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.

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.

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.

Lack of tailless leads to an increase in expression variability in Drosophila embryos.

Developmental processes are robust, or canalised: dynamic patterns of gene expression across space and time are regulated reliably and precisely in the presence of genetic and environmental perturbations. It remains unclear whether canalisation relies on specific regulatory factors (such as heat-shock proteins), or whether it is based on more general redundancy and distributed robustness at the network level. The latter explanation implies that mutations in many regulatory factors should exhibit loss of canalisation. Here, we present a quantitative characterisation of segmentation gene expression patterns in mutants of the terminal gap gene tailless (tll) in Drosophila melanogaster. Our analysis provides new insights into the dynamic mechanisms underlying gap gene regulation, and reveals significantly increased variability of gene expression in the mutant compared to the wild-type background. We show that both position and timing of posterior segmentation gene expression domains vary strongly from embryo-to-embryo in tll mutants. This variability must be caused by a vulnerability in the regulatory system which is hidden or buffered in the wild-type, but becomes uncovered by the deletion of tll. Our analysis provides evidence that loss of canalisation in mutants could be more widespread than previously thought.

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.

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.

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.

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.

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.

Pathologic nonresponders after neoadjuvant chemoradiation for esophageal cancer demonstrate no survival benefit compared with patients treated with primary esophagectomy.

BACKGROUND: Neoadjuvant chemoradiation (NCRT) has become the preferred treatment for patients with locally advanced esophageal cancer. Survival often is correlated to degree of pathologic response; however, outcomes in patients who are found to be pathologic nonresponders (pNR) remain uninvestigated. This study was designed to evaluate survival in pNR to NCRT compared with patients treated with primary esophagectomy (PE). METHODS: Using our comprehensive esophageal cancer database, we identified patients treated with NCRT and deemed pNR along with patients who proceeded to PE. Clinical and pathologic data were compared using Fisher's exact and χ(2), whereas Kaplan-Meier estimates were used for survival analysis. RESULTS: We identified 63 patients treated with NCRT and were found to have a pNR, and 81 patients who underwent PE. Disease-free (DFS) and overall survival (OS) were significantly decreased in the pNR group compared with those treated with PE (10 vs. 50 months (0-152), P < 0.001 and 13 vs. 50 months (0-152), P < 0.001, respectively). For patients with stage II disease, DFS and OS were similarly decreased in pathologic nonresponders (13 vs. 62 months (0-120), P < 0.001 and 31 vs. 62 months (0-120), P = 0.024, respectively). There were no differences in DFS or OS for patients with stage III disease (10 vs. 14 months (0-152), P = 0.29 and 10 vs. 19 months (0-152), P = 0.16, respectively). CONCLUSIONS: Pathologic nonresponders to NCRT for esophageal cancer receive no benefit in DFS or OS compared with patients treated with PE. For patients with stage II disease, DFS and OS are, in fact, significantly decreased in the pNR.

An elevated body mass index does not reduce survival after esophagectomy for cancer.

BACKGROUND: Incidences of esophageal cancer and obesity are both rising in the United States. The aim of this study was to determine the influence of elevated body mass index on outcomes after esophagectomy for cancer. METHODS: Overall and disease-free survivals in obese (BMI ≥ 30), overweight (BMI 25-29), and normal-weight (BMI 20-24) patients undergoing esophagectomy constituted the study end points. Survivals were calculated by the Kaplan-Meier method, and differences were analyzed by log rank method. RESULTS: The study included 166 obese, 176 overweight, and 148 normal-weight patients. These three groups were similar in terms of demographics and comorbidities, with the exception of younger age (62.5 vs. 66.2 vs. 65.3 years, P = 0.002), and 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) in obese patients. Rates of adenocarcinoma histology were higher in obese patients (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). Response to neoadjuvant treatment, type of surgery performed, extent of lymphadenectomy, rate of R0 resections, perioperative complications, and administration of adjuvant chemotherapy were not influenced by BMI. At a median follow-up of 25 months, 5-year overall and disease-free survivals were longer in obese patients (respectively, 48, 41, 34%, P = 0.01 and 48, 44, 34%, P = 0.01). CONCLUSIONS: In our experience, an elevated BMI did not reduce overall and disease-free survivals after esophagectomy for cancer.

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.

Pathologic response after neoadjuvant therapy is the major determinant of survival in patients with esophageal cancer.

BACKGROUND: Esophageal cancer remains a malignancy with high morbidity and mortality despite improvements to diagnosis, staging, chemotherapy, radiation, and surgery. Neoadjuvant therapy (NT) may improve oncologic outcome in many patients, however the degree to which patients benefit remains unclear. We examined the relationship between pathologic response to NT and magnitude of benefit in patients with esophageal cancer. METHODS: Using a comprehensive esophageal cancer database, we identified patients who underwent esophagectomy between 1994 and 2008. Pathologic response was denoted as complete (pCR), partial (pPR), and nonresponse (NR). Clinical and pathologic data were compared using Fisher's exact and chi-square when appropriate, while Kaplan-Meier estimates were used for survival analysis. RESULTS: We identified 347 patients who underwent esophagectomy, and 262 (75.5%) were treated with NT. The median age was 66 years (28-86 years) with median follow-up of 20 months (1-177 months). There were 106 (40.5%) patients exhibiting pCR, 95 (36.3%) with pPR, and 61 (23.3%) with NR. The rate of R0 resections was higher amongst pCR (100%) compared with 94.7% in pPR (P = 0.02) and 87.5% in NR (P = 0.0007). There were 15 (14.2%) recurrences in pCR, 22 (23.7%) in pPR, and 17 (28.8%) in NR (P = 0.04). Patients achieving pCR had 5-year disease-free survival (DFS) and overall survival (OS) of 52% and 52%, respectively, compared with 36% and 38% in pPR and 22% and 19% in NR (P < 0.0001, P < 0.0001). CONCLUSIONS: Esophageal cancer patients frequently succumb to their disease. However, patients treated with neoadjuvant therapy who achieve pCR have a higher rate of R0 resections, fewer recurrences, and improved 5-year OS and DFS.

Correlations between neoadjuvant treatment, anemia, and perioperative complications in patients undergoing esophagectomy for cancer.

INTRODUCTION: The influence of preoperative hemoglobin levels on outcomes of patients undergoing esophagectomy for cancer is not clearly defined. The goal of this article was to explore the association between combined modality therapy, preoperative anemia status, and perioperative blood transfusion and risk of postoperative complications among patients undergoing esophageal resection. METHODS: From a retrospective esophageal database, 413 patients were identified. Anemia was defined according to the World Health Organization classification of <13 g/dL or <12 g/dL for men or women, respectively. Statistical analysis was performed with analysis of variance, Pearson's chi(2), or Fisher exact test as appropriate. The independent association of anemia, blood transfusion, and combined modality treatment on risk of postoperative complications were examined using multiple logistic regression. RESULTS: Information on combined modality treatment, preoperative hemoglobin levels, and blood transfusion was available for 413 patients, of whom 57% received combined modality treatment. Overall 197 (47.6%) patients were preoperatively found to be anemic, and those who had received combined modality treatment were more likely to be anemic (60.6% versus 30.7%, P < 0.001). Anemic patients required more blood transfusions than nonanemic patients (46.7% versus 29.6%, P < 0.001). Seventy-five percent of patients who required transfusion during the hospital stay had received combined modality treatment (P = 0.01). Combined modality treatment and anemia were not associated with increased risk of complications. Patients with any perioperative complication and surgical site infections were more likely to have received blood transfusion compared to patients without complications (OR = 1.73; 95% CI 1.04-2.87 and OR = 2.98; 95% CI 1.04-8.55; respectively). CONCLUSIONS: Overall, we determined that administration of neoadjuvant treatment to esophageal cancer patients was not associated with an increased rate of perioperative complications. Preoperative anemia did not predict worsened short-term outcomes, but increased the chances of red blood cell transfusion, which were significantly associated with higher overall complications and increased risk of surgical site infections. These data confirm previous studies that allogenic red blood cell transfusions are independent risk factors for increased morbidity and mortality and should be minimized during surgery for esophageal cancer.

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.

Outcomes following resection of pancreatic adenocarcinoma: 20-year experience at a single institution.

BACKGROUND: Pancreatectomy for ductal adenocarcinoma has been performed with increasing frequency since the late 1980s as postoperative mortality decreased and long-term survival became more common. However, the belief persists among some clinicians that pancreatectomy offers little survival benefit. This report reviews our institutional experience with pancreatectomy for pancreatic adenocarcinoma and provides a critical overview of the controversies regarding the benefits of surgical intervention for patients who are candidates for curative resection. METHODS: We determined the survival of 142 patients who underwent pancreatectomy for ductal adenocarcinoma with curative intent (stage IA-IIB) at Moffitt Cancer Center during the last two decades by using data obtained from review of the medical record, the Moffitt Cancer Registry, and the Social Security Death Index. Histologic diagnosis was confirmed by expert review of stained sections cut from fixed surgical specimens. RESULTS: In the 137 patients who survived at least 30 days after surgery, the median survival was 21.2 months after resection, with Kaplan-Meier 3- and 5-year disease-specific survival rates of 36% and 32%, respectively. One patient has survived without evidence of recurrent disease for more than 15 years after pancreatectomy. Survival for patients greater than 75 year of age did not differ from that of younger patients. The postoperative mortality rate was 1.5% during the most recent years of highest operative volume (2003 to 2006) and 3.5% for the entire patient cohort. CONCLUSIONS: Review of our 20-year experience with resection of pancreatic adenocarcinoma indicates that pancreatectomy with curative intent offers a real chance of long-term survival to patients with this highly lethal disease for which there is no other curative modality.

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.