamics simulations were performed and indicated that the corresponding mutations induced conformational changes within TMH2, which altered the number of stabilizing hydrogen bonds. Together, our results offer insight into the ability of the cellular quality control machinery to recognize conformationally distinct misfolded topomers, provide a model to assess TMH insertion in vivo, and indicate that TMH insertion energy scales may be limited depending on the specific protein and the mutation present.

Impact of Physical Exercise on Growth and Progression of Cancer in Rodents-A Systematic Review and Meta-Analysis.

Background: Physical exercise is suspected to reduce cancer risk and mortality. So far, little is known about the underlying mechanisms. Although limited, murine models represent a promising attempt in order to gain knowledge in this field. Objective: A systematic review and meta-analysis examining various treatment protocols was conducted in order to determine the impact of exercise on tumor growth in rodents. Methods: PubMed, Google scholar and System for information on Gray literature in Europe were screened from inception to October 2017. Risk of bias within individual studies was assessed using the Office of Health Assessment and Translation risk of bias rating tool for human and animal trials. The effect of exercise on tumor growth over and above non-exercise control was pooled using random-effects model. Subgroup analyses were conducted to identify potential moderators. Results: The quality of the included 17 articles ranged between "probably low" and "high risk of bias." A significant reduction in tumor growth in exercising animals compared to controls was detected (Hedges' g = -0.40; 95% CI -0.66 to -0.14, p < 0.01) with between-study heterogeneity (τ2 = 0.217, I 2 = 70.28%, p < 0.001). The heterogeneity was partially explained by three moderators representing the in-between group differences of "maximum daily exercise" R 2 = 33% (p < 0.01), "type of cancer administration" R 2 = 28% (p < 0.05), and "training initiation" R 2 = 27% (p < 0.05). Conclusion: This meta-analysis suggests that physical exercise leads to reduction of tumor size in rodents. Since "maximum daily exercise" was found to have at least modest impact on tumor growth, more clinical trials investigating dose-response relationships are needed.

Protein Quality Control of the Endoplasmic Reticulum and Ubiquitin-Proteasome-Triggered Degradation of Aberrant Proteins: Yeast Pioneers the Path.

Cells must constantly monitor the integrity of their macromolecular constituents. Proteins are the most versatile class of macromolecules but are sensitive to structural alterations. Misfolded or otherwise aberrant protein structures lead to dysfunction and finally aggregation. Their presence is linked to aging and a plethora of severe human diseases. Thus, misfolded proteins have to be rapidly eliminated. Secretory proteins constitute more than one-third of the eukaryotic proteome. They are imported into the endoplasmic reticulum (ER), where they are folded and modified. A highly elaborated machinery controls their folding, recognizes aberrant folding states, and retrotranslocates permanently misfolded proteins from the ER back to the cytosol. In the cytosol, they are degraded by the highly selective ubiquitin-proteasome system. This process of protein quality control followed by proteasomal elimination of the misfolded protein is termed ER-associated degradation (ERAD), and it depends on an intricate interplay between the ER and the cytosol.

Transmembrane helix hydrophobicity is an energetic barrier during the retrotranslocation of integral membrane ERAD substrates.

Integral membrane proteins fold inefficiently and are susceptible to turnover via the endoplasmic reticulum-associated degradation (ERAD) pathway. During ERAD, misfolded proteins are recognized by molecular chaperones, polyubiquitinated, and retrotranslocated to the cytoplasm for proteasomal degradation. Although many aspects of this pathway are defined, how transmembrane helices (TMHs) are removed from the membrane and into the cytoplasm before degradation is poorly understood. In this study, we asked whether the hydrophobic character of a TMH acts as an energetic barrier to retrotranslocation. To this end, we designed a dual-pass model ERAD substrate, Chimera A*, which contains the cytoplasmic misfolded domain from a characterized ERAD substrate, Sterile 6* (Ste6p*). We found that the degradation requirements for Chimera A* and Ste6p* are similar, but Chimera A* was retrotranslocated more efficiently than Ste6p* in an in vitro assay in which retrotranslocation can be quantified. We then constructed a series of Chimera A* variants containing synthetic TMHs with a range of ΔG values for membrane insertion. TMH hydrophobicity correlated inversely with retrotranslocation efficiency, and in all cases, retrotranslocation remained Cdc48p dependent. These findings provide insight into the energetic restrictions on the retrotranslocation reaction, as well as a new computational approach to predict retrotranslocation efficiency.

Effect of body mass index on operative outcome after robotic-assisted Ivor-Lewis esophagectomy: retrospective analysis of 129 cases at a single high-volume tertiary care center.

The impact of body weight on outcomes after robotic-assisted esophageal surgery for cancer has not been studied. We examined the short-term operative outcomes in patients according to their body mass index following robotic-assisted Ivor-Lewis esophagectomy at a high-volume tertiary-care referral cancer center and evaluated the safety of robotic surgery in patients with an elevated body mass index. A retrospective review of all patients who underwent robotic-assisted Ivor-Lewis esophagectomy between April 2010 and June 2013 for pathologically confirmed distal esophageal cancer was conducted. Patient demographics, clinicopathologic data, and operative outcomes were collected. We stratified body mass index at admission for surgery according to World Health Organization criteria; normal range is defined as a body mass index range of 18.5-24.9 kg/m2. Overweight is defined as a body mass index range of 25.0-29.9 kg/m2 and obesity is defined as a body mass index of 30 kg/m2 and above. Statistics were calculated using Pearson's Chi-square and Pearson's correlation coefficient tests with a P-value of 0.05 or less for significance. One hundred and twenty-nine patients (103 men, 26 women) with median age of 67 (30-84) years were included. The majority of patients, 76% (N = 98) received neoadjuvant therapy. When stratified by body mass index, 28 (22%) were normal weight, 56 (43%) were overweight, and 45 (35%) were obese. All patients had R0 resection. Median operating room time was 407 (239-694) minutes. When stratified by body mass index, medians of operating room time across the normal weight, overweight and obese groups were 387 (254-660) minutes, 395 (310-645) minutes and 445 (239-694), respectively. Median estimated blood loss (EBL) was 150 (25-600) cc. When stratified by body mass index, medians of EBL across the normal weight, overweight and obese groups were 100 (50-500) cc, 150 (25-600) cc and 150 (25-600), respectively. Obesity significantly correlated with longer operating room time (P = 0.05) but without significant increased EBL (P = 0.348). Among the three body mass index groups there was no difference in postoperative complications including thrombotic events (pulmonary embolism and deep venous thrombosis) (P = 0.266), pneumonia (P = 0.189), anastomotic leak (P = 0.090), wound infection (P = 0.390), any cardiac events (P = 0.793) or 30 days mortality (P = 0.414). Our data study demonstrates that patients with esophageal cancer and an elevated body mass index undergoing robotic-assisted Ivor-Lewis esophagectomy have increased operative times but no significantly increased EBL during the procedure. Other potential morbidities did not differ with the robotic approach.

Body Mass Index and Perioperative Complications After Esophagectomy for Cancer.

BACKGROUND: Given the increasing rate of obesity, the effects of excessive body weight on surgical outcomes constitute a relevant quality of care concern. Our aim was to determine the relationship between preoperative body mass index (BMI) on perioperative complications after esophagectomy for cancer. METHODS: From our comprehensive esophageal cancer database consisting of 510 patients, we identified 166 obese (BMI ≥30), 176 overweight (BMI 25-29), and 148 normal-weight (BMI 20-24) patients. Malnourished patients (BMI of <20) were excluded. Incidence of preoperative risk factors and perioperative complications in each group were analyzed. RESULTS: The patient group consists of 420 men and 70 women with a mean age at time of surgery were 64 years (range 28-86 years). The categories of patients (obese, overweight, and normal-weight) were similar in terms of demographics and comorbidities, with the exception of a younger age (62.5 years vs 66.2 years vs 65.3 years, P = 0.002), and a higher incidence of diabetes (23.5% vs 11.4% vs 10.1%, P = 0.001) and hiatal hernia (28.3% vs 14.8% vs 20.3%, P = 0.01) for obese patients. More patients with BMI >24 were found with adenocarcinoma, compared with the normal-weight group (90.8% vs 90.9% vs 82.5%, P = 0.03). Despite similar preoperative stage, obese patients were less likely to receive neoadjuvant treatment (47.6% vs 54.5% vs 66.2%, P = 0.004). The type of surgery performed, overall blood loss, extent of lymphadenectomy, rate of resections with negative margins, and postoperative complications were not influenced by BMI on univariate and multivariate analysis. CONCLUSIONS: In our experience, BMI did not affect number of harvested lymph-nodes, rates of negative margins, and morbidity and mortality after esophagectomy for cancer. In our experience, esophagectomy could be performed safely and efficiently in mildly obese patients.

A human factors subsystems approach to trauma care.

IMPORTANCE: A physician-centered approach to systems design is fundamental to ameliorating the causes of many errors, inefficiencies, and reliability problems. OBJECTIVE: To use human factors engineering to redesign the trauma process based on previously identified impediments to care related to coordination problems, communication failures, and equipment issues. DESIGN, SETTING, AND PARTICIPANTS: This study used an interrupted time series design to collect historically controlled data via prospective direct observation by trained observers. We studied patients from a level I trauma center from August 1 through October 31, 2011, and August 1 through October 31, 2012. INTERVENTIONS: A range of potential solutions based on previous observations, trauma team engagement, and iterative cycles identified the most promising subsystem interventions (headsets, equipment storage, medication packs, whiteboard, prebriefing, and teamwork training). Five of the 6 subsystem interventions were successfully deployed. Communication headsets were found to be unsuitable in simulation. MAIN OUTCOMES AND MEASURES: The primary outcome measure was flow disruptions, with treatment time and length of stay as secondary outcome measures. RESULTS: A total of 86 patients were observed before the intervention and 120 after the intervention. Flow disruptions increased if the patient had undergone computed tomography (CT) (F1200 = 20.0, P < .001) and had been to the operating room (F1200 = 63.1, P < .001), with an interaction among the intervention, trauma level, and CT (F1200 = 6.50, P = .01). For total treatment time, there was an effect of the intervention (F1200 = 21.7, P < .001), whether the patient had undergone CT (F1200 = 43.0, P < .001), and whether the patient had been to the operating room (F1200 = 85.8, P < .001), with an interaction among the intervention, trauma level, and CT (F1200 = 15.1, P < .001), reflecting a 20- to 30-minute reduction in time in the emergency department. Length of stay was reduced significantly for patients with major mortality risk (P = .01) from a median of 8 to 5 days. CONCLUSIONS AND RELEVANCE: Deployment of complex subsystem interventions based on detailed human factors engineering and a systems analysis of the provision of trauma care resulted in reduced flow disruptions, treatment time, and length of stay.

Single-institution retrospective comparison of preoperative versus definitive chemoradiotherapy for adenocarcinoma of the esophagus.

PURPOSE: We sought to determine the impact of esophagectomy on survival in patients with adenocarcinoma of the esophagus cancer after chemoradiotherapy (CRT). METHODS: A database of esophageal cancer was queried for nonmetastatic patients with adenocarcinoma treated between 2000 and 2011 with CRT. Overall survival (OS) and recurrence-free survival (RFS) curves were calculated according to the Kaplan-Meier method and log-rank analysis. Multivariate analysis was performed by the Cox proportional hazard model. RESULTS: We identified 154 patients (60 without surgery; 94 with surgery) who were included in the analysis. The only differences between the 2 groups were more advanced disease stage, improved performance status, and younger age in the surgery group. Patients undergoing surgery had significantly higher survival. Median and 5-year OS for surgical patients were 4.1 years and 43.6 %, versus 1.9 years and 35.6 % for nonsurgical patients (p = 0.007). Multivariate analysis for OS and RFS revealed that factors associated with increased survival were surgical resection, tumor length < 5 cm, male gender, and lower stage. Age, tumor location, radiation dose/technique, and induction chemotherapy were not prognostic. There was a trend toward improved survival on univariate analysis (p = 0.10) and multivariate analysis (p = 0.063) for surgical patients compared to nonsurgical patients who were healthy enough for surgery before CRT (n = 38), and no difference in OS in nonsurgical patients healthy enough for surgery after CRT (n = 22). CONCLUSION: Esophagectomy after CRT is associated with improved survival in patients with adenocarcinoma after CRT. Trimodal therapy should continue to remain the standard of care for esophageal adenocarcinoma.

Flow disruptions during trauma care.

BACKGROUND: Flow disruptions (FDs) are deviations from the progression of care that compromise safety or efficiency. The frequency and specific causes of FDs remain poorly documented in trauma care. We undertook this study to identify and quantify the rate of FDs during various phases of trauma care. METHODS: Seven trained observers studied a Level I trauma center over 2 months. Observers recorded details on FDs using a validated Tablet-PC data collection tool during various phases of care-trauma bay, imaging, operating room (OR)-and recorded work-system variables including breakdowns in communication and coordination, environmental distractions, equipment issues, and patient factors. RESULTS: Researchers observed 86 trauma cases including 72 low-level and 14 high-level activations. Altogether, 1,759 FDs were recorded (20.4/case). High-level trauma comprised a significantly higher number (p = 0.0003) and rate of FDs (p = 0.0158) than low-level trauma. Across the three phases of trauma care, there was a significant effect on FD number (p < 0.0001) and FD rate (p = 0.0005), with the highest in the OR, followed by computed tomography. The highest rates of FD per case and per hour were related to breakdowns in coordination. CONCLUSIONS: This study is the largest direct observational study of the trauma process conducted to date. Complexities associated with the critical patient who arrives in the trauma bay lead to a high prevalence of disruptions related to breakdowns in coordination, communication, equipment issues, and environmental factors. Prospective observation allows individual hospitals to identify and analyze these systemic deficiencies. Appropriate interventions can then be evaluated to streamline the care provided to trauma patients.

Extent of lymphadenectomy does not predict survival in patients treated with primary esophagectomy.

BACKGROUND: The number of lymph nodes resected and its impact on survival for patients with esophageal cancer remains undefined. Current guidelines recommend extended lymphadenectomy in patients not receiving neoadjuvant therapy. We reviewed our single institutional experience with nodal harvest for esophageal cancer in a non-neoadjuvant therapy setting. METHODS: Patients who underwent esophagectomy as primary therapy were indentified from a prospectively maintained database consisting of 704 patients who underwent esophagectomy. Patients were stratified by number of lymph nodes (LN) resected: >5, 10, 12, 15, or 20. Survival, clinical, and pathologic parameters were analyzed with Kaplan-Meier curves, chi-square, or Fisher's exact tests where appropriate. RESULTS: We identified 246 patients who underwent esophagectomy as initial treatment. The mean age was 65 ±10 years. The majority of patients were male (87%). Ivor-Lewis esophagectomy was performed for 71%, minimally invasive esophagectomy for 15%, transhiatal esophagectomy for 12%, and three-field esophagectomy for 2%. At 60 months follow-up, there was no statistically significant difference in overall survival (OS) or disease-free survival (DFS) between patients with < vs. >5 LN resected (p = 0.74 and p = 0.67, respectively) or in the < vs. >10 (p = 0.33, p = 0.11), 12 (p = 0.82, p = 0.90), 15 (p = 0.45, p = 0.79), or 20 (p = 0.72, p = 0.86) resected LN groups. Patients were then subdivided into node-positive and node-negative cohorts and stratified by nodal harvest. In the subgroups of patients with node-negative and node-positive disease, OS and DFS also did not significantly differ between groups with respect to number of nodes resected (p > 0.05). A total of 49 (20%) patients developed recurrent disease; however, recurrence was not statistically associated with number of LN resected (p > 0.05). CONCLUSION: We found no impact of extent of lymphadenectomy on overall or disease-free survival in patients treated with esophagectomy without neoadjuvant therapy. In addition, the number of nodes resected at esophagectomy did not affect recurrence rates. Current recommendations for increased nodal resection during esophagectomy in patients not receiving neoadjuvant therapy may not improve patient outcomes, and this phenomenon warrants further investigation.

Plasma vitamin C, but not vitamin E, is associated with reduced risk of heart failure in older men.

BACKGROUND: Oxidative stress has been implicated in the pathogenesis of heart failure (HF). However, data on the association between antioxidant intakes and circulating levels and risk of incident HF in the older general population are limited. We have examined prospectively the associations between plasma vitamin C and E, dietary intakes of vitamin C and E, and incident HF. METHODS AND RESULTS: Prospective study of 3919 men aged 60 to 79 years with no prevalent HF followed up for a mean period of 11 years, in whom there were 263 cases with incident HF. Higher plasma vitamin C level was associated with significantly lower risk of incident HF in both men with and without previous myocardial infarction after adjustment for lifestyle characteristics, diabetes mellitus, blood lipids, blood pressure, and heart rate (hazards ratio [95% confidence interval], 0.81 [0.70, 0.93] and 0.75 [0.59, 0.97] for 1 SD increase in log vitamin C, respectively). Plasma vitamin E and dietary vitamin C intake showed no association with HF. High levels of dietary vitamin E intake (which correlated weakly with plasma vitamin E) were associated with increased risk of HF in men with no previous myocardial infarction even after adjustment (adjusted hazards ratio [95% confidence interval], 1.23 [1.06, 1.42] for 1 SD increase). CONCLUSIONS: Higher plasma vitamin C is associated with a reduced risk of HF in older men with and without myocardial infarction. High intake of dietary vitamin E may be associated with increased HF risk. Primary intervention trials assessing the effect of vitamin C supplements on HF risk in the elderly are needed.

Adjuvant radiation therapy and lymphadenectomy in esophageal cancer: a SEER database analysis.

OBJECTIVES: This study seeks to determine the effects of postoperative radiation therapy and lymphadenectomy on survival in esophageal cancer. METHODS: An analysis of patients with surgically resected esophageal cancer from the SEER database between 2004 and 2008 was performed to determine association of adjuvant radiation and lymph node dissection on survival. Survival curves were calculated according to the Kaplan-Meier method and log-rank analysis. Multivariate analysis (MVA) was performed by the Cox proportional hazard model. RESULTS: We identified 2109 patients who met inclusion criteria. Radiation was associated with increased survival in stage III patients (p = 0.005), no benefit in stage II (p = 0.075) and IV (p = 0.913) patients, and decreased survival in stage I patients (p < 0.0001). Univariate analysis revealed that radiation therapy was associated with a survival benefit node positive (N1) patients while it was associated with a detriment in survival for node negative (N0) patients. Removing >12 and >15 lymph nodes was associated with increased survival in N0 patients, while removing >8, >10, >12, >15, and >20 lymph nodes was associated with a survival benefit in N1 patients. MVA revealed that age, gender, tumor and nodal stage, tumor location, and number of lymph nodes removed were prognostic for survival in N0 patients. In N1 patients, MVA showed the age, tumor stage, number of lymph nodes removed, and radiation were prognostic for survival. CONCLUSION: The number of lymph nodes removed in esophageal cancer is associated with increased survival. The benefit of adjuvant radiation therapy on survival in esophageal cancer is limited to N1 patients.

Body mass index and perioperative complications after oesophagectomy for adenocarcinoma: a systematic database review.

OBJECTIVE: Given the increasing rate of obesity, the effects of excessive body weight on surgical outcomes constitute a relevant quality of care concern. Our aim was to determine the relationship between preoperative body mass index (BMI) on perioperative complications after oesophagectomy for adenocarcinoma of the oesophagus. DESIGN: Retrospective database review. SETTING: Single institution high volume oncological tertiary care referral centre. PARTICIPANTS: From our comprehensive oesophageal cancer database consisting of 709 patients, we stratified patients according to BMI: 155 normal-weight (BMI 20-24), 198 overweight (BMI 25-29) and 187 obese (BMI ≥30) patients. INTERVENTIONS: All patients underwent oesophagectomy for cancer. PRIMARY AND SECONDARY OUTCOME MEASURES: Incidences of preoperative risk factors and perioperative complications in each group were analysed. RESULTS: The patient cohort consisted of 474 men and 66 women with a mean age of 64.3 years (28-86). They were similar in terms of demographics and comorbidities, with the exception of a younger age (65.2 vs 65.4 vs 62.5 years, p=0.0094), and a higher incidence of diabetes (9.1% vs 13.2% vs 22.7%, p=0.001), hiatal hernia (16.8% vs 17.8% vs 28.8%, p=0.009) and Barrett oesophagus (24.7% vs 25.4% vs 36.2%, p=0.025) for obese patients. The type of surgery performed, overall blood loss, extent of lymphadenectomy, R0 resections and complications were not influenced by BMI on univariate and multivariate analysis. CONCLUSIONS: In our experience, patients with an elevated BMI and oesophageal adenocarcinoma do not experience an increase in morbidity and mortality after oesophagectomy as stated in previous reports, when performed at a high volume centre. Additionally, BMI did not affect the quality of oncological resection as determined by number of harvested lymph-nodes and rates of R0 resections. TRIAL REGISTRATION: MCC 15030, IRB 105286.

Defining the learning curve for robotic-assisted esophagogastrectomy.

INTRODUCTION: The expansion of robotic-assisted surgery is occurring quickly, though little is generally known about the "learning curve" for the technology with utilization for complex esophageal procedures. The purpose of this study is to define the learning curve for robotic-assisted esophagogastrectomy with respect to operative time, conversion rates, and patient safety. METHODS: We have prospectively followed all patients undergoing robotic-assisted esophagogastrectomy and compared operations performed at our institutions by a single surgeon in successive cohorts of 10 patients. Our measures of proficiency included: operative times, conversion rates, and complications. Statistical analyses were undertaken utilizing Spearman regression analysis and Mann-Whitney U test. Significance was accepted with 95 % confidence. RESULTS: Fifty-two patients (41 male: 11 female) of mean age 66.2 ± 8.8 years underwent robotic-assisted esophagogastrectomies for malignant esophageal disease. Neoadjuvant chemoradiation was administered to 30 (61 %) patients. A significant reduction in operative times (p <0.005) following completion of 20 procedures was identified (514 ± 106 vs. 397 ± 71.9). No conversions to open thoracotomy were required. Complication rates were low and not significantly different between any 10-patient cohort; however, no complications occurred in the final 10-patient cohort. There were no in-hospital mortalities. CONCLUSIONS: For surgeons proficient in performing minimally-invasive esophagogastrectomies, the learning curve for a robotic-assisted procedure appears to begin near proficiency after 20 cases. Operative complications and conversions were infrequent and unchanged across successive 10-patient cohorts.

Initial experience from a large referral center with robotic-assisted Ivor Lewis esophagogastrectomy for oncologic purposes.

BACKGROUND: We report our initial experience of patients undergoing robotic-assisted Ivor Lewis esophagogastrectomy (RAIL) for oncologic purposes at a large-referral center. METHODS: A retrospective review of all consecutive patients undergoing RAIL from 2010-2011 was performed. Basic demographics were recorded. Oncologic variables recorded included: tumor type, location, postoperative tumor margins, and nodal harvest. Immediate 30-day postoperative complications also were analyzed. RESULTS: Fifty patients underwent RAIL with median age of 66 (range 42-82) years. The mean body mass index was 28.6 ± 0.7 kg/m(2); 54% and the majority had an American Society of Anesthesiologists classification of 3. The mean and median number of lymph nodes retrieved during surgery was 20 ± 1.4 and 18.5 respectively. R0 resections were achieved in all patients. Postoperative complications occurred in 14 (28%) patients, including atrial fibrillation in 5 (10%), pneumonia in 5 (10%), anastomotic leak in 1 (2%), conduit staple line leak in 1 (2%), and chyle leak in 2 (4%). The median ICU stay and length of hospitalization (LOH) were 2 and 9 days respectively. Total mean operating time calculated from time of skin incision to wound closure was 445 ± 85 minutes; however, operative times decreased over time. Similarly, there was a trend toward lower complications after the first 29 cases but this did not reach statistical significance. There were no in-hospital mortalities. CONCLUSIONS: We demonstrated that RAIL for esophageal cancer can be performed safely and may be associated with fewer complications after a learning curve, shorter ICU stay, and LOH.

Minimally invasive surgery for esophageal cancer: review of the literature and institutional experience.

BACKGROUND: Esophageal cancer represents a major public health problem in the world. Several minimally invasive esophagectomy (MIE) techniques have been described and represent a safe alternative for the surgical management of esophageal cancer in selected centers with high volume and surgeons experienced in minimally invasive procedures. METHODS: The authors reviewed the most recent and largest studies published in the medical literature that reported the outcomes for MIE techniques. RESULTS: In larger series, MIE has proven to be equivalent in postoperative morbidity and mortality to the open esophagectomy. However, MIE has been associated with less blood loss, reduced postoperative pain, decreased time in the intensive care unit, and shortened length of hospital stay compared with the conventional open approaches. Despite limited data, no significant difference in survival stage for stage has been observed between open esophagectomy and MIE. CONCLUSIONS: The myriad of MIE techniques complicates the debate for defining the optimal surgical approach for the treatment of esophageal cancer. Randomized controlled trials comparing MIE with conventional open esophagectomy are needed to clarify the ideal procedure with the lowest postoperative morbidity, best quality of life after surgery, and long-term survival.

The impact of body mass index on esophageal cancer.

BACKGROUND: Surgeons are increasingly operating on patients who are overweight or obese. The influence of obesity on surgical and oncologic outcomes has only recently been addressed. We focus this review on obesity and its impact on esophageal cancer. METHODS: Recent literature and our own institutional experience were reviewed to determine the impact of body mass index on the perioperative and long-term outcomes of patients with esophageal cancer. RESULTS: With few exceptions, no significant differences were seen in perioperative outcomes or survival in patients treated for esophageal cancer when stratified by body mass index. CONCLUSIONS: Although obesity poses increased operative challenges to the surgeon, surgical and oncologic outcomes remain unchanged in obese patients compared with patients who are not obese.

Lymph node harvest in esophageal cancer after neoadjuvant chemoradiotherapy.

BACKGROUND: This study was designed to determine the effects of lymph node (LN) harvest on survival in esophageal cancer after neoadjuvant chemoradiation (nCRT). METHODS: An analysis of surgically resected esophageal cancer patients after nCRT was performed to determine an association between the number of LNs resected and survival. Overall survival (OS) and disease-free survival (DFS) curves were calculated according to the Kaplan-Meier method and log-rank analysis. Multivariate analysis (MVA) was performed by the Cox proportional hazard model. RESULTS: We identified 358 patients with a mean follow-up of 27.3 months. The number of LN removed was not impacted by the type of surgical procedure. The number of LNs removed (<10 vs. ≥10, <12 vs. ≥12, and <15 vs. ≥15) did not impact OS or DFS. We found a significant difference in OS and DFS by pathologic response. The median and 5-year OS for patients with complete, partial, and no response was 65.6 months and 52.7%, 29.7 months and 30.4%, and 17.7 months and 25.4% (p=0.0002). However, the number of LN harvested did not impact OS and DFS when patients were stratified by pathologic response. MVA also revealed that the number of lymph nodes removed was not prognostic for OS or DFS. Higher age, higher stage, and less than a complete response were associated with a decreased OS. Higher stage and less than a complete response were prognostic for worse DFS. CONCLUSIONS: The number of LNs harvested during esophagectomy does not impact survival after nCRT. Stage and pathologic response continue to be the strongest prognostic factors for survival in esophageal cancer after nCRT.

Outcomes associated with surgery for T4 esophageal cancer.

BACKGROUND: T4 esophageal cancer often portends a dismal prognosis even after surgical resection. Historical incomplete resections and poor survival rates often make surgery palliative rather than curative. METHODS: Using a comprehensive esophageal cancer database, we identified patients who underwent an esophagectomy for T4 tumors between 1994 and 2011. Neoadjuvant treatment (NT) and pathologic response variables were recorded, and response was denoted as complete response (pCR), partial response (pPR), and nonresponse (NR). Clinical and pathologic data were compared. Survival was calculated using Kaplan-Meier curves with log-rank tests for significance. RESULTS: We identified 45 patients with T4 tumors all who underwent NT. The median age was 60 years (range, 31-79 years) with a median follow-up of 27 months (range, 0-122 months). There were 19 pCR (42 %), 22 pPR (49 %), and 4 NR (9 %). R0 resections were accomplished in 43 (96 %). There were 18 recurrences (40 %) with a median time to recurrence of 13.5 months (2.2-71 months). In this group pCR represented 7 (38.9 %), whereas pPR and NR represented 10 (55.5 %), and 1 (5.5 %) respectively. The overall and disease-free survival for all patients with T4 tumors were 35 and 36 %, respectively. Patients achieving a pCR had a 5 year overall and disease-free survival of 53 and 54 %, compared with pPR 23 and 28 %, while there were no 5 year survivors in the NR cohort. CONCLUSION: We have demonstrated that neoadjuvant therapy and downstaging of T4 tumors leads to increased R0 resections and improvements in overall and disease-free survival.