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.

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.

Intraperitoneal administration of nanoparticles containing tocopheryl succinate prevents peritoneal dissemination.

Intraperitoneal administration of anticancer nanoparticles is a rational strategy for preventing peritoneal dissemination of colon cancer due to the prolonged retention of nanoparticles in the abdominal cavity. However, instability of nanoparticles in body fluids causes inefficient retention, reducing its anticancer effects. We have previously developed anticancer nanoparticles containing tocopheryl succinate, which showed high in vivo stability and multifunctional anticancer effects. In the present study, we have demonstrated that peritoneal dissemination derived from colon cancer was prevented by intraperitoneal administration of tocopheryl succinate nanoparticles. The biodistribution of tocopheryl succinate nanoparticles was evaluated using inductively coupled plasma mass spectroscopy and imaging analysis in mice administered quantum dot encapsulated tocopheryl succinate nanoparticles. Intraperitoneal administration of tocopheryl succinate nanoparticles showed longer retention in the abdominal cavity than by its intravenous (i.v.) administration. Moreover, due to effective biodistribution, tumor growth was prevented by intraperitoneal administration of tocopheryl succinate nanoparticles. Furthermore, the anticancer effect was attributed to the inhibition of cancer cell proliferation and improvement of the intraperitoneal microenvironment, such as decrease in the levels of vascular endothelial growth factor A, interleukin 10, and M2-like phenotype of tumor-associated macrophages. Collectively, intraperitoneal administration of tocopheryl succinate nanoparticles is expected to have multifaceted antitumor effects against colon cancer with peritoneal dissemination.

Distal gastric tube resection with preservation of the right gastroepiploic artery for gastric tube cancer: a case report.

BACKGROUND: The incidence of gastric tube cancer is increasing because of improved survival rates in patients with esophageal cancer treated by esophagectomy. Total resection of the gastric tube is expected to be highly curative, but it is associated with a higher risk of severe postoperative complications. Herein we report a case of early gastric tube cancer that was successfully treated by distal gastric tube resection with preservation of the right gastroepiploic artery (RGEA). CASE PRESENTATION: An 82-year-old man was diagnosed as having gastric tube cancer, B-12-O, Type 0-IIc, T1b, N0, M0, cStage IA (Japanese Classification of Gastric Carcinoma). Upper gastrointestinal endoscopy showed a Type 0-IIc lesion measuring 30 mm in length in the lower part of the gastric tube, and histopathological examination of biopsy specimens revealed the features of poorly differentiated adenocarcinoma. The primary lesion could not be identified by computed tomography, and there was no obvious lymph node metastasis or distant metastasis. Considering that total resection of the gastric tube would have been highly invasive and that the gastric tube cancer was at a relatively early stage, we performed distal gastric tube resection with preservation of the RGEA. The postoperative course was uneventful, and the patient was discharged on postoperative day 12. There has been no recurrence during the 17 months of follow-up. CONCLUSION: We successfully treated a patient with gastric tube cancer by distal gastric tube resection with preservation of the RGEA. This treatment strategy may be acceptable for patients with early gastric tube cancer without lymph node metastasis, considering the balance between the surgical invasiveness and curability of the tumor.

Coexistence of gastric cancer and gastric GIST with intra-tumor bleeding: successful embolization with subsequent total gastrectomy.

BACKGROUND: Gastrointestinal stromal tumor (GIST) is a rare tumor, however, simultaneous development of gastric cancer and gastric GIST has been documented more frequently in recent years. Rupture of gastric GIST is even more rare and occurred in 7% of all GISTs. Although ruptured GIST might be occasionally difficult to be managed by endoscopy, transcatheter arterial embolization (TAE) was reported to control bleeding from GIST effectively. We report herein a case of coexistence of gastric cancer and gastric GIST with progressing intra-tumor bleeding managed successfully by TAE and review the clinicopathological characteristics of this rare condition reported previously in the Japanese literature. CASE PRESENTATION: A 75-year-old woman with dyspnea and systemic edema was diagnosed as simultaneous occurrence of gastric cancer (histopathologically detected tubular adenocarcinoma pT2N1M0 fStageIIA) and gastric GIST (65 × 92 mm in diameter at the anterior wall of the fornix) with intra-tumor hemorrhage. Perceiving the progress of bleeding from tumor growth and exacerbating anemia, TAE of left gastric artery was performed. Then remission of anemia has been obtained, the patient underwent an elective radical surgery. CONCLUSIONS: Simultaneous occurrence of gastric cancer and gastric GIST was speculated to be more common. TAE for ruptured GIST may be effective for hemostasis and reduction of tumor burden, which could facilitate minimal invasive surgery.

The Present Status and Future of Barrett's Esophageal Adenocarcinoma in Japan.

BACKGROUND: The incidence of esophageal adenocarcinoma in Europe and the United States rapidly increased from the latter half of the 1970s and exceeded that of esophageal squamous cell carcinoma in the latter half of the 1990s, currently accounting for approximately 60% of all esophageal carcinomas. Recently, its incidence has also increased in Japan, raising concerns that it will follow a course similar to that in Europe and the United States. SUMMARY: The incidence of esophageal adenocarcinoma in Japan was about 2% until the 1990s, but in recent years, it has risen to 6.5-7.1%. Causes include the increase in the incidence of obesity due to changes in eating habits with resultant increases in the incidence of hiatal hernia and reflux esophagitis, a decrease in the rate of Helicobacter pylori infection, and the increased interest of physicians in the gastroesophageal junction. The number of gastroesophageal reflux disease patients in Japan rapidly increased from the 1990s, which accordingly increased the number of Barrett's esophageal adenocarcinoma patients from the latter half of the 1990s. Tabulation and analysis of 1,794 reported cases of Barrett's esophageal adenocarcinoma in Japan showed that superficial cancers accounted for 77.6%, and that the concomitant rates of hiatal hernia and reflux esophagitis were high at 87 and 70% respectively. Key Message: The future trend in the incidence of Barrett's esophageal adenocarcinoma in Japan will depend on the increase in the incidence of reflux esophagitis, which is essential for the development of Barrett's esophagus and Barrett's esophageal carcinoma. The obesity rate is lower in Japan than that in Europe and the United States, and the incidence and severity of reflux esophagitis are low. We expect that the incidence of Barrett's esophageal adenocarcinoma in Japan will not rise as high as in Europe and the United States, and will remain below 10%.

Perforated gastrointestinal stromal tumor in the small intestine: A rare case of Torricelli-Bernoulli sign.

The Torricelli-Bernoulli sign is a computed tomography (CT) finding that occurs when ulceration/necrosis of a submucosal gastrointestinal tumor releases a stream of air bubbles into the intestinal lumen. A 75-year-old man developed acute abdominal pain at night and presented to a local doctor. Acute abdomen was diagnosed and he was referred to the Emergency Department at Tokai University Oiso Hospital. On CT scans, disseminated intestinal tumor-like lesions were seen in the right lower abdomen. The Torricelli-Bernoulli sign and free intraabdominal gas were observed, so perforation of an intestinal tumor was diagnosed and emergency surgery was performed. At operation, there was scanty opaque ascites in the right lower abdomen and an ileal tumor associated with nodules that suggested peritoneal dissemination. Partial resection of the ileum was performed and peritoneal lavage was conducted. The patient was discharged on postoperative day 11. Histopathological examination revealed a high risk gastrointestinal stromal tumor. The abdominal nodules were metastases, indicating that the tumor was Stage IV. The patient is currently on treatment with an oral tyrosine kinase inhibitor (imatinib).

Expandable Metallic Stent for Endobronchial Metastasis from Colorectal Cancer: Reports of 2 Cases.

In recent years, there have been many reports about the efficacy of stenting for central bronchial stenosis. When central bronchial stenosis is due to metastasis of a malignant tumor to the trachea and/or bronchi (endobronchial metastasis: EM), it is classified as "narrow EM" and "broad EM." [1] We managed two patients in whom bilateral stent placement was required for narrow and broad EM arising from colorectal cancer. Case 1: In September 2011, a 66-year-old man underwent low anterior resection for advanced colorectal cancer associated with unresectable liver metastasis. The liver metastasis became resectable after chemotherapy, with two resection procedures and radiofrequency ablation (RFA) being performed. Thereafter, lung metastasis occurred and a tumor in the left lung was resected. In May 2015, he developed respiratory distress. CT identified multiple lesions protruding into the lumen of the trachea and the left and right main bronchi. There was no evidence of mediastinal relapse or local relapse at the resection margin, and tumors were only detected in the tracheobronchial walls. Accordingly, narrow EM was diagnosed. An expandable metallic stent (EMS) was placed on the right side where stenosis was more severe, and radiation therapy was conducted for the non-stented tumors. The patient died 8 months later. Case 2: A 69-year-old woman had undergone laparoscopic right hemicolectomy and adjuvant chemotherapy for Stage lllb cancer of the ascending colon. Due to subsequent elevation of tumor markers, PET-CT was conducted and abnormal uptake was seen in the apex of the right lung and right upper abdomen. Both lesions were resected, and omental and lung metastases were diagnosed. She received treatment with UFT / calcium folinate, but relapse occurred at the resection margin in the right lung. At 7 years and 5 months after initial surgery, she complained of respiratory distress at an outpatient visit. CT demonstrated displacement of the trachea and right main bronchus due to enlargement of upper mediastinal lymph nodes. There was also severe stenosis of the right main bronchus due to tumor infiltration. Because there was both infiltration from local recurrence after resection and upper mediastinal lymph node enlargement, broad EM was diagnosed. An EMS was placed at the site of severe stenosis in the right main bronchus. Similar to Case 1, radiation therapy was also conducted, but respiratory distress occurred after 3 months due to tumor re-growth at the stent margin. Accordingly, stent-in-stent placement was performed and her respiratory symptoms improved. However, superior vena cava syndrome occurred 1 month later and the patient died. We consider that placing an EMS is effective in patients with tracheal stenosis due to EM that is judged to be an oncological emergency.

Pulmonary artery hypoplasia associated with posterior mediastinal hematoma accompanied by a ruptured pseudoaneurysm of the esophageal branch of the left gastric artery.

A 65-year-old woman with no significant medical history visited the emergency department complaining of epigastric discomfort. A computed tomography of the thorax and abdomen showed the attenuation of the pulmonary artery and a posterior mediastinal hematoma. Angiography showed a tortuous esophageal branch of the left gastric artery and a pseudoaneurysm, and during the later phase, the left lower lobe of the lung was enhanced, and finally, the left pulmonary vein was enhanced. We considered that the patient was exhibiting hypoperfusion of the left pulmonary artery arising from left pulmonary artery hypoplasia, since the left lung was supplying the systemic circulation. Transcatheter arterial embolization was performed. The patient has not experienced any recurrence of a ruptured pseudoaneurysm or epigastric discomfort. Here, we report the first documented case of pulmonary artery hypoplasia associated with posterior mediastinal hematoma accompanied by a ruptured aneurysm of the left gastric artery.

Tumor Microenvironment-Sensitive Liposomes Penetrate Tumor Tissue via Attenuated Interaction of the Extracellular Matrix and Tumor Cells and Accompanying Actin Depolymerization.

Delivery of anticancer drugs into tumor cores comprised of malignant cancer cells can result in potent therapeutic effects. However, conventional nanoparticle-based drug delivery systems used for cancer therapy often exhibit inefficient tumor-penetrating properties, thus, suggesting the need to improve the functional design of such systems. Herein, we focus on the interactions between cancer cells and the extracellular matrix (ECM) and demonstrate that liposomes modified with slightly acidic pH-sensitive peptide (SAPSp-lipo) can penetrate in vivo tumor tissue and in vitro spheroids comprised of cancer cells and ECM. We previously reported SAPSp-lipo, tumor microenvironment-sensitive liposomes, are effectively delivered to tumor tissue (Hama et al. J Control Release 2015, 206, 67-74). Compared with conventional liposomes, SAPSp-lipo could be delivered to deeper regions within both spheroids and tumor tissues. Furthermore, tumor penetration was found to be promoted at regions where actin depolymerization was induced by SAPSp-lipo and inhibited by the polymerization of actin. In addition, SAPSp-lipo attenuated the interaction between cancer cells and ECM, contributing to the penetration of SAPSp-lipo. These results suggest that SAPSp-lipo penetrates tumors via the interspace route and is accompanied by actin depolymerization. Taken together, SAPSp-lipo demonstrates potential as a novel tumor-penetrable drug carrier for induction of therapeutic effects against malignant cells that comprise tumor cores.

Small Cell Type of Esophageal Neuroendocrine Carcinoma Resembling a Submucosal Tumor.

We report a rare case of primary small cell type esophageal neuroendocrine carcinoma with a unusual endoscopic form similar to a submucosal tumor with the results of the histological and immunohistochemical analyses. A 57-year-old woman with dysphagia was referred to our hospital for further examination and treatment, and was diagnosed as type 1s esophageal carcinoma in the middle thoracic esophagus. Endoscopy revealed a protruding esophageal carcinoma resembling a submucosal tumor with an irregular and nodular surface covered by non-neoplastic epithelium stained with iodine. Analysis of the esophageal biopsy specimen revealed poorly differentiated squamous cell carcinoma. Based on a diagnosis of type 1s carcinoma in the middle thoracic esophagus that was 5 cm in size longitudinally, a radical esophagectomy with three-field lymph node dissection was performed. The pathological examination with histological and immunohistochemical analysis of the resected specimen revealed a small cell type neuroendocrine carcinoma overlaid by a non-neoplastic epithelium, extending into the adventitia without lymph node metastasis (T3, N0, M0, Stage II). However, multiple metastases in the brain and lung developed 3 months postoperatively, and the patient died of the cancer 7 months after the operation. This was a rare case of a highly malignant primary small cell type esophageal neuroendocrine carcinoma showing extremely rare form.

Small Intestinal Metastasis from Esophageal Squamous Cell Carcinoma Presenting with Perforated Peritonitis.

Metastatic tumors of the small intestinal tract from extra-abdominal sites are rare. We report herein a rare case of small intestinal metastasis from esophageal carcinoma that presented with perforated peritonitis. A 71-year-old man with dysphagia was referred to our hospital for further examination and treatment, and was diagnosed with type 3 advanced esophageal squamous cell carcinoma of the lower thoracic esophagus. Based on a diagnosis of Stage II cancer, a radical esophagectomy with three-field lymph node dissection was performed after neoadjuvant chemotherapy composed of 5-fluorouracil plus cisplatin. Pathological examination of the resected specimen revealed a moderately differentiated squamous cell carcinoma, extending into the adventitia with lymph node metastasis (T3, N2, M0, Stage III). During postoperative adjuvant chemotherapy, the patient complained of abdominal pain and was found to have perforated peritonitis. Emergency laparotomy was performed. A jejunal perforation with a submucosal nodule approximately 80 cm distal from the ligament of Treitz was detected, and completely resected by jejunal partial resection. Histopathology of the specimen showed a perforation of the small intestine due to metastasis of esophageal squamous cell carcinoma with mesenteric lymph node metastasis. The patient died of cancer 9 months after surgery. An extremely rare case of small intestinal metastasis from esophageal carcinoma presenting with perforated peritonitis was described.

Lipocalin2 as a plasma marker for tumors with hypoxic regions.

Hypoxic tumors have been identified as appropriate indicators of tumor malignancy. However, no convenient plasma marker for hypoxic tumors has been described. Therefore, to identify a novel, convenient plasma marker for hypoxic tumors, we used microarray analysis to compare gene expression profiles of normoxic and hypoxic tumor tissues of mice bearing melanomas. Among the upregulated genes detected in hypoxic tumors, we chose to study the secretory protein lipocalin2 (LCN2) as a marker for hypoxic tumors. LCN2 protein levels in the plasma of mice bearing hypoxic tumors were significantly increased compared with those in mice bearing normoxic tumors. Interestingly, LCN2 mRNA levels were 17-fold higher in HIF-1α-positive hypoxic tumors than in HIF-1α-negative normoxic tumors. Furthermore, LCN2 mRNA levels were significantly higher in the B16-F1 cells and various human tumor cells cultured under hypoxic conditions than in cells cultured under normoxic conditions, while no changes in mRNA expression were observed in nontumor NIH-3T3 cells, even under hypoxic conditions. In cultured cells, the expression pattern of LCN2 was mostly consistent with that of HIF-1α, whereas that of a conventional hypoxic marker, carbonic anhydrase IX, was not. Collectively, our data suggested that LCN2 was a useful plasma marker for hypoxic tumors.

Histopathology of gastrointestinal neuroendocrine neoplasms.

Gastrointestinal neuroendocrine neoplasms (GI-NENs) arise from neuroendocrine cells distributed mainly in the mucosa and submucosa of the gastrointestinal tract. In 2010, the World Health Organization (WHO) classification of NENs of the digestive system was changed, categorizing these tumors as grade 1 neuroendocrine tumor (NET), grade-2NET, neuroendocrine carcinoma (large- or small-cell type), or mixed adenoneuroendocrine carcinoma (MANEC). Such a classification is based on the Ki-67 index and mitotic count in histological material. For the accurate pathological diagnosis and grading of NENs, it is important to clearly recognize the characteristic histological features of GI-NENs and to understand the correct method of counting Ki-67 and mitoses. In this review, we focus on the histopathological features of GI-NENs, particularly regarding biopsy and cytological diagnoses, neuroendocrine markers, genetic and molecular features, and the evaluation of the Ki-67 index and mitotic count. In addition, we will address the histological features of GI-NEN in specific organs.

New invasive patterns as a prognostic factor for superficial esophageal cancer.

BACKGROUND: Prognostic factors for superficial esophageal cancer cannot be limited to such factors as lymph node metastasis (N factor), depth of tumor invasion (T factor), and genetic alterations. The purpose of this study was to examine whether invasive growth patterns of tumors, such as infiltrative growth pattern c (INFc) and budding, represent new useful prognostic factors for superficial esophageal cancer. METHODS: We investigated 87 cases of superficial esophageal cancer in patients treated with radical surgery. First, the invasive growth pattern of the tumor was pathologically evaluated based on the traditional infiltrative growth pattern (INF) classification. Next, new INF criteria were proposed, and the invasive pattern was re-evaluated. We also investigated budding (Bud) in the stroma of the invasive frontal lesion. RESULTS: When the patients were divided into two groups, with and without an INFc component, the group with an INFc component had a poorer outcome than the group without an INFc component. When the group with an INFc component was defined as "new INFc", new INFc was correlated with the T factor (p = 0.006) and the ly factor (lymphatic invasion) (p = 0.041). Bud was correlated with the T factor (p = 0.001), the N factor (p = 0.030), and new INFc (p < 0.001). An analysis of survival revealed new INFc (p = 0.002) and Bud (p = 0.006) to be prognostic factors. The survival of the group with new INFc(+)/Bud(+) was poorer than that with new INFc(-)/Bud(-) (p = 0.007). CONCLUSIONS: New INFc and Bud, which represent new invasive patterns, were prognostic factors for superficial esophageal cancer.

A case of pericecal hernia with a hernial orifice located on the lateral side of the cecum.

The patient was a female in her 70s without previous laparotomy who visited our hospital for right lower abdominal pain. Marked small intestinal gas was noted on plain abdominal X-ray radiography. The patient was diagnosed with ileus and admitted. On contrast imaging through an ileus tube inserted for decompression, the small intestine was obstructed in the right lower abdominal region, and emergency laparotomy was performed. A hernial orifice was present on the lateral side of the cecum, and the small intestine was partially incarcerated, based on which a pericecal hernia was diagnosed. Since no circulatory disorder was noted in the incarcerated intestine, only reduction was performed without enterectomy. The hernial orifice was left open, considering that there was no possibility of re-incarceration. The postoperative course was favorable, and the patient was discharged on the 7th hospital day. Since this was a rare pericecal hernia case of internal hernia, we searched for and reviewed cases reported in Japan. This was a very rare case with a hernial orifice located on the lateral side of the cecum, not included in the current classification of pericecal hernia.

[Recent advances in endoscopic resection for esophageal cancer].

The indications for endoscopic resection (ER) in esophageal cancer are limited to cases without lymph node metastasis because it is a local therapy. The relationship between cancer depth and lymph node metastasis has been clarified according to the pathologic analysis of lymph nodes removed during esophagectomy for early esophageal cancer. Cancer invasion remaining in the lamina propria mucosa rarely metastasizes to the lymph nodes, and ER is thus indicated. ER allows the esophagus to be preserved and is less invasive, enabling the specimen to be examined pathologically. Lesions extending to a large area can be resected by repeated endoscopic mucosal resection (EMR), but have recently been resected en bloc in the endoscopic submucosal dissection (ESD) procedure, which is also indicated for the treatment of gastric cancer. The selection of EMR or ESD depends on the size of the lesion, the technique of the surgeon, the time the patient can safely spend under anesthesia, and economic management. ER is now employed in T1a-MM, SM1 cases without lymph node metastasis, although some require additional treatment including surgery after pathologic examination of the resected lesions.

Polyassembly formation of complementary half-sliding oligo-DNAs and atomic force microscopic observation.

Oligonucleotides, especially oligo-DNAs, are useful building blocks for construction nanometer scale ordered architectures. Many researchers have been carried out to construct nano-architectures using complementary hydrogen bonding of DNAs. However, in order to achieve rational and robust design of various functional nano-architectures using DNAs, it is extremely important to establish basic principles of assembly patterns of oligo-DNAs based on their complementarity. In this study, to obtain basic information of polyassembly for simple oligo-DNA systems, formation of multiple assemblies of complementary half-sliding oligo-DNAs (cHSOs) was investigated with varying the length and sequence (GC content). A pairs of cHSOs were mixed in combination of complementary each other, and then the formation of high-molecular-weight polyassembly was evaluated by polyacrylamide gel electrophoresis (PAGE) and size exclusion chromatography (SEC). Moreover, the morphology and shape of the polyassembly was investigated by atomic force microscope (AFM) observation on mica. The obtained polyassembly displayed linear and networked morphology, and the continuous length and patterns of the assembly was depend on the length, GC contents and the concentration of the cHSOs.

[Recent advances of endoscopic treatment for esophageal cancer].

The indications for endoscopic treatment are limited to cases without lymph node metastasis, because it is only a local therapy. The relationship between cancer depth and lymph node metastasis has been clarified based on the pathologic analysis of lymph nodes removed during esophagectomy for early esophageal cancer. Cancer confined to the lamina propria mucosa rarely undergoes lymph node metastasis and complete endoscopic resection (ER) is indicated. ER allows the esophagus to be preserved and is less invasive, enabling specimens to be pathologically examined. Lesions extending over large area can be resected by repeating endoscopic mucosal resection (EMR), but have recently been resected using endoscopic submucosal dissection (ESD), as indicated for gastric cancer. Which of the two procedures, EMR or ESD, to be chosen depends on the difficulty, skill of the surgeon, time to be spared, and economic management. ER is now performed in SM1 without lymph node metastasis, although some patients require additional treatment after pathologic examination of resected lesions.