Esophageal cancer: Recent advances in screening, targeted therapy, and management.

The incidence of esophageal cancer remains on the rise worldwide and despite aggressive research in the field of gastrointestinal oncology, the survival remains poor. Much remains to be defined in esophageal cancer, including the development of an effective screening tool, identifying a good tumor marker for surveillance purposes, ways to target esophageal cancer stem cells as well as circulating tumor cells, and developing minimally invasive protocols to treat early-stage disease. The goal of this chapter is to highlight some of the recent advances and ongoing research in the field of esophageal cancer.

Identification of cancer stem cells in human gastrointestinal carcinoid and neuroendocrine tumors.

BACKGROUND & AIMS: Metastatic gastrointestinal neuroendocrine tumors (NETs) frequently are refractory to chemotherapy. Chemoresistance in various malignancies has been attributed to cancer stem cells (CSCs). We sought to identify gastrointestinal neuroendocrine CSCs (N-CSCs) in surgical specimens and a NET cell line and to characterize novel N-CSC therapeutic targets. METHODS: Human gastrointestinal NETs were evaluated for CSCs using the Aldefluor (Stemcell Technologies, Vancouver, Canada) assay. An in vitro, sphere-forming assay was performed on primary NET cells. CNDT2.5, a human midgut carcinoid cell line, was used for in vitro (sphere-formation) and in vivo (tumorigenicity assays) CSC studies. N-CSC protein expression was characterized using Western blotting. In vivo, systemic short interfering RNA administration targeted Src. RESULTS: By using the Aldefluor assay, aldehyde dehydrogenase-positive (ALDH+) cells comprised 5.8% ± 1.4% (mean ± standard error of the mean) of cells from 19 patient samples. Although many primary cell lines failed to grow, CNDT96 ALDH+ cells formed spheres in anchorage-independent conditions, whereas ALDH- cells did not. CNDT2.5 ALDH+ cells formed spheres, whereas ALDH- cells did not. In vivo, ALDH+ CNDT2.5 cells generated more tumors, with shorter latency than ALDH- or sham-sorted cells. Compared with non-CSCs, ALDH+ cells demonstrated increased expression of activated Src, Erk, Akt, and mammalian target of rapamycin (mTOR). In vivo, anti-Src short interfering RNA treatment of ALDH+ tumors reduced tumor mass by 91%. CONCLUSIONS: CSCs are present in NETs, as shown by in vitro sphere formation and in vivo tumorigenicity assays. Src was activated in N-CSCs and represents a potential therapeutic target in gastrointestinal NETs.

Thymic neuroendocrine tumors: a SEER database analysis of 160 patients.

INTRODUCTION: Thymic neuroendocrine tumors (NETs) are uncommon but malignant tumors of the thymus gland that are usually associated with systemic symptoms due to hypersecretion of biogenic amines from metastatic lesions. Due to the limited number of studies in the literature, very little is known about progress or trends made in the treatment and survival of patients with thymic NET. METHODS: We reviewed 160 patients diagnosed with thymic NET in the SEER database to evaluate patient demographics and their clinical course. Specifically, we evaluated the role of surgery and adjuvant radiation in the SEER cohort. We also performed univariable and multivariate Cox proportional hazard modeling of standard prognostic factors. RESULTS: According to our results, thymic NETs afflict males and whites primarily. As expected, advanced stage correlates with poorer long-term survival (P = 0.009) and those patients who undergo surgery do better than their counterpart (P = 0.005). We did not observe any survival benefit for radiation delivered as a part of primary therapy. Univariable and multivariate analyses demonstrated that tumor stage (P = 0.009), grade (P = 0.002), surgical resection (P = 0.005), and tumor size (P = 0.02) correlated with overall survival. CONCLUSIONS: Our study demonstrates that surgery continues to be the mainstay of treatment, and that there is a need to define a staging system for thymic NETs that can perhaps allow clinicians to formulate better therapeutic strategies for such patients.

A clinical nomogram predicting pathologic lymph node involvement in esophageal cancer patients.

BACKGROUND: Esophageal cancer patients with pathologic lymph-node involvement (pN1) generally have a poor prognosis with surgery alone. We, therefore, constructed a nomogram to predict the risk of pN1 prior to surgical resection and externally validated the clinical utility of the model. METHODS: A total of 273 esophageal adenocarcinoma patients treated with surgery alone were reviewed from 2 different institutions (University of Texas M. D. Anderson Cancer Center = 164, training set; University of Rochester School of Medicine and Dentistry = 109, validation set). Pretreatment clinical parameters were used to construct a nomogram for predicting the risk of pN1. Internal and external validation of the nomogram was performed to assess clinical utility. RESULTS: Of the 164 patients in the training set, 56 patients (34%) had lymph-node involvement (pN1). Significant factors associated with pN1 on univariable logistic regression analysis (using a P < 0.05) included endoscopically determined clinical tumor depth (cT), clinical nodal (cN) status, and clinical tumor length (cL). Multivariable analysis suggested the significant independent factors were cT (odds ratio, 5.6; 95% confidence interval, 1.7-18.6; P < 0.01) and cL >2 cm (odds ratio, 7.0; 95% confidence interval, 2.7-18.1; P < 0.001). Regression tree analysis was used to determine the best cutoff for cL. A nomogram was created for pN1 using these clinical parameters and was internally validated by bootstrapping with a predicted accuracy of 85.1%. External validation performed on the validation set demonstrated an original C-index of 0.777 suggesting good clinical utility. CONCLUSIONS: Our analyses demonstrate that the risk of pathologic nodal involvement in esophageal adenocarcinoma patients can be estimated by this clinical nomogram, which will allow the identification of patients at high-risk of harboring positive lymph-nodes, who may be candidates for en bloc resection and/or neoadjuvant treatment.

Targeting tumor angiogenesis.

Our understanding of the process of tumor angiogenesis has changed significantly since the late 1970s, when vascular endothelial growth factor (VEGF) was first identified as vascular permeability factor and later found to be the major mediator of physiologic and pathologic angiogenesis. Since then, several additional VEGF-related ligands, VEGF receptors (VEGFRs), and complementary/alternative pathways that regulate tumor angiogenesis have been identified. Over the last decade, several antiangiogenic agents have been developed with the aim to inhibit new blood vessel growth, and we have learned that VEGF inhibition does far more than simply block new blood vessel growth. Clinical studies have demonstrated an improvement of progression-free and overall survivals with anti-VEGF therapy (with or without chemotherapy) in patients with advanced-stage malignancies. Unfortunately, even when anti-VEGF therapy is effective, the benefit of therapy is short-lived, with the development of tumor growth. We now recognize the presence of numerous complementary and redundant pathways that regulate tumor vasculature. For example, VEGF/VEGFR and angiopoietin/Tie-2 axes are two redundant, complementary components regulating tumor angiogenesis and vascular maintenance. The current clinical challenge is to identify: (1) factors that predict efficacy, and (2) markers of tumor response to anti-VEGF therapy, which can be achieved only by developing a thorough understanding of the biology of the VEGF system and the role of complementary pathways that may mediate resistance to anti-VEGF therapy.

Neuropilin-2-mediated tumor growth and angiogenesis in pancreatic adenocarcinoma.

PURPOSE: Neuropilin-2 (NRP-2) is a coreceptor for vascular endothelial growth factor (VEGF) on endothelial cells. NRP-2 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) cells relative to nonmalignant ductal epithelium. This study determined the role of NRP-2 in PDAC cells. EXPERIMENTAL DESIGN: NRP-2 expression was reduced in PDAC cells with stable short-hairpin RNA (shRNA) transfection. Western blotting was done to evaluate signaling intermediates. Migration and invasion studies were carried out in Boyden chambers. Anchorage-independent growth was assessed by soft-agar colony formation. In vivo growth was evaluated using murine subcutaneous and orthotopic xenograft models. Immunohistochemical analysis evaluated in vivo proliferation and angiogenesis. RESULTS: shRNA-NRP-2 decreased NRP-2 levels without affecting neuropilin-1 levels. Akt activation was decreased in clones with reduced NRP-2 (shRNA-NRP-2). shRNA-NRP-2 cells showed decreased migration, invasion, and anchorage-independent growth compared with control cells. In vitro proliferation rates were similar in control- and shRNA-transfected cells. Subcutaneous and orthotopic xenografts from shRNA-transfected cells were significantly smaller than those resulting from control-transfected cells (P < 0.05). Furthermore, shRNA-NRP-2 tumors exhibited less cellular proliferation and decreased microvascular area relative to control tumors (P < 0.05). Constitutive expression of the angiogenic mediator Jagged-1 was reduced in shRNA-NRP-2 cells, whereas vascular endothelial growth factor levels were unchanged. CONCLUSION: Reduction of NRP-2 expression in PDAC cells decreased survival signaling, migration, invasion, and ability to grow under anchorage-independent conditions. In vivo, reduction of NRP-2 led to decreased growth of xenograft tumors and decreased vascular area, which was associated with decreased Jagged-1 levels. NRP-2 is a potential therapeutic target on PDAC cells.

Cervical Esophago-Gastric Tubes for Patients with Malignant Ascites.

Patients with chronic small bowel obstruction and malignant ascites from diffuse peritoneal carcinomatosis have limited options for gastrointestinal decompression as part of end-of-life palliation. Insertion of a percutaneous gastrostomy tube is relatively contraindicated in patients with ascites. Alternatively, nasogastric tube placement often leads to significant discomfort to patients and necessitates hospitalization during their last days of life. Here, we demonstrate how placing a percutaneous cervical esophago-gastric tube can allow adequate gastrointestinal decompression for terminal patients with malignant small bowel obstruction. This palliative measure allows them to remain in the comfort of their own homes after the procedure.

Management of the Solitary Pulmonary Nodule.

CONTEXT: - Optimal management of the patient with a solitary pulmonary nodule entails early diagnosis and appropriate treatment for patients with malignant tumors, and minimization of unnecessary interventions and procedures for those with ultimately benign nodules. With the growing number of high-resolution imaging modalities and studies available, incidentally found solitary pulmonary nodules are an increasingly common occurrence. OBJECTIVE: - To provide guidance to clinicians involved in the management of patients with a solitary pulmonary nodule, including aspects of risk stratification, workup, diagnosis, and management. DATA SOURCES: - Data for this review were gathered from an extensive literature review on the topic. CONCLUSIONS: - Logical evaluation and management pathways for a patient with a solitary pulmonary nodule will allow providers to diagnose and treat individuals with early stage lung cancer and minimize morbidity from invasive procedures for patients with benign lesions.

Endoscopic evaluation of gastric conduit perfusion in minimally invasive Ivor Lewis esophagectomy.

INTRODUCTION: Laser-assisted indocyanine green (ICG) fluorescent dye angiography has been used in esophageal reconstructive surgery where it has been shown to significantly decrease the anastomotic leak rate. Recent advances in technology have made this possible in minimally invasive esophagectomy. PRESENTATION OF CASE: We present a 69-year-old male with a cuT2N0M0 adenocarcinoma of the esophagus at the gastroesophageal junction who presented to our clinic after chemoradiation and underwent a minimally invasive Ivor Lewis esophagectomy. The perfusion of the gastric conduit was assessed intraoperatively using endoscopic ICG fluorescent imaging system. The anastomosis was created at the well-perfused site identified on the fluorescent imaging. The patient tolerated the procedure well, had an uneventful recovery going home on postoperative day 6 and tolerating a regular diet 2 weeks after the surgery. DISCUSSION: Combination of minimally invasive surgery and endoscopic evaluation of perfusion of gastric conduit provide improved outcomes for surgical treatment for patients with esophageal cancer. CONCLUSION: The gastric conduit during minimally invasive Ivor Lewis esophagectomy can be evaluated using endoscopic ICG fluorescent imaging.

Emerging therapeutic targets in esophageal adenocarcinoma.

The incidence of gastro-esophageal disease and associated rate of esophageal adenocarcinoma (EAC) is rising at an exponential rate in the United States. However, research targeting EAC is lagging behind, and much research is needed in the field to identify ways to diagnose EAC early as well as to improve the rate of pathologic complete response (pCR) to systemic therapies. Esophagectomy with subsequent reconstruction is known to be a morbid procedure that significantly impacts a patient's quality of life. If indeed the pCR rate of patients can be improved and those patients destined to be pCR can be identified ahead of time, they may be able to avoid this life-altering procedure. While cancer-specific biological pathways have been thoroughly investigated in other solid malignancies, much remains unexplored in EAC. In this review, we will highlight some of the latest research in the field in regards with EAC, along with new therapeutic targets that are currently being explored. After reviewing conventional treatment and current changes in medical therapy for EAC, we will focus on unchartered grounds such as cancer stem cells, genetics and epigenetics, immunotherapy, and chemoradio-resistant pathways as we simultaneously propose some investigational possibilities that could be applicable to EAC.

Minimally invasive esophagectomy in a patient with end-stage renal disease.

Renal failure has been identified as a major predictor of surgical complications and esophagectomy carries high morbidity for patients. We discuss the preoperative and postoperative considerations for performing a minimally invasive Ivor-Lewis esophagectomy for a benign long-segment stricture in a patient with end-stage renal failure.

Case report of using curved tip electrothermal bipolar coagulation to improve hilar dissection in VATS lobectomy.

INTRODUCTION: Thoracoscopic lobectomy has gained a pivotal role in the resection of lung cancer. To facilitate the minimally invasive approach, new surgical devices have been developed to help improve the feasibility of performing complex cases. Recently, we adopted the use of a 5mm curved tip electrothermal bipolar sealing device. PRESENTATION OF CASE: We highlight two patients with different type of hilum during VATS lobectomy. First patient had a peripheral lung cancer with simple hilum while second patient had bronchiectasis with very complex hilum. In both cases, use of 5mm curved tip electrothermal bipolar sealing device helped in successful completion of video-assisted thoracoscopic lobectomy. DISCUSSION: In these two cases, we were able to take advantage of the 5mm curved tip electrothermal bipolar sealing device in completion of the hilar dissection. CONCLUSION: Curved tip electrothermal bipolar sealing device allows complete dissection of hilar structures more easily during a lobectomy for simple and complex hilum. Use of this device may lead to more efficient VATS lobectomy.

Pseudoachalasia presenting 20 years after Nissen fundoplication: a case report.

BACKGROUND: Pseudoachalasia is a rare diagnosis manifested by clinical and physiologic symptoms of achalasia, with alternative etiology for outflow obstruction. While malignancy is a frequent cause of pseudoachalasia, prior surgical intervention especially surgery involving the esophagogastric junction, may result in a misdiagnosis of achalasia. CASE PRESENTATION: We present a case of a 70 year-old male with dysphagia and weight loss after undergoing a Billroth I and Nissen fundoplication several decades ago. His preoperative studies suggested achalasia and he was therefore referred for an endoscopic myotomy. However, careful interpretation of all the data and intra-operative findings revealed a classic mechanical and functional obstruction requiring takedown of his prior wrap. CONCLUSIONS: Individualized interpretation of preoperative studies in the setting of prior foregut surgery is critical to appropriate diagnosis and intervention. This case highlights the significance of endoscopic findings and features of high-resolution manometry specific to pseudoachalasia, which contrasts with classical features of achalasia.

Endoluminal suturing of an anastomotic leak.

An anastomotic leak can be one of the most morbid and complex complications after esophagectomy. Typically, management can entail repair, stenting, or diversion. The leak complicates a patient's postoperative course and delays initiation of any adjuvant therapy. Novel minimally invasive tools created to expedite healing of the anastomotic leak may potentially limit additional procedures traditionally used to treat the leak. We present the case of a 49-year-old man who sustained an anastomotic leak 5 days after undergoing esophagectomy for cancer. He was initially managed with drainage, and when this failed, he was transferred to our hospital. An endoscopic suturing device was used to close the leak and pexy a partially covered self-expanding metal stent that was left in place for 2 weeks. At the end of 2 weeks, the leak healed and there was no stent migration.

Three dimensional model for surgical planning in resection of thoracic tumors.

INTRODUCTION: The computed tomography scan provides vital information about the relationship of thoracic malignancies to the surrounding structures and aids in surgical planning. However, it can be difficult to visualize the images in a two-dimensional screen to interpret the full extent of the relationship between important structures in the surgical field. PRESENTATION OF CASE: We report two cases where we used a three-dimensional printed model to aid in the surgical resection of thoracic malignancies. DISCUSSION: Careful planning is necessary to resect thoracic malignancies. Although two-dimensional images of the thoracic malignancies provide vital information about the tumor and its surrounding structures, the three-dimensional printed model can provide more accurate information about the tumor and assist in surgical planning. CONCLUSION: Three-dimensional printed model provide better visualization of complex thoracic tumors, aid in counseling the patient about the surgical procedure and assisted in surgical resection of thoracic malignancy.

Super-Charged Pedicled Jejunal Interposition Performance Compares Favorably With a Gastric Conduit After Esophagectomy.

BACKGROUND: A variety of conduits can be utilized for esophageal reconstruction, but their postoperative function remains unknown. The objective of our study was to compare functional performance of super-charged pedicled jejunal (SPJ) to gastric conduits using a novel conduit assessment tool. METHODS: Patients who underwent esophageal reconstruction between January 1, 2009 and December 31, 2013 were asked to complete questionnaires measuring postoperative functional outcomes. Conduit emptying and postoperative variables were recorded. Statistical analysis was performed using the Mann-Whitney U test and Fisher exact test for crosstabs. RESULTS: Forty-five of the 94 esophageal reconstruction patients (48%) were alive, had either a gastric conduit or SPJ reconstruction, and completed the questionnaire. The mean age was 60.6 ± 12.5 years, 69% were male, and the majority of patients had cancer (87%). While the majority of the gastric patients underwent an oncologic resection for adenocarcinoma (65%), 50% of SPJ patients had undergone a previous resection (p = 0.008). The average time after surgery for last conduit assessment was 15 ± 13 months for the gastric conduit group and 17 ± 12 months for the SPJ group (p = 0.315). The average reflux, dumping, dysphagia, stricture, conduit emptying, and Zubrod scores were low and similar between groups: reflux 1.7 ± 1.9 for gastric conduit and 0.7 ± 1.3 for SPJ; dumping 0.97 ± 1.2 and 0.93 ± 1.1; dysphagia 0.60 ± 0.72 and 0.79 ± 0.89; stricture 0.7 ± 1.4 and 0.38 ± 0.96; conduit emptying 0.46 ± 0.93 and 0.33 ± 0.88; and Zubrod 0.84 ± 0.64 and 1.21 ± 0.8, respectively. The SPJ patients had a higher pain score (7.0 ± 3.2 vs 2.4 ± 2.4, p = 0.043). CONCLUSIONS: Super-charged pedicled jejunal interposition performance is comparable with a gastric conduit after esophagectomy according to a novel, comprehensive conduit assessment tool.

Jejunal graft conduits after esophagectomy.

INTRODUCTION: The jejunum is uniquely suitable for esophageal reconstruction because it is relatively abundant, does not require a formal preparation, is typically free of disease, has similar luminal size compared to the esophagus, has intrinsic peristalsis, and may not undergo senescent lengthening to the extent that colon does. METHODS: To obtain data to determine the outcomes of jejunal interposition for esophageal replacement, electronic databases were searched, including MEDLINE (Ovid SP), Scopus, EMBASE (Ovid SP), Science Direct's full-text database, and the Cochrane Library from January 1990 to September 2013. RESULTS: Two-hundred and forty-six abstracts were reviewed and an article search was performed on selected abstracts. Additional references from article bibliographies were included as appropriate. A thorough search of the literature demonstrates the widespread use of jejunum, either as a free, pedicled, or free- and pedicled-graft with acceptable results. CONCLUSIONS: Any region of the esophagus can be replaced by jejunum, whether it is distal esophagus as a Merendino procedure for a vagal-sparing esophagectomy and segmental jejunal reconstruction connected to stomach, mid-thoracic esophagus as a pedicled jejunal interposition or free flap, cervical esophagus as a free segmental interposition, or the entire length as a long-segment super-charged pedicled jejunal interposition. When used, the jejunum is either pedicled, augmented ("super-charged"), a free segment (requiring microvascular anastomosis of artery and vein), or a combination of the above.

Endoscopic management of Boerhaave's syndrome presenting with hematemesis.

Hematemesis is an uncommon yet challenging presentation of Boerhaave's syndrome. Here, we present minimally invasive management of an esophageal perforation with hematemesis using esophageal stenting in an elderly male with multiple comorbidities.

Robot assisted thoracoscopic resection of giant esophageal leiomyoma.

INTRODUCTION: Esophageal leiomyoma represents the most common benign esophageal tumor. Robot-assisted thoracoscopic surgery has provided ability to remove it successfully using a minimally invasive approach. PRESENTATION OF CASE: A 63-year old female with history of chronic chest pain presented with an esophageal mass on chest CT and endoscopic ultrasound. Robot-assisted surgery was performed using three robot arms, a camera and an assistant port. A 10cm leiomyoma was enucleated and removed through a 2cm myotomy. Completion endoscopy confirmed integrity of the esophagus. Patient's chest pain resolved postoperatively, and she was discharged on postoperative day 3. DISCUSSION: Our case describes successful removal of the giant esophageal leiomyoma (10cm) by robot assisted minimally invasive resection through a 2cm myotomy. CONCLUSION: Use of robot allows for removal of large esophageal leiomyoma. The improved dexterity and patient outcome offered by robot suggests its potential as the mainstay technique for giant esophageal leiomyoma removal.

Bronchopleural fistula and the role of contemporary imaging.

One of the most morbid postoperative complications after a lobectomy or a pneumonectomy is a bronchopleural fistula (BPF). The diagnosis and identification of BPF may be challenging, often requiring repeat imaging and invasive tests, including bronchoscopy, thoracoscopic exploration, or even open exploration. The purpose of this article is to review the types and presentations of BPF and to describe the role of noninvasive imaging for diagnosis and surgical treatment planning. We focused on multidetector computed tomography and advanced postprocessing applications such as multiplanar reconstructions, virtual bronchoscopy, and volume rendering images, including minimum-intensity and maximum-intensity projections. Both multidetector computed tomography and nuclear scintigraphy are reliable noninvasive imaging modalities that can be used expeditiously in an outpatient setting and may prove to be a more cost-effective strategy to identify the fistula as well as conduct postoperative surveillance. These modalities can be used for accurate and efficient testing for earlier diagnosis and treatment planning, thereby significantly improving patient outcome. Additional advanced postprocessing techniques using already acquired imaging data can provide complementary information that is both visually accessible and anatomically meaningful for the surgeon. Better understanding of the potential uses and benefits of these techniques will eventually improve the diagnostic accuracy, optimize preoperative planning, and facilitate follow-up for patients with BPF with improved patient outcomes.