Immunotherapy for esophageal cancer: Where are we now and where can we go.

Immune checkpoint inhibitor therapy has dramatically improved patient prognosis, and thereby transformed the treatment in various cancer types including esophageal squamous cell carcinoma (ESCC) in the past decade. Monoclonal antibodies that selectively inhibit programmed cell death-1 (PD-1) activity has now become standard of care in the treatment of ESCC in metastatic settings, and has a high expectation to provide clinical benefit during perioperative period. Further, anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) monoclonal antibody has also been approved in the treatment of recurrent/metastatic ESCC in combination with anti-PD-1 antibody. Well understanding of the existing evidence of immune-based treatments for ESCC, as well as recent clinical trials on various combinations with chemotherapy for different clinical settings including neoadjuvant, adjuvant, and metastatic diseases, may provide future prospects of ESCC treatment for better patient outcomes.

Thoracoscopic McKeown esophagectomy in a patient with an azygos lobe.

BACKGROUND: The azygos lobe is a relatively rare anatomical variation, and there have been no reports, until date, of thoracoscopic McKeown esophagectomy for esophageal cancer in a patient with an azygos lobe. The azygos lobe can be diagnosed by chest X-ray or CT, and is usually not associated with any symptoms. However, surgeons should be aware that transthoracic surgical procedures in patients with an azygos lobe could be associated with a high risk of complications. CASE PRESENTATION: An 83-years-old man was brought to our emergency room with fever, severe headache, and difficulty in moving. MRI revealed a brain abscess, which was treated by abscess drainage and systemic antibiotic treatment. Further examinations to determine the cause of the brain abscess revealed esophageal cancer. In addition, CT revealed an azygos lobe in the right thoracic cavity. Although intrathoracic adhesions were anticipated on account of a previous history of bacterial pyothorax, we decided to perform esophagectomy via a thoracoscopic approach. Despite the difficulty in dissecting the intrathoracic adhesions, we were able to obtain the surgical field thoracoscopically. Then, we found the azygos lobe, as diagnosed preoperatively, and the azygos vein was supported by the mesentery draining into the superior vena cava. After dividing the mesentery, we clipped and cut the vessel, and both ends were further ligated. After these procedures, we safely performed esophagectomy with 3-field lymph node dissection. The postoperative course was uneventful, and the patient was discharged on the 21st postoperative day. CONCLUSIONS: Although there was a firm adhesion in the thoracic cavity, preoperative recognition of the azygos lobe could help in preventing intraoperative injury. Especially, esophageal surgeons are required to deal with the azygos lobe safely to avoid serious intraoperative injury.

Current status and future perspectives for the treatment of resectable locally advanced esophagogastric junction cancer: A narrative review.

Incidence rates for esophagogastric junction cancer are rising rapidly worldwide possibly due to the economic development and demographic changes. Therefore, increased attention has been paid to the prevention, diagnosis, and the treatment of esophagogastric junction cancer. Although there are discrepancies in the treatment strategy between Asian and Western countries, surgery remains the mainstay of treatment for esophagogastric junction cancer. Recent developments of perioperative multidisciplinary treatment may lead to better therapeutic effect, higher complete resection rate, and better control of the residual diseases, thus result in prolonged prognosis. In this review, we will focus on the treatment of locally advanced resectable esophagogastric junction cancer, and discuss the current status and future perspectives of the perioperative treatment including chemotherapy, radiation therapy, and immunotherapy, as well as the surgical strategy. Better understanding of the latest treatment strategy and future overlook may enable to standardize and individualize the treatment for esophagogastric junction cancer, thus leading to better prognosis for those patients.

Effective Postoperative Surveillance Protocol after Thoracoscopic Esophagectomy Focusing on Symptoms in Patients with Esophageal Cancer.

BACKGROUND: The optimal postoperative surveillance protocol after esophagectomy for patients with esophageal cancer has still not been established. We investigated the risk factors for recurrence of esophageal cancer to devise an appropriate surveillance protocol. We focused on the appearance and worsening of symptoms to determine if additional imaging examinations should be performed. STUDY DESIGN: We enrolled 416 patients with esophageal and esophagogastric junctional cancer who had undergone thoracoscopic esophagectomy at Tokai University Hospital. Outpatient visits for the patients are usually scheduled at least 4 times per year with CT imaging and blood biochemical examination. We evaluated the time to recurrence after esophagectomy, especially the correlation of this parameter with the appearance and worsening of symptoms during the postoperative outpatient follow-up. RESULTS: Of the 416 patients, recurrence occurred in 127 patients (30.5%). The median time to recurrence was 6 months after esophagectomy; recurrence occurred within 24 months in 112 patients (88%), and 51 of these patients (40%) developed some new symptom(s) (symptomatic group) before the diagnosis of recurrence. The number of patients who developed recurrence within 6 months was significantly higher in the symptomatic group compared with that in the asymptomatic group (66.7% vs 46.0%, p = 0.02). The overall survival in the symptomatic group was significantly shorter than that in the asymptomatic group (p < 0.001). CONCLUSIONS: We advocate an effective surveillance protocol depending on the appearance and worsening of symptoms to diagnose recurrence of esophageal cancer; we recommend routine imaging examinations every 6 months and clinical outpatient follow-up at even shorter intervals for the first 24 months after esophagectomy.

Usefulness of three-dimensional thoracoscope for prone position thoracoscopic esophagectomy improves mediastinal lymph node dissection and prognosis for esophageal cancer.

OBJECTIVES: This study aimed to assess the superiority of 3D flexible thoracoscope against 2D thoracoscope for lymph node dissection (LND) and prognosis for prone-position thoracoscopic esophagectomy (TE) in esophageal cancer. METHODS: Three hundred and sixty-seven esophageal cancer patients who underwent prone-position TE with 3-field LND between 2009 and 2018 were evaluated. 2D and 3D thoracoscope was used in 182 (2D group) and 185 cases (3D group), respectively. Short-term surgical outcomes, numbers of retrieved mediastinal lymph node (LN), and rates of LN recurrence were compared. Risk factors for mediastinal LN recurrence and long-time prognosis were also evaluated. RESULTS: No differences in postoperative complications were observed between the groups. The numbers of retrieved mediastinal LN were significantly higher, and the rates of LN recurrence were significantly lower in the 3D group compared to 2D group. Use of 2D thoracoscope was a significant independent factor of middle mediastinal LN recurrence by multivariable analysis. Survival was compared by cox regression analysis, and the 3D group had a significantly better prognosis than the 2D group. CONCLUSIONS: Prone position TE using 3D thoracoscope may improve the accuracy of mediastinal LND and prognosis without increasing postoperative complications for esophageal cancer.

Usefulness of skeletal muscle measurement by computed tomography in patients with esophageal cancer: changes in skeletal muscle mass due to neoadjuvant therapy and the effect on the prognosis.

PURPOSE: This analysis was performed to clarify the usefulness of skeletal muscle measurements using computed tomography (CT) in patients with esophageal cancer and the effect of treatment-induced changes in the skeletal muscle mass on the prognosis. METHODS: Ninety-seven male patients who underwent thoracoscopic esophagectomy for esophageal squamous cell carcinoma were included in the study. The preoperative CT images were analyzed retrospectively. RESULTS: In a survival analysis performed according to the preoperative data of skeletal muscle, the low-skeletal muscle index (l-SMI) group had a poorer outcome than the normal skeletal muscle index (n-SMI) group in terms of both the overall survival (OS) and the relapse-free survival (RFS) (OS: P < 0.01, RFS: P = 0.01). In the multivariate analysis for the OS, preoperative l-SMI was an independent predictor (hazard ratio: 3.68, 95% confidence interval 1.32-10.2, P = 0.01). In patients who underwent neoadjuvant therapy (NAT), the SMI was significantly reduced after NAT (P < 0.01). The preoperative skeletal muscle area on CT was strongly correlated with the results of a bioelectrical impedance analysis (BIA) (ρ = 0.77, P < 0.01). CONCLUSIONS: A decreased preoperative skeletal muscle mass was associated with a poor outcome. In patients who underwent NAT, the SMI was significantly reduced after NAT. An analysis of the skeletal muscle mass using CT images was found to be useful for providing data that corresponded with BIA data.

Thoracoscopic esophagectomy for stenosis of thoracic esophagus due to acute esophageal necrosis associated with alcoholic ketoacidosis.

Acute esophageal necrosis (AEN) is a rare disease characterized by the appearance of diffuse black mucosa on upper gastrointestinal endoscopy; the condition often progresses to esophageal stenosis in the chronic phase. A 70-year-old man was admitted to a neighborhood hospital with the diagnosis of alcoholic ketoacidosis and an upper gastrointestinal endoscopy performed to investigate the symptom of esophageal tightness revealed AEN. The patient developed esophageal stenosis with scarring in the chronic phase and was referred to our hospital for surgery 6 months after the diagnosis of AEN. We performed thoracoscopic esophagectomy with the patient in the prone position. Although the esophagus was thickened and strong adhesions were present around the esophagus due to inflammation, we were able to complete the surgical procedure thoracoscopically. In patients presenting with benign esophageal stenosis developing after AEN, thoracoscopic esophagectomy may be a useful treatment option, even in the presence of severe fibrosis.

Internal hernia caused by bridge formation between the medial and lateral segments of the liver: a case report.

BACKGROUND: Despite numerous reports on ischemic bowel obstruction caused by internal hernia, no case presentation has been reported of an internal hernia caused by a bridge formed between the medial and lateral zones of the liver. Herein, we report the first case of ischemic bowel obstruction caused by a hepatic bridge. CASE PRESENTATION: A 24-year-old man complaining of abdominal pain was referred to our hospital and admitted. Computed tomography showed formation of a closed loop of small bowel with a hernia orifice near the hilar region, and poor contrast of the prolapsed small bowel. We suspected ischemic bowel obstruction caused by an internal hernia with a fissure of the greater omentum as the hernia orifice, and performed emergency surgery. Laparoscopic observation revealed that the medial and lateral segments of the liver formed a bridge on the dorsal side at the liver portal, and that the small intestine was ischemic in the gap created between the bridge and the medial and lateral liver segments. A Meckel's diverticulum was also invaginated in the gap. The bridge was dissected out and the hernia orifice was opened to release the bowel obstruction. The small bowel was preserved and the Meckel's diverticulum was resected. The patient's postoperative course was uneventful. CONCLUSIONS: We experienced a case of ischemic bowel obstruction caused by hepatic bridge formation, which was successfully treated by laparoscopic surgery.

Impact of Subclassification of Serosal Invasion on the Survival of Patients With T4a Gastric Cancer.

BACKGROUND/AIM: In the Japanese Classification of Gastric Carcinoma, T4a gastric cancer is defined as tumor invasion contiguous to the serosa or penetrating the serosa with exposure to the peritoneal cavity. The aim of this study was to assess the impact of T4a subclassification of gastric cancer on survival. PATIENTS AND METHODS: A total of 326 patients with T4a cancer who had undergone gastrectomy were enrolled. The T4a tumors were classified into two groups: serosa-contiguous or serosa-exposed. RESULTS: The serosa-exposed group had a significantly worse prognosis, and multivariate analysis identified the T4a subclass as an independent prognostic factor. Analysis of the risk factors for recurrence identified the T4a subclass as a significant risk factor for peritoneal recurrence in patients undergoing curative gastrectomy. CONCLUSION: The serosa-contiguous and serosa-exposed subgroups of T4a gastric cancer showed different biological behaviors. These groups may need to be treated as separate.

Indocyanine green fluorescence imaging for evaluating blood flow in the reconstructed conduit after esophageal cancer surgery.

We investigated the effectiveness of indocyanine green (ICG) fluorescence blood flow imaging of the gastric conduit to evaluate anastomotic leakage after esophagectomy. We identified 19 articles using the PRISMA standard for systematic reviews. The more recent studies reported attempts at objective quantification of ICG fluorescence imaging, rather than qualitative assessment. Anastomotic leakage after esophagectomy occurred in 0-33% of the patients who underwent ICG fluorescence imaging. According to the six studies that compared the incidence of anastomotic leakage in the ICG group and the control group, it ranged from 0 to 18.3% in the ICG group and from 0 to 25.2% in the control group, respectively. Overall, the incidence of anastomotic leakage in the ICG group (8.4%) was lower than that in the control group (18.5%). Although the incidence of anastomotic leakage was as high as 43.1% in patients who did not undergo any intraoperative intervention for poor blood flow, it was only 24% in patients who underwent intraoperative intervention. This systematic review revealed that ICG fluorescence imaging may be a crucial adjunctive tool for reducing anastomotic leakage after esophagectomy, suggesting that it should be performed during esophageal reconstruction.

Does synchronous early head and neck cancer with esophageal cancer need treatment after preoperative chemotherapy?

OBJECTIVE: Treatment options for patients with resectable thoracic esophageal squamous cell cancer (ESCC) and synchronous head and neck cancer (HNC) are unclear. Little has been reported about the effects of chemotherapy on early HNC. The aim of this study was to investigate the treatment outcomes of resectable thoracic ESCC with synchronous early HNC. METHODS: We retrospectively reviewed 37 patients undergoing esophagectomy for thoracic ESCC with synchronous early HNC from January 2008 to December 2018. RESULTS: Among 37 patients who had synchronous early HNC, 27 patients received preoperative therapy for ESCC before HNC treatment, and 16 of 27 patients achieved a complete response for HNC by preoperative chemotherapy. Fifteen of 16 patients did not receive additional treatment, and regional recurrence of HNC was not observed. In one other case, an oral excision was performed, but no cancer cell remnants were found pathologically. No significant difference in overall survival and disease-free survival was observed between 15 patients with follow-up and 22 patients with surgery or radiation. CONCLUSION: Our results indicate that early HNC with comorbid ESCC could be followed up without additional treatment if preoperative chemotherapy is successful.

Multimodal Treatment Strategies to Improve the Prognosis of Locally Advanced Thoracic Esophageal Squamous Cell Carcinoma: A Narrative Review.

Esophageal cancer is the seventh most common malignancy and sixth most common cause of cancer-related death globally. Esophageal squamous cell carcinoma (ESCC) with aortic or tracheal invasion is considered unresectable, and has an extremely poor prognosis; its standard treatment is definitive chemoradiotherapy (dCRT). In recent years, induction chemotherapy (ICT) has been reported to yield high response rates for locally advanced ESCC, and the efficacy and safety of ICT followed by conversion surgery (CS) have been investigated. Multimodal treatment, combining surgery with induction chemoradiotherapy (ICRT) or ICT, is necessary to improve ESCC prognosis. CS is generally performed for locally advanced ECC after ICRT or ICT when tumor downstaging is achieved, although its prognostic benefit remains controversial. The Japan Clinical Oncology Group (JCOG) has conducted a three-arm phase III randomized controlled trial (JCOG1510) to confirm the superiority of DCF (docetaxel, cisplatin, and 5-fluorouracil) ICT, over conventional dCRT, among patients with initially unresectable ESCC. In recent years, researchers have reported favorable outcomes of induction therapy followed by CS and salvage surgery, after dCRT or systemic immunochemotherapy. In this review, we will describe the latest developments in the multimodal treatment including chemotherapy, CRT, surgery, and immunotherapy, which may improve oncological and survival outcomes for patients with cT4 ESCC.

Small bowel obstruction caused by a true ileo-ileal knot: a rare case successfully treated by prior ligation of mesenteric vessels.

BACKGROUND: Intestinal knot formation, in which two segments of the intestine become knotted together, can result in intestinal obstruction. An ileo-ileal knot refers to knot formation between two ileal segments and is a very rare benign disease. We report a case of strangulated bowel obstruction caused by true ileo-ileal knot formation. CASE PRESENTATION: An 89-year-old woman was referred to our hospital with the diagnosis of intestinal obstruction. Contrast-enhanced computed tomography revealed the small bowel forming a closed loop, with poor contrast effect. Based on the findings, the patient was diagnosed as having strangulated bowel obstruction, and emergency surgery was performed. At laparotomy, two segments of the ileum were found to be tied together forming a knot, and both segments were necrotic. Although it was necessary to release the strangulated small bowel, we did not immediately release the knot, but first proceeded with ligation of the mesenteric vessels to the strangulated small bowel to prevent dissemination of toxic substances from the necrotic bowel into the systemic circulation. The surgery was completed with resection of the necrotic ileum and anastomosis of the small intestine. The postoperative course was uneventful, and the patient was discharged home. CONCLUSION: We encountered a case of strangulated bowel obstruction caused by true ileo-ileal knot formation. Resection of the necrotic small intestine without releasing the knot could be performed safely, and might be considered as an option of surgical procedure.

Progress in Multimodal Treatment for Advanced Esophageal Squamous Cell Carcinoma: Results of Multi-Institutional Trials Conducted in Japan.

In Japan, the therapeutic strategies adopted for esophageal carcinoma are based on the results of multi-institutional trials conducted by the Japan Esophageal Oncology Group (JEOG), a subgroup of the Japan Clinical Oncology Group (JCOG). Owing to the differences in the proportion of patients with squamous cell carcinoma among all patients with esophageal carcinoma, chemotherapeutic drugs available, and surgical procedures employed, the therapeutic strategies adopted in Asian countries, especially Japan, are often different from those in Western countries. The emphasis in respect of postoperative adjuvant therapy for patients with advanced esophageal squamous cell carcinoma (ESCC) shifted from postoperative radiotherapy in the 1980s to postoperative chemotherapy in the 1990s. In the 2000s, the optimal timing of administration of perioperative adjuvant chemotherapy returned from the postoperative adjuvant setting to the preoperative neoadjuvant setting. Recently, the JEOG commenced a three-arm randomized controlled trial of neoadjuvant therapies (cisplatin + 5-fluorouracil (CF) vs. CF + docetaxel (DCF) vs. CF + radiation therapy (41.4 Gy) (CRT)) for localized advanced ESCC, and patient recruitment has been completed. Salvage and conversion surgeries for ESCC have been developed in Japan, and the JEOG has conducted phase I/II trials to confirm the feasibility and safety of such aggressive surgeries. At present, the JEOG is conducting several trials for patients with resectable and unresectable ESCC, according to the tumor stage. Herein, we present a review of the JEOG trials conducted for advanced ESCC.

Extra-gastrointestinal stromal tumor arising in the lesser omentum with a platelet-derived growth factor receptor alpha (PDGFRA) mutation: a case report and literature review.

BACKGROUND: Gastrointestinal stromal tumors (GIST) arising from sites other than the gastrointestinal (GI) tract, termed extra-gastrointestinal stromal tumors (EGIST), are rare. Among EGIST, those with platelet-derived growth factor receptor alpha (PDGFRA) mutations are even rarer, with only a few cases reported. About 80% of GIST has KIT mutations, and 10% of GIST have PDGFRA mutations, which commonly affect the TK2 domain (exon 18). Among the exon 18 mutations, the D842V substitution is limited to gastric GIST. In EGIST, the degree of KIT and PDGFRA mutations varies on where the location of the tumor is, and it is suggested that omental EGIST is similar to gastric GIST. Adjuvant imatinib therapy is recommended for high-risk GIST; however, it is known that imatinib is less effective against GIST with a PDGFRA D842V mutation. CASE PRESENTATION: A 75-year-old man was referred to our hospital with an extrinsic tumor of the lesser curvature of the gastric body. Intraoperative findings showed a tumor located outside of the lesser omentum with no connection between the tumor and the gastric wall. The tumor was subsequently resected. Pathological examination indicated a GIST arising in the lesser omentum measuring 70 mm in its longer dimension. Because the tumor had a PDGFRA mutation (D842V substitution), imatinib was suspected to lack efficacy to the tumor. Thus, although the tumor was considered clinically to have a high risk of recurrence, adjuvant imatinib therapy was not indicated. The patient has been free of recurrence for 29 months since the surgery. CONCLUSION: We described a case of EGIST with a PDGFRA mutation arising in the lesser omentum. And we reviewed 57 cases of omental EGIST and showed that the clinicopathological characteristics and mutation status in omental EGIST were very similar to gastric GIST. In particular, PDGFAR D842V mutation rate in omental EGIST seemed as high as that in gastric GIST. These results suggested that omental EGIST is strongly related to gastric GIST, so the behavior of omental EGIST might be akin to gastric GIST. However, further studies are required to determine the prognosis and the necessity of adjuvant therapy for EGIST with a PDGFRA mutation.

Early and midterm results of minimally invasive aortic and mitral valve surgery via right mini-thoracotomy.

OBJECTIVES: There are few reports regarding minimally invasive aortic valve replacement concomitant with mitral valve surgery (MIAMVS). The aim of this study was to evaluate early and midterm MIAMVS results. METHODS: We reviewed the medical records of 21 consecutive patients (nine females, 43%) who underwent MIAMVS through a right mini-thoracotomy from December 2014 to April 2017. Mean patient age was 73 ± 7.4 years and four (19%) were New York Heart Association Class III or IV. Aortic stenosis and mitral valve insufficiency were the most common pathologies. All patients were followed for a mean period of 30 ± 8.5 months. RESULTS: The types of surgery consisted of aortic valve replacement with mitral valve repair in 11 (52%) patients, and replacement of both aortic and mitral valves in 10 (48%), while a tricuspid valve repair, was performed in four. No conversion to a full sternotomy was necessary in any of the cases. Postoperatively, the median intensive care unit and hospital stays were 4.7 and 11.8 days, respectively, with no in-hospital mortality. Following the initial treatment, all 21 patients were followed for a mean period of 30 ± 8.5 months (14-45 months). All patients returned to NYHA Class I or II following the procedure. During the follow-up period, there was no need for a heart valve reoperation for any of the patients and none showed recurrent mitral regurgitation (>mild), though one died from respiratory failure caused by pneumonia. CONCLUSIONS: MIAMVS can be performed via a right mini-thoracotomy, with acceptable early and midterm results expected. This may be a feasible alternative to the standard median sternotomy approach.