Oesophagectomy: The expanding role of minimally invasive surgery in oesophageal cancer.

Historically, open oesophagectomy was the gold standard for oesophageal cancer surgery. This was associated with a relatively higher morbidity. In the last two decades, we have seen significant improvements in short and long term outcomes due to centralisation of oesophagectomy, multidisciplinary approach, enhanced recovery after surgery programmes, neoadjuvant treatments and advances in minimally invasive oesophagectomy (MIO) techniques. MIO has significantly reduced postoperative morbidity and improved functional recovery, while maintaining comparable long-term oncological outcomes. MIO is technically demanding, and requires a long learning curve. However, it has been proven to be safe and successful in expert centres. This is a review on the current role of MIO in the management of oesophageal cancer.

Worldwide Esophageal Cancer Collaboration: pathologic staging data.

We report data-simple descriptions of patient characteristics, cancer categories, and non-risk-adjusted survival-for patients with pathologically staged cancer of the esophagus and esophagogastric junction after resection or ablation with no preoperative therapy from the Worldwide Esophageal Cancer Collaboration (WECC). Thirty-three institutions from six continents submitted de-identified data using standard definitions: demographics, comorbidities, clinical cancer categories, and all-cause mortality from first management decision. Of 13,300 patients, 5,631 had squamous cell carcinoma, 7,558 adenocarcinoma, 85 adenosquamous carcinoma, and 26 undifferentiated carcinoma. Patients were older (62 years) men (80%) with normal body mass index (51%), little weight loss (1.8 kg), 0-2 ECOG performance status (83%), and a history of smoking (70%). Cancers were pT1 (24%), pT2 (15%), pT3 (50%), pN0 (52%), pM0 (93%), and pG2-G3 (78%); most involved distal esophagus (71%). Non-risk-adjusted survival for both squamous cell carcinoma and adenocarcinoma was monotonic and distinctive across pTNM. Survival was more distinctive for adenocarcinoma than squamous cell carcinoma when pT was ordered by pN. Survival for pTis-1 adenocarcinoma was better than for squamous cell carcinoma, although monotonic and distinctive for both. WECC pathologic staging data is improved over that of the 7th edition, with more patients studied and patient and cancer variables collected. These data will be the basis for the 8th edition cancer staging manuals following risk adjustment for patient, cancer, and treatment characteristics, and should direct 9th edition data collection. However, the role of pure pathologic staging as the principal point of reference for esophageal cancer staging is waning.

Worldwide Esophageal Cancer Collaboration: clinical staging data.

To address uncertainty of whether clinical stage groupings (cTNM) for esophageal cancer share prognostic implications with pathologic groupings after esophagectomy alone (pTNM), we report data-simple descriptions of patient characteristics, cancer categories, and non-risk-adjusted survival-for clinically staged patients from the Worldwide Esophageal Cancer Collaboration (WECC). Thirty-three institutions from six continents submitted data using variables with standard definitions: demographics, comorbidities, clinical cancer categories, and all-cause mortality from first management decision. Of 22,123 clinically staged patients, 8,156 had squamous cell carcinoma, 13,814 adenocarcinoma, 116 adenosquamous carcinoma, and 37 undifferentiated carcinoma. Patients were older (62 years) men (80%) with normal body mass index (18.5-25 mg/kg2 , 47%), little weight loss (2.4 ± 7.8 kg), 0-1 ECOG performance status (67%), and history of smoking (67%). Cancers were cT1 (12%), cT2 (22%), cT3 (56%), cN0 (44%), cM0 (95%), and cG2-G3 (89%); most involved the distal esophagus (73%). Non-risk-adjusted survival for squamous cell carcinoma was not distinctive for early cT or cN; for adenocarcinoma, it was distinctive for early versus advanced cT and for cN0 versus cN+. Patients with early cancers had worse survival and those with advanced cancers better survival than expected from equivalent pathologic categories based on prior WECC pathologic data. Thus, clinical and pathologic categories do not share prognostic implications. This makes clinically based treatment decisions difficult and pre-treatment prognostication inaccurate. These data will be the basis for the 8th edition cancer staging manuals following risk adjustment for patient characteristics, cancer categories, and treatment characteristics and should direct 9th edition data collection.

Worldwide Esophageal Cancer Collaboration: neoadjuvant pathologic staging data.

To address uncertainty of whether pathologic stage groupings after neoadjuvant therapy (ypTNM) for esophageal cancer share prognostic implications with pathologic groupings after esophagectomy alone (pTNM), we report data-simple descriptions of patient characteristics, cancer categories, and non-risk-adjusted survival-for pathologically staged cancers after neoadjuvant therapy from the Worldwide Esophageal Cancer Collaboration (WECC). Thirty-three institutions from six continents submitted data using variables with standard definitions: demographics, comorbidities, clinical cancer categories, and all-cause mortality from first management decision. Of 7,773 pathologically staged neoadjuvant patients, 2,045 had squamous cell carcinoma, 5,686 adenocarcinoma, 31 adenosquamous carcinoma, and 11 undifferentiated carcinoma. Patients were older (61 years) men (83%) with normal (40%) or overweight (35%) body mass index, 0-1 Eastern Cooperative Oncology Group performance status (96%), and a history of smoking (69%). Cancers were ypT0 (20%), ypT1 (13%), ypT2 (18%), ypT3 (44%), ypN0 (55%), ypM0 (94%), and G2-G3 (72%); most involved the distal esophagus (80%). Non-risk-adjusted survival for yp categories was unequally depressed, more for earlier categories than later, compared with equivalent categories from prior WECC data for esophagectomy-alone patients. Thus, survival of patients with ypT0-2N0M0 cancers was intermediate and similar regardless of ypT; survival for ypN+ cancers was poor. Because prognoses for ypTNM and pTNM categories are dissimilar, prognostication should be based on separate ypTNM categories and groupings. These data will be the basis for the 8th edition cancer staging manuals following risk adjustment for patient, cancer, and treatment characteristics and should direct 9th edition data collection.

A novel dual ex vivo lung perfusion technique improves immediate outcomes in an experimental model of lung transplantation.

The lungs are dually perfused by the pulmonary artery and the bronchial arteries. This study aimed to test the feasibility of dual-perfusion techniques with the bronchial artery circulation and pulmonary artery circulation synchronously perfused using ex vivo lung perfusion (EVLP) and evaluate the effects of dual-perfusion on posttransplant lung graft function. Using rat heart-lung blocks, we developed a dual-perfusion EVLP circuit (dual-EVLP), and compared cellular metabolism, expression of inflammatory mediators, and posttransplant graft function in lung allografts maintained with dual-EVLP, standard-EVLP, or cold static preservation. The microvasculature in lung grafts after transplant was objectively evaluated using microcomputed tomography angiography. Lung grafts subjected to dual-EVLP exhibited significantly better lung graft function with reduced proinflammatory profiles and more mitochondrial biogenesis, leading to better posttransplant function and compliance, as compared with standard-EVLP or static cold preservation. Interestingly, lung grafts maintained on dual-EVLP exhibited remarkably increased microvasculature and perfusion as compared with lungs maintained on standard-EVLP. Our results suggest that lung grafts can be perfused and preserved using dual-perfusion EVLP techniques that contribute to better graft function by reducing proinflammatory profiles and activating mitochondrial respiration. Dual-EVLP also yields better posttransplant graft function through increased microvasculature and better perfusion of the lung grafts after transplantation.

A multicenter phase II study of cetuximab in combination with chest radiotherapy and consolidation chemotherapy in patients with stage III non-small cell lung cancer.

BACKGROUND: Cetuximab has demonstrated improved efficacy in combination with chemotherapy and radiotherapy. We evaluated the integration of cetuximab in the combined modality treatment of stage III non-small cell lung cancer (NSCLC). METHODS: Patients with surgically unresectable stage IIIA or IIIB NSCLC were treated with chest radiotherapy, 73.5 Gy (with lung and tissue heterogeneity corrections) in 35 fractions/7 weeks, once daily (63 Gy without heterogeneity corrections). Cetuximab was given weekly during radiotherapy and continued during consolidation therapy with carboplatin and paclitaxel up to a maximum of 26 weekly doses. The primary endpoint was overall survival. Baseline tumor tissue was analyzed for EGFR by fluorescence in situ hybridization (FISH). RESULTS: Forty patients were enrolled in this phase II study. The median overall survival was 19.4 months and the median progression-free survival 9.3 months. The best overall response rate in 31 evaluable patients was 67%. No grade 3 or 4 esophagitis was observed. Three patients experienced grade 3 rash; 16 patients (69%) developed grade 3/4 neutropenia during consolidation therapy. One patient died of pneumonitis, possibly related to cetuximab. EGFR gene copy number on baseline tumor tissues, analyzed by FISH, was not predictive of efficacy outcomes. CONCLUSIONS: The addition of cetuximab to chest radiotherapy and consolidation chemotherapy was tolerated well and had modest efficacy in stage III NSCLC. Taken together with the lower incidence of esophagitis, our results support evaluation of targeted agents instead of chemotherapy with concurrent radiotherapy in this setting.

Lung T-cell subset composition at the time of surgical resection is a prognostic indicator in non-small cell lung cancer.

NSCLC arises in the complex environment of chronic inflammation. Depending on lung immune polarization, infiltrating immune cells may either promote or suppress tumor growth. Despite the importance of the immune microenvironment, current staging techniques for NSCLC do not take into consideration the immune milieu in which the neoplasms arise. T-cell subset content was compared between paired tumor-bearing and contralateral lungs, patient and control peripheral blood. The relationship between T-cell subset distribution and survival were evaluated. CD4 and CD8+ T cells were subsetted by CD45RA/CD27 and analyzed for expression of activation, adhesion, and homing markers. Strikingly, T-cell content was indistinguishable between lungs. Compared with peripheral blood, naïve CD4 and CD8 T cells were rare in BAL. CD4+ BAL T cells showed increased CD95 (higher apoptotic potential) and CD103 expression (epithelial adhesion), but decreased CD38 (activation) and CCR7 expression (lymph node homing). CD8+ BAL T cells showed increased CD103 expression and decreased CD28 expression (co-stimulation). Differences in CD28, CD95, and CCR7 expression were more pronounced within memory cells, while differences in CD4+ CD103 expression were more prominent in effector/memory cells. Of these populations, the absence of lung CD4 T cells with an effector-like phenotype (CD45RA+/CD27-) emerged as a predictor of favorable outcome. Patients with a low proportion (≤0.44%) had 90% 5-year survival (n = 10, median survival 2,343 days), compared with 0% (n = 9, median survival 516 days) of patients with a higher proportion. Further study is required to confirm this association prospectively and define the function of this subpopulation.

Endoluminal management of bronchogenic carcinoma in 2010: diagnosis, staging, and therapy.

Endoluminal bronchogenic carcinoma, though a minority of lung cancer cases, presents a unique opportunity to utilize techniques for the diagnosis and therapy that are unavailable for more peripheral tumors. This review explores current techniques for the diagnosis, staging, and therapy of endoluminal central bronchogenic tumors and also introduces techniques currently under investigation as potential improvements or replacements for current techniques using recent literature. Additionally, the new staging criteria set forth in the 7th edition of the TMN staging system as a result of the American Joint Committee on Cancer (AJCC), International Union Against Cancer (IUCC), and the International Association for the Study of Lung Cancer (IASLC) are discussed with respect to endoluminal bronchogenic carcinoma.

Trends in the management of esophageal carcinoma based on provider volume: treatment practices of 618 esophageal surgeons.

Controversy exists regarding optimal treatment practices for esophageal cancer. Esophagectomy has received focus as one of the index procedures for both hospital and surgical quality despite a relative paucity of controlled trials to define best practices. A survey was created to determine the degree of heterogeneity in the treatment of esophageal cancer among a diverse group of surgeons and to use high-volume (HV) (>/=15 cases/year) and low-volume (LV) (<15 cases/year) designations to discern specific differences in the management of esophageal cancer from the surgeon's perspective. Based on society rosters, surgeons (n = 4000) in the USA and 15 countries were contacted via mail and queried regarding their treatment practices for esophageal cancer using a 50-item survey instrument addressing demographics, utilization of neoadjuvant chemoradiotherapy, and choice of surgical approach for esophageal resection and palliation. There were 618 esophageal surgeons among respondents (n = 1447), of which 77 (12.5%) were considered HV. The majority of HV surgeons (87%) practiced in an academic setting and had cardiothoracic training, while most LV surgeons were general surgeons in private practice (52.3%). Both HV and LV surgeons favored the hand-sewn cervical anastomosis and the stomach conduit. Minimally invasive esophagectomy is performed more frequently by HV surgeons when compared with LV surgeons (P = 0.045). Most HV surgeons use neoadjuvant therapy for patients with nodal involvement, while LV surgeons are more likely to leave the decision to the oncologist. With a few notable exceptions, substantial heterogeneity exists among surgeons' management strategies for esophageal cancer, particularly when grouped and analyzed by case volume. These results highlight the need for controlled trials to determine best practices in the treatment of this complex patient population.

Stereotactic radiosurgery for lung cancer.

Lung cancer is the most common cause of cancer death in both men and women in the United States. Anatomic lobectomy is the standard treatment and offers the best results for curative treatment of early stage non-small cell lung cancer (NSCLC). With an aging population, a significant proportion of patients are not surgical candidates at the time of diagnosis. In medically inoperable patients, standard external beam radiation has been offered as treatment, with suboptimal results. Stereotactic radiosurgery (SRS), a term coined by Leksell describes an approach using multiple convergent beams, precise localization with a stereotactic coordinate system, and rigid immobilization. It provides precise delivery of beams from multiple collimated paths which maximizes radiation delivery to the tumor, and minimizes the exposure of normal tissue. Early results with SRS are very encouraging, and prospective trials are underway in our institution and others to evaluate its role in early stage NSCLC. In article we review the role of stereotactic radiosurgery for the treatment of lung cancer.

Management of giant paraesophageal hernia.

Management of giant paraesophageal hernia remains one of the most difficult challenges faced by surgeons treating complex benign esophageal disorders. These large hernias are acquired disorders; therefore, they invariably present in elderly patients. The dilemma that surgeons faced in the open surgical era was the risk of open surgery in this elderly, sick patient population versus the life threatening catastrophic complications, nearly 30% in some series, observed with medical management. During the 1990s, it was clearly recognized that laparoscopic surgery led to decreased morbidity with a quicker recovery. This has lead to a 6-fold increase in the surgical management of giant paraesophageal hernias over the last decade compared to a period of five decades of open surgery; however, this has not necessarily translated into better outcomes. One of the major issues with giant paraesophageal hernias is recognizing short esophagus and performing a lengthening procedure, if needed. Open series which report liberal use of Collis gastroplasty leading to a tension-free intraabdominal fundoplication have shown the best anatomic and clinical outcomes. As we duplicate the open experience laparoscopically, the principle of identifying a shortened esophagus and constructing a neo-esophagus must be honored for the success of the operation. The benefits of laparoscopy are obvious but should not come at the cost of a lesser operation. This review will illustrate that laparoscopic repair of giant paraesophageal hernia at experienced centers can be performed safely with similar outcomes to open series when the fundamental principles of the operation are maintained.

An increased proportion of inflammatory cells express tumor necrosis factor alpha in idiopathic achalasia of the esophagus.

Achalasia is a motility disorder characterized by the absence of coordinated peristalsis and incomplete relaxation of the lower esophageal sphincter. The etiology remains unclear although dense inflammatory infiltrates within the myenteric plexus have been described. The nature of these infiltrating cells is unknown. The aim of this study was to evaluate the expression of proinflammatory cytokines - namely, tumor necrosis factor alpha and interleukin-2 - in the distal esophageal muscle in patients with achalasia. Lower esophageal sphincter muscle from eight patients undergoing myotomy or esophagectomy for achalasia of the esophagus were obtained at the time of surgery. Control specimens consisted of similar muscle taken from eight patients undergoing operation for cancer or Barrett's esophagus. The expression of tumor necrosis factor alpha and interleukin-2 were assessed by immunohistochemistry. The total number of inflammatory cells within the myenteric plexus were counted in five high power fields. The percentage of infiltrating cells expressing tumor necrosis factor alpha or interleukin-2 was calculated. Clinical data including demographics, preoperative lower esophageal sphincter pressure, duration of symptoms, and dysphagia score (1 = no dysphagia to 5 = dysphagia to saliva) were obtained through electronic medical records. Statistical comparisons between the groups were made using the unpaired t-test, Fisher's exact test, or Mann-Whitney U test, with a two-tailed P-value less than 0.05 being considered significant. The total number of inflammatory cells was found to be similar between the groups. A significantly higher proportion of inflammatory cells expressed tumor necrosis factor alpha in achalasia as compared with controls (22 vs. 11%; P= 0.02). A similar percentage of infiltrating cells expressed interleukin-2 (40 vs. 41%; P= 0.87). Age, gender, preoperative lower esophageal sphincter pressure, or dysphagia score were not correlated to expression of these cytokines. There was, however, a significant inverse correlation between duration of symptoms and the proportion of inflammatory cells expressing tumor necrosis factor alpha in achalasia (P= 0.007). In conclusion, a higher proportion of infiltrating inflammatory cells expressed tumor necrosis factor alpha in achalasia. Furthermore, this proportion appears to be highest early in the disease process. Further studies are required to more clearly delineate the role of tumor necrosis factor alpha in the pathogenesis of this idiopathic disease.

Minimally invasive esophagectomy. An update on the options available.

Minimally invasive techniques have been successfully applied to esophageal surgery. Initially, they were used for benign disease, but as experience has increased, so have the indications for minimally invasive esophageal surgery. Today, minimally invasive esophagectomy has been reported in all types of patients with a variety of esophageal diseases and different stages of esophageal cancer. Currently, the biggest limitation for proceeding with minimally invasive esophagectomy is experience in performing the procedure. This article provides an update on the myriad of options for performing minimally invasive esophagectomy including advantages and disadvantages of each option and outlines the surgical technique for each. It highlights the current debate on open versus minimally invasive esophagectomy. Since there is no consensus on the operative approach to open esophagectomy, it is not surprising that a number of debates over the best operative approach to minimally invasive esophagectomy exist today.

A pilot study of botulinum toxin injection for the treatment of delayed gastric emptying following esophagectomy.

OBJECTIVE: Esophagectomy may lead to impairment in gastric emptying, unless a pyloroplasty or pyloromyotomy is performed. These procedures may be technically challenging during minimally invasive esophagectomy, and they are associated with a small but definable morbidity, such as leakage and dumping syndrome. We sought to determine the results of our early experience with injecting the pylorus with botulinum toxin instead of conventional pyloric drainage. METHODS: Fifteen patients who had undergone esophagectomy and injection of the pylorus with botulinum toxin were identified. Twelve patients had undergone botulinum toxin injection at the time of minimally invasive esophagectomy, and the remaining three had been treated endoscopically after surgery. The latter three patients had undergone esophagectomy with either no pyloric drainage (n = 2) or an inadequate pyloromyotomy (n = 1), and they presented in the postoperative period with delayed gastric emptying. The adequacy of emptying after injection was assessed by the patients' ability to tolerate a regular diet, a barium swallow, and a nuclear gastric emptying study. RESULTS: No patient injected with botulinum toxin during esophagectomy developed delayed gastric emptying or aspiration pneumonia in the perioperative period. Eight of these patients underwent a nuclear emptying scan at a median of 4.2 months after surgery, which showed a mean emptying half-life of 100 min. With a median follow-up of 5.3 months, one patient (8%) required reintervention for symptoms of gastric stasis, presumably after the effect of the toxin subsided. All three patients injected postoperatively demonstrated an improvement in symptoms of gastric outlet obstruction and were able to resume a regular diet. CONCLUSIONS: Injection of the pylorus with botulinum toxin can be performed safely in patients undergoing esophagectomy. Longer-term studies are needed to clarify the efficacy and durability of this technique compared to the accepted procedures of pyloromyotomy or pyloroplasty.

Minimally invasive esophagectomy: state of the art.

Open esophagectomy is associated with significant mortality and morbidity, even in experienced centers. Two of the more frequent complications following esophagectomy are pneumonia and respiratory failure. Single-institution series have suggested that the incidence of these complications may be decreased with minimally invasive esophagectomy, with equivalent survival compared to open esophagectomy. However, this operation is technically challenging. In this review we detail the procedure as performed in our center, and also discuss some recent developments.

Tumorigenic epithelial stem cells and their normal counterparts.

ABC transporters are highly conserved and represent a major protective mechanism for barrier tissues as well as adult tissue stem cells. Emerging data support the existence of a cancer stem cell that shares features of tissue stem cells, including the ability to self-renew and undergo dysregulated differentiation. Here we show that a rare population of cells coexpressing MDR transporters and stem cell markers is a common feature across therapy-naive epithelial cancers as well as normal epithelial tissue. MDR+ and MDR- candidate tumor stem and progenitor populations were all capable of generating highly anaplastic transplantable human tumors in NOD/SCID. The finding that rare cells bearing stem cell markers and having intrinsic MDR expression and activity are already present within the tumorigenic compartment before treatment with cytotoxic agents is of critical importance to cancer therapy. Just as damaged normal epithelial tissues regenerate after chemotherapy by virtue of highly protected resting tissue stem cells, the existence of malignant counterparts in therapy-naive epithelial cancers suggests a common mechanism by which normal and tumor stem cells protect themselves against toxic injury.

Laparoscopic esophagectomy.

Minimally invasive esophagectomy is emerging as an alternative option to open esophagectomy for benign and malignant esophageal diseases. This article provides a detailed review of the history of minimally invasive esophagectomy and an update on the currently accepted techniques for minimally invasive esophagectomy and its outcomes.

Current status of minimally invasive esophagectomy.

Minimally invasive esophagectomy is emerging as an option in the management of benign and malignant esophageal diseases. With minimally invasive esophagectomy, the conventional laparotomy is substituted with laparoscopy and the open thoracotomy with thoracoscopy. This article discusses the surgical techniques and outcomes for a variety of minimally invasive esophagectomy options.