Management of Gastric Neuroendocrine Tumors: A Review.

Gastric neuroendocrine tumors (G-NET) are rare tumors arising from enterochromaffin-like cells of the gastric mucosa. They belong to a larger group called gastroenteropancreatic neuroendocrine tumors and are classified as low, intermediate, or high-grade tumors based on their proliferative indices. They are further categorized into three subtypes based on their morphologic characteristics, pathogenesis, and behavior. Types 1 and 2 tumors are characterized by elevated serum gastrin and are usually multifocal. They typically occur in the setting of atrophic gastritis or MEN1/Zollinger Ellison syndrome, respectively. Type 2 tumors are associated with the most symptoms, such as abdominal pain and diarrhea. Type 3 tumors are associated with normal serum gastrin, are usually solitary, and occur sporadically. This type has the most aggressive phenotype and metastatic potential. Treatment and prognosis for G-NET is dependent on their type, size, and stage. Type 1 has the best prognosis, and Type 3 has the worst. This review discusses the presentation, workup, and surgical management of these tumors.

The cckOMA syndrome and its relation to the Zollinger-Ellison syndrome: a diagnostic challenge.

OBJECTIVE: Among patients with enteropancreatic neuroendocrine tumor syndromes only one case with a cholecystokinin (CCK) secreting tumor has been reported. She had significant hyperCCKemia leading to a specific syndrome of severe diarrheas, weight loss, repeated duodenal ulcers and a permanently contracted gallbladder with gallstones. There are, however, reasons to believe that further CCKomas exist, for instance among Zollinger-Ellison patients with normal plasma gastrin concentrations. The present review is a call to gastroenterologists for awareness of such CCKoma patients. METHOD: After a short case report, the normal endocrine and oncological biology of CCK is described. Subsequently, the CCKoma symptoms are discussed with particular reference to the partly overlapping symptoms of the Zollinger-Ellison syndrome. In this context, the diagnostic use of truly specific CCK and gastrin assays are emphasized. The discussion also entails the problem of access to accurate CCK measurements. CONCLUSION: Obviously, the clinical awareness about the CCKoma syndrome is limited. Moreover, it is also likely that the knowledge about the necessary specificity demands of diagnostic gastrin and CCK assays have obscured proper diagnosis of the CCKoma syndromes in man.

Middle-segment preserving pancreatectomy: a literature review and case report.

PURPOSE: Middle segment-preserving pancreatectomy (MSPP) is a relatively new parenchymal-sparing surgery that has been introduced as an alternative to total pancreatectomy (TP) for multicentric benign and borderline pancreatic diseases. To date, only 36 cases have been reported in English. METHODS: We reviewed 22 published articles on MSPP and reported an additional case. RESULTS: Our patient was a 49-year-old Japanese man diagnosed with Zollinger-Elison syndrome (ZES) caused by duodenal and pancreatic gastrinoma associated with multiple endocrine neoplasia syndrome type 1. We avoided TP and chose MSPP as the operative technique due to his relatively young age. The patient developed a grade B postoperative pancreatic fistula (POPF), which improved with conservative treatment. He was discharged without further treatment. To date, no tumor has recurred, and pancreatic function seems to be maintained. According to a literature review, the morbidity rate of MSPP is as high as 54%, mainly due to the high incidence of POPF (32%). In contrast, there was no perioperative mortality, and postoperative pancreatic function was comparable to that after conventional pancreatectomy. CONCLUSIONS: Despite the high incidence of POPF, MSPP appears to be safe, with low perioperative mortality and good postoperative pancreatic sufficiency.

Sporadic and MEN1-related gastrinoma and Zollinger-Ellison syndrome: differences in clinical characteristics and survival outcomes.

PURPOSE: Gastrinoma with Zollinger-Ellison syndrome (ZES) may occur sporadically (Sp) or as part of the inherited syndrome of multiple endocrine neoplasia 1 (MEN-1). Data comparing Sp and MEN-1/ZES are scanty. We aimed to identify and compare their clinical features. METHODS: Consecutive patients with ZES were evaluated between 1992 and 2020 among a monocentric Italian patient cohort. RESULTS: Of 76 MEN-1 patients, 41 had gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN), 18 of whom had ZES; of 320 Sp-GEP-NEN, 19 had Sp-ZES. MEN-1/ZES patients were younger (p = 0.035) and the primary MEN-1/ZES gastrinoma was smaller than Sp-ZES (p = 0.030). Liver metastases occurred in both groups, but only Sp-ZES developed extrahepatic metastases. 13 Sp-ZES and 8 MEN-1/ZES underwent surgery. 8 Sp-ZES and 7 MEN-1/ZES received somatostatin analogs (SSAs). Median overall survival (OS) was higher in MEN-1/ZES than in Sp-ZES (310 vs 168 months, p = 0.034). At univariate-logistic regression, age at diagnosis (p = 0.01, OR = 1.1), G3 grading (p = 0.003, OR = 21.3), Sp-ZES (p = 0.02, OR = 0.3) and presence of extrahepatic metastases (p = 0.001, OR = 7.2) showed a significant association with OS. At multivariate-COX-analysis, none of the variables resulted significantly related to OS. At univariate-logistic regression, age (p = 0.04, OR = 1.0), size (p = 0.039, OR = 1.0), G3 grade (p = 0.008, OR = 14.6) and extrahepatic metastases (p = 0.005, OR = 4.6) were independently associated with progression-free survival (PFS). In multivariate-COX-analysis, only extrahepatic metastases (p = 0.05, OR = 3.4) showed a significant association with PFS. Among SSAs-treated patients, MEN-1/ZES showed better PFS (p = 0.0227). After surgery, the median PFS was 126 and 96 months in MEN-1 and Sp, respectively. CONCLUSION: MEN-1/ZES patients generally show better OS and PFS than Sp-ZES as well as better SSAs response.

How to treat gastrinomas in patients with multiple endocrine neoplasia type1: surgery or long-term proton pump inhibitors?

In patients with multiple endocrine neoplasia type 1 syndrome (MEN 1) and Zollinger-Ellison syndrome (ZES), gastrinomas arise from the duodenum, about 60% are multiple, and about 15% of patients have coexisting pancreatic gastrinomas, which can be localized by the selective arterial secretagogue injection test (SASI test). The guidelines (GLs) by the Japanese Neuroendocrine Tumor Society (JNETS) recommend surgical resection for functioning duodenopancreatic neuroendocrine tumors (NETs), including gastrinomas, in patients with MEN1 (Grade A, 100% agreement among members). Conversely, the GLs of the National Comprehensive Cancer Network (NCCN) in the USA recommend observation and treatment with proton pump inhibitors (PPIs) or exploratory surgery for occult gastrinomas. An international Consensus Statement (ICS) from the European Union (EU) also does not recommend resection of gastrinomas in patients with MEN1, despite some surgeons having reported surgery being curative for gastrinomas in MEN1 patients. In this review, we discuss the serious side effects and tumorigenic effects of the prolonged use of PPIs and the safety and curability of surgery, supported by our results of curative surgery for gastrinomas in 20 patients with MEN1 over 30 years. We conclude that surgery should be the first-line treatment for gastrinomas in MEN1 patients.

GIST. Duodenopancreatectomía. Tumor neuroendocrino no funcionante.

Zollinger Ellison syndrome is an unusual entity. This termn is used to describe the clinical manifestations of a gastrin-synthesizing neoplasm. Gastrinomas occur mainly in the duodenum and pancreas. Primary gastrinomas are rarely found in other intra-abdominal sites, such as the ovary, bile ducts, spleen or kidney, or even more unusual in extra-abdominal locations. Several studies provide strong evidence that gastrinomas can also occur in the lymph nodes. However, the existence of primary lymph node gastrinomas is controversial.

[Primary lymph node gastrinoma]. / Gastrinoma primario de ganglio linfático.

Gastrinomas are neuroendocrine tumors usually located in the duodenum and pancreas, in the context of a Multiple Endocrine Neoplasm and forming a Zollinger-Ellison syndrome. The location of this type of lymph node tumor is extremely unusual and its early diagnosis constitutes a real challenge to be able to establish an adequate treatment and manage the complications that these entail. We present the case of a 64-year-old male patient with a lymph node gastrinoma and whose surgical removal resulted in the immediate remission of the patient's symptoms.

Validity of Secretin Stimulation Testing on Proton Pump Inhibitor Therapy for Diagnosis of Zollinger-Ellison Syndrome.

INTRODUCTION: Zollinger-Ellison syndrome (ZES) is characterized by gastrinoma-induced hypergastrinemia causing excessive gastric acid secretion. Secretin stimulation tests (SSTs) are required for diagnosis in the majority of patients. Two case reports suggest that proton pump inhibitors (PPIs) cause false SST results. Consequently, PPIs are discontinued to allow hyperchlorhydria to recur; however, uncontrolled acidity can cause life-threatening complications in those with underlying undiagnosed ZES. The aim of this study was to determine whether PPIs influence the validity of SSTs for the diagnosis of ZES. METHODS: A retrospective chart review was performed. Charts of patients who underwent SSTs were reviewed to determine whether they were performed on or off PPI and the test's accuracy by comparing the results with gold standard tests (diagnostic laboratory testing performed off PPI or surgical pathology consistent with gastrinoma). Sensitivity, specificity, and positive predictive value (PPV) of SST on PPI were calculated and results compared with SST off PPI using noninferiority analyses. RESULTS: Twenty-eight patients corresponding to 29 SSTs were performed on PPI, and 70 patients corresponding to 107 SSTs were performed off PPI. Most of them were female and white and had multiple endocrine neoplasia type 1. We found no false-positive or false-negative SSTs on PPI. Sensitivity, specificity, and PPV of SSTs on PPI were determined to be noninferior to SSTs off PPI (P ≤ 0.05 for all). DISCUSSION: In our cohort, SSTs on PPI compared with SSTs off PPI were noninferior for sensitivity, specificity, and PPV. These results suggest that PPI withdrawal before SSTs may not be necessary.

Gastric enterochromaffin-like cell changes in multiple endocrine neoplasia type 1.

BACKGROUND: Gastric enterochromaffin-like cell (ECL) tumours can occur in patients with multiple endocrine neoplasia type 1 (MEN1), especially in those affected by Zollinger Ellison syndrome (ZES). Since the prevalence of ECL lesions is not well defined yet, the present study evaluated the presence and extent of ECL lesions in MEN1 patients with and without ZES. METHODS: Multiple endocrine neoplasia type 1 patients being part of a regular screening program (2014-2018) underwent gastroduodenoscopies with biopsies of the stomach and determination of serum gastrin and chromogranin A levels. Haematoxylin- and immunostaining with chromogranin A, gastrin and VMAT I and II (vesicular monoamine transporter I and II) of the biopsies were performed. RESULTS: Thirty-eight MEN1 patients, of whom 16 (42%) were diagnosed and treated earlier for ZES, were analysed. In ten of 16 (62.5%) ZES patients, a locally scattered, mixed image of diffuse, linear and micronodular mild hyperplasia was present. In addition, two of these patients (13%) showed small (max 1.5 mm in size) intramucosal ECL tumours. Neither ECL changes, nor tumours were found in MEN1 patients without ZES (n = 22). In MEN1/ZES patients, the median serum gastrin level was significantly elevated compared to MEN1 patients without ZES (206 pg/ml vs. 30.5 pg/ml, p < .001). A subgroup analysis of the serum gastrin and chromogranin A levels of MEN1/ZES patients with or without ECL hyperplasia did not show significant differences (gastrin level: p = .302, chromogranin A: p = .464). CONCLUSION: Enterochromaffin-like cell hyperplasia and gastric carcinoids occur only in MEN1 patients with ZES, but less frequently than reported.

Total gastrectomy for severe proton pump inhibitor-induced hypomagnesemia in a MEN1/Zollinger Ellison syndrome patient.

We report here the first case of life-threatening hypomagnesemia in a Zollinger-Ellison syndrome patient with multiple endocrine neoplasia type 1 (MEN1) syndrome. The severe symptomatic hypomagnesemia proved to be due to proton pump inhibitors (PPIs), but withdrawal of PPIs led to early severe peptic complications despite a substitution by histamine H2-receptor antagonist therapy. Simultaneous management of life-threatening hypomagnesemia, severe gastric acid hypersecretion and MEN1-associated gastrinomas was complex. A total gastrectomy was performed in order to definitely preclude the use of PPIs in this frail patient who was not eligible for curative pancreatoduodenal resection.

Gastric neuroendocrine tumours from long-term proton pump inhibitor users are indolent tumours with good prognosis.

AIMS: Proton pump inhibitors (PPIs) are among the most widely used medications in the United States. Most PPI users have persistent hypergastrinaemia during treatment. However, gastric neuroendocrine tumours diagnosed in long-term PPI users are rarely reported. Their clinicopathological features and prognosis are not characterised. It remains unclear whether or not they can be classified as Type III sporadic tumours. METHODS AND RESULTS: We retrospectively characterised 66 gastric neuroendocrine tumours from patients without atrophic gastritis and gastrinoma from two tertiary care medical centres, including 38 tumours in patients who had used PPIs for at least 1 year and 28 tumours from patients without long-term PPI use (control group, Type III tumours). Compared to controls, tumours from long-term PPI users tended to be in the pT1-2 category (98% versus 79%, P = 0.09) and less often invaded the serosa (3% versus 18%, P = 0.08) or lymphovascular spaces (11% versus 32%, P = 0.06). Using Kaplan-Meier analysis, long-term PPI users had significantly longer overall survival than controls (P = 0.035). While three control patients developed distant metastasis and seven died, long-term PPI users were without distant metastasis (P = 0.06) or death (P = 0.002) during follow-up. However, five long-term PPI users developed additional gastric neuroendocrine tumour(s), while none of the controls did (P = 0.07). CONCLUSIONS: Our results show that gastric neuroendocrine tumours of long-term PPI users are probably less aggressive compared to Type III sporadic tumours and have an indolent disease course. Our findings support the classification of gastric neuroendocrine tumours in long-term PPI users as a separate subtype.

Proton Pump Inhibitor Use, Hypergastrinemia, and Gastric Carcinoids-What Is the Relationship?

Neuroendocrine tumors (NETs) throughout the body are the focus of much current interest. Most occur in the gastrointestinal tract and have shown a major increase in incidence over the past 30 years, roughly paralleling the world-wide increase in the use of proton pump inhibitor (PPI) drugs. The greatest rise has occurred in gastric carcinoids (g-NETs) arising from enterochromaffin-like (ECL) cells. These tumors are long known to occur in auto-immune chronic atrophic gastritis (CAG) and Zollinger-Ellison syndrome (ZES), with or without multiple endocrine neoplasia type-1 (MEN-1), but the incidences of these conditions do not appear to have increased over the same time period. Common to these disease states is persistent hypergastrinemia, generally accepted as causing g-NETs in CAG and ZES, and postulated as having similar tumorigenic effects in PPI users. In efforts to study the increase in their occurrence, g-NETs have been classified in a number of discussed ways into different grades that differ in their incidence and apparent pathogenesis. Based on a large amount of experimental data, tumorigenesis is mediated by gastrin's effects on the CCK2R-receptor on ECL-cells that in turn leads to hyperplasia, dysplasia, and finally neoplasia. However, in all three conditions, the extent of response of ECL-cells to gastrin is modified by a number of genetic influences and other underlying risk factors, and by the duration of exposure to the hormonal influence. Data relating to trophic effects of hypergastrinemia due to PPI use in humans are reviewed and, in an attached Appendix A, all 11 reports of g-NETs that occurred in long-term PPI users in the absence of CAG or ZES are summarized. Mention of additional suspected cases reported elsewhere are also listed. Furthermore, the risk in humans may be affected by the presence of underlying conditions or genetic factors, including their PPI-metabolizer phenotype, with slow metabolizers likely at increased risk. Other problems in estimating the true incidence of g-NETs are discussed, relating to non-reporting of small tumors and failure of the Surveillance, Epidemiology, and End Results Program (SEER) and other databases, to capture small tumors or those not accorded a T1 rating. Overall, it appears likely that the true incidence of g-NETs may be seriously underestimated: the possibility that hypergastrinemia also affects tumorigenesis in additional gastrointestinal sites or in tumors in other organ systems is briefly examined. Overall, the risk of developing a g-NET appears greatest in patients who are more than 10 years on drug and on higher doses: those affected by chronic H. pylori gastritis and/or consequent gastric atrophy may also be at increased risk. While the overall risk of g-NETs induced by PPI therapy is undoubtedly low, it is real: this necessitates caution in using PPI therapy for long periods of time, particularly when initiated in young subjects.

Case report: optimal tumor cytoreduction and octreotide with durable disease control in a patient with MEN-1 and Zollinger-Ellison syndrome-over a decade of follow-up.

BACKGROUND: Zollinger-Ellison syndrome (ZES) is a rare condition characterized by hypersecretion of gastrin by gastrinoma tumors leading to severe peptic ulcer disease with potential development of gastric carcinoid tumors. Herein, we report the clinical course of a 68-year-old patient with multiple endocrine neoplasia type 1 (MEN-1) who underwent several surgeries to ultimately undergo optimal tumor cytoreduction of locally advanced gastrinomas and symptomatic gastric carcinoids. The patient was subsequently maintained on octreotide long-acting release (LAR). This case report supports consideration for aggressive tumor cytoreduction and octreotide in similar patients with MEN-1-associated ZES for durable disease control and symptom management. CASE PRESENTATION: The patient is a 68-year-old male with multiple endocrine neoplasia type 1 (MEN-1), diagnosed in 1993 after presenting with recurrent renal calculi and hypercalcemia. Soon thereafter, he presented with symptoms and elevated gastrin levels suggestive of ZES prompting abdominal exploration with partial resection of the duodenum to remove gastrinoma tumor nodules. Within 4 years of the operation, he represented with intractable hypergastrinemia despite optimal medical management with peak gastrin levels exceeding 29,000 pg/mL, in 2006. In January 2007, the patient returned to the operating room for resection of regional peripancreatic and perigastric lymph nodes and enucleation of pancreatic body and tail gastrinoma tumors. Although his gastrin level decreased to 5000 pg/mL with resultant improvement of symptoms, in less than 2 years, he developed disease progression with obstructive symptomatology from enlarging gastric carcinoids and rising gastrin levels. In May of 2008, he underwent pancreaticoduodenectomy and near-total gastrectomy. Since June of 2008, the patient shows no demonstrable progression of disease and remains asymptomatic on LAR octreotide (30 mgs). Gastrin levels have been well controlled (range, 100-624 pg/mL; current 114 pg/mL). CONCLUSION: Success of this procedure in our case report highlights the potential role for optimal tumor cytoreduction and LAR octreotide to control disease progression in a patient with MEN-I and Zollinger-Ellison syndrome with locally advanced gastrinoma and secondary large gastric carcinoids.

Insights into Effects/Risks of Chronic Hypergastrinemia and Lifelong PPI Treatment in Man Based on Studies of Patients with Zollinger-Ellison Syndrome.

The use of proton pump inhibitors (PPIs) over the last 30 years has rapidly increased both in the United States and worldwide. PPIs are not only very widely used both for approved indications (peptic ulcer disease, gastroesophageal reflux disease (GERD), Helicobacter pylori eradication regimens, stress ulcer prevention), but are also one of the most frequently off-label used drugs (25-70% of total). An increasing number of patients with moderate to advanced gastroesophageal reflux disease are remaining on PPI indefinitely. Whereas numerous studies show PPIs remain effective and safe, most of these studies are <5 years of duration and little data exist for >10 years of treatment. Recently, based primarily on observational/epidemiological studies, there have been an increasing number of reports raising issues about safety and side-effects with very long-term chronic treatment. Some of these safety issues are related to the possible long-term effects of chronic hypergastrinemia, which occurs in all patients taking chronic PPIs, others are related to the hypo-/achlorhydria that frequently occurs with chronic PPI treatment, and in others the mechanisms are unclear. These issues have raised considerable controversy in large part because of lack of long-term PPI treatment data (>10-20 years). Zollinger-Ellison syndrome (ZES) is caused by ectopic secretion of gastrin from a neuroendocrine tumor resulting in severe acid hypersecretion requiring life-long antisecretory treatment with PPIs, which are the drugs of choice. Because in <30% of patients with ZES, a long-term cure is not possible, these patients have life-long hypergastrinemia and require life-long treatment with PPIs. Therefore, ZES patients have been proposed as a good model of the long-term effects of hypergastrinemia in man as well as the effects/side-effects of very long-term PPI treatment. In this article, the insights from studies on ZES into these controversial issues with pertinence to chronic PPI use in non-ZES patients is reviewed, primarily concentrating on data from the prospective long-term studies of ZES patients at NIH.

Roar Strøm - the Norwegian surgeon who was three years ahead of Zollinger and Ellison. / Roar Strøm ­ kirurgen som kom Zollinger og Ellison i forkjøpet.

BACKGROUND: In 1952, Norwegian surgeon Roar Strøm (1903-58) published the medical history of a 32-year-old man with recurrent peptic ulcer disease and a pancreatic tumour. Three years later, two American surgeons described a similar condition and, only the following year, the condition was named after them: Zollinger-Ellison syndrome. Strøm's contribution has gone remarkably unrecognised. This article aims to highlight his professional achievements. MATERIAL AND METHOD: We searched archives and reference databases for information on Roar Strøm. RESULTS: Roar Strøm grew up in Oslo, where he graduated with a medical degree in 1926, at just 23 years of age. Strøm pursued a focused career in surgery: specialist in surgery in 1935, medical doctorate in 1942, and senior consultant in surgery at Rogaland Hospital in Stavanger over the period 1945-1956. While in Stavanger, he published the extensive case history in Acta Chirurgica Scandinavica. The patient had a multi-year medical history of peptic ulcers, for which he had undergone surgery twice previously before being operated on by Strøm in the spring of 1951. The man died two years after the last operation. INTERPRETATION: Neither Strøm nor Zollinger and Ellison were the first to identify this clinical condition as a new disease entity. But Strøm's article was an important contribution to the early literature on the syndrome.

[Gastric neuroendocrine tumors]. / Neiroéndokrinnye opukholi zheludka.

Gastrointestinal neuroendocrine tumors are rare neoplasms. Currently, incidence of gastric neuroendocrine tumors (gNETs) is being significantly increased. There are 3 groups of gNETs: types I, II and III. Each type has important features regarding clinical picture, prognosis and treatment strategy. Type I is the most common (70-80%) and associated with chronic atrophic gastritis including autoimmune gastritis and Helicobacter associated atrophic gastritis. Type II (5-6%) is associated with multiple endocrine neoplasia type I and Zollinger-Ellison syndrome (MEN I - ZES). Both types are characterized by hypergastrinemia and small tumor dimension. These neoplasms are multiple and mostly benign. On the contrary, NETs type III (10-15%) is not associated with hypergastrinemia and represented by single large neoplasms. Tumors are malignant as a rule. Therefore, surgical resection and chemotherapy are preferred for these tumors. Endoscopic surgery followed by observation is acceptable for almost all NETS type I and II. At the same time, this approach is advisable only for small and highly differentiated neoplasms type III.

Prospective Evaluation of Results of Reoperation in Zollinger-Ellison Syndrome.

OBJECTIVE: To determine the role of reoperation in patients with persistent or recurrent Zollinger-Ellison Syndrome (ZES). BACKGROUND: Approximately, 0% to 60% of ZES patients are disease-free (DF) after an initial operation, but the tumor may recur. METHODS: A prospective database was queried. RESULTS: A total of 223 patients had an initial operation for possible cure of ZES and then were subsequently evaluated serially with cross sectional imaging-computed tomography, magnetic resonance imaging, ultrasound, more recently octreoscan-and functional studies for ZES activity. The mean age at first surgery was 49 years and with an 11-year mean follow-up 52 patients (23%) underwent reoperation when ZES recurred with imageable disease. Results in this group are analyzed in the current report. Reoperation occurred on a mean of 6 years after the initial surgery with a mean number of reoperations of 1 (range 1-5). After reoperation 18/52 patients were initially DF (35%); and after a mean follow-up of 8 years, 13/52 remained DF (25%). During follow-up, 9/52 reoperated patients (17%) died, of whom 7 patients died a disease-related death (13%). The overall survival from first surgery was 84% at 20 years and 68% at 30 years. Multiple endocrine neoplasia type 1 status did not affect survival, but DF interval and liver metastases did. CONCLUSIONS: These results demonstrate that a significant proportion of patients with ZES will develop resectable persistent or recurrent disease after an initial operation. These patients generally have prolonged survival after reoperation and 25% can be cured with repeat surgery, suggesting all ZES patients postresection should have systematic imaging, and if tumor recurs, advise repeat operation.

Per-oral endoscopic tunneling for restoration of the esophagus: a novel endoscopic submucosal dissection technique for therapy of complete esophageal obstruction.

BACKGROUND AND AIMS: Total aphagia from complete esophageal obstruction (CEO) can be seen in patients with head-neck or thoracic malignancies undergoing chemoradiation or surgery. Combined antegrade and retrograde endoscopy (via gastrostomy tube [G-tube] tract) is often performed for esophageal reconstruction but is limited by the length of the obstructed esophagus. We describe per-oral endoscopic tunneling for restoration of the esophagus (POETRE) for patients with longer segments of esophageal obstruction. The aim of this study was to assess the efficacy and safety of POETRE for CEO. METHODS: All patients with CEO undergoing endoscopy with POETRE from October 2013 to September 2015 were enrolled in this single-center prospective study. Clinical, endoscopic, and radiologic records were maintained as required for clinical care and for the study. Dysphagia score was recorded before and after POETRE. Adverse events were assessed based on the American Society for Gastrointestinal Endoscopy criteria. RESULTS: Four patients (3 men; mean age, 72.3 years) underwent POETRE for CEO ≥3 cm in length. Esophageal reconstruction was technically successful in all patients (100%). Antegrade submucosal tunneling was performed in 2 of 4 patients (50%), and retrograde tunneling was performed in the other 2 patients, all with simultaneous dual endoscope and fluoroscopic guidance. The mean dysphagia score of 4 before the procedure improved to 2.5 after POETRE during follow-up (mean, 27.8 weeks). All patients required subsequent serial endoscopic dilations as needed after POETRE. One adverse event (pneumonia) was seen (25%). CONCLUSIONS: We present a novel ESD technique, POETRE, for therapy of complete esophageal obstruction. This approach is specifically useful for lumen restoration in patients with longer segments of esophageal obstruction. (Clinical trial registration number: NCT00968552.).