Inflammatory prognostic factors in advanced or recurrent esophageal squamous cell carcinoma treated with nivolumab.

BACKGROUND: In Japan, nivolumab administration is the standard treatment for patients with unresectable advanced or recurrent esophageal squamous cell carcinoma (ESCC) who are refractory or intolerant to fluoropyrimidines and platinum-based chemotherapy. We determined if inflammatory prognostic factors are useful in patients with ESCC treated with nivolumab monotherapy. METHODS: The clinical data of patients with ESCC treated with nivolumab monotherapy as the second- or later-line treatment were retrospectively analyzed. Neutrophil/lymphocyte, platelet/lymphocyte, and C-reactive protein/albumin ratios (CAR); prognostic index; and prognostic nutritional index were investigated. Cut-off values for each factor were determined according to overall survival using time-dependent receiver operating characteristic curves. RESULTS: During January 2017-June 2021, 93 consecutive patients with ESCC were enrolled from five institutions (median age, 70 years; male, 77%). With a median follow-up period of 9.1 (range, 1.0-34.7) months, the median overall and progression-free survival were 12.8 (95% confidence interval [CI], 9.0-16.6) and 4.0 (95% CI, 2.6-5.4) months, respectively. Of five inflammatory prognostic factors, the cut-off value for CAR was 0.62; prognosis was significantly longer in those with CAR < 0.62 (hazard ratio, 0.39; 95% CI, 0.22-0.67; p = 0.001). CONCLUSIONS: Inflammatory prognostic factors were useful in predicting prognosis for ESCC patients pretreated with nivolumab, especially for those with CAR < 0.62, suggesting that CAR adequately reflects prognosis.

[Evaluation of the safety and efficacy of endoscopic treatment for early gastric cancers in patients aged over 80 years].

Endoscopic treatments, including endoscopic mucosal resection or endoscopic submucosal dissection, are well accepted as standard treatments for early gastric cancers. However, there are few studies evaluating the safety and efficacy of this approach for early gastric cancers in patients aged over 80 years, and the post-treatment prognosis remains unclear. Here, we retrospectively analyzed the medical records and evaluated the safety and efficacy of endoscopic treatment for early gastric cancers in patients aged over 80 years (group A) compared with non-elderly patients aged 65-79 years (group B) and under 65 years (group C). In this study, we enrolled 53 patients (mean age, 82 years) in group A, 217 patients (mean age, 73 years) in group B, and 89 patients (mean age, 60 years) in group C who received endoscopic treatment at Kyoto University Hospital between 2001 and 2010. The incidence of treatment-related complications including aspiration pneumonia, bleeding, and perforation was 19% (10/53) in group A, 9.7% (21/217) in group B, and 6.7% (6/89) in group C, respectively. In particular, only the incidence of aspiration pneumonia was significantly higher in group A [11% (6/53) ] than in the other two groups [1.8% (4/217) in group B and 1.1% (1/89) in group C]. There was no significant difference in the curative resection rate and recurrence rate including metachronous lesions among the three groups. In group A, the median survival calculated using the Kaplan-Meier method was 8.0 years, and the 5-year survival rate was 73%. No gastric cancer-related deaths were observed in all groups. In conclusion, endoscopic treatment for early gastric cancers may contribute to an improvement in life expectancy, even among patients aged over 80 years, provided an experienced gastroenterologist selects the appropriate patients based on not only the endoscopic findings for the lesion but also the severity of any comorbidities. However, it is noteworthy that our elderly group aged over 80 years had a high risk of developing aspiration pneumonia.

Endoscopic laryngo-pharyngeal surgery for superficial laryngo-pharyngeal cancer.

BACKGROUND AND STUDY AIMS: Narrow band imaging (NBI) combined with magnifying endoscopy enables us to detect superficial laryngo-pharyngeal cancers, which are difficult to detect by standard endoscopy. Endoscopic laryngo-pharyngeal surgery (ELPS) is a technique developed to treat such lesions and the purpose of this study is to evaluate the usefulness of ELPS for superficial laryngo-pharyngeal cancer. PATIENTS AND METHODS: Seventy five consecutive patients with 104 fresh superficial laryngo-pharyngeal cancers are included in this study. Under general anesthesia, a specially-designed curved laryngoscope was inserted to create a working space in the pharyngeal lumen. A magnifying endoscope was inserted transorally to visualize the field and a head & neck surgeon dissected the lesion using the combination of the orally-inserted curved grasping forceps and electrosurgical needle knife in both hands. The safely, functional outcomes, and oncologic outcomes of ELPS were evaluated retrospectively. RESULTS: Median operation time per lesion was 35 min. Post-operative bleeding occurred in 3 cases and temporal subcutaneous emphysema occurred in 10 cases. No vocal fold impairment occurred after surgery. The median fasting period was 2 days and all patients except one have a normal diet with no limitations. Local recurrence occurred in 1 case, and the 3-year overall survival rate and the 3-year disease specific survival rate was 90% and 100%, respectively. CONCLUSIONS: ELPS is a hybrid of head and neck surgery and gastrointestinal endoscopic treatment, and enjoys the merit of both procedures. ELPS makes it possible to perform minimally-invasive surgery, preserving both the swallowing and phonation functions.

Clinical outcome after endoscopic resection for superficial pharyngeal squamous cell carcinoma invading the subepithelial layer.

BACKGROUND AND STUDY AIMS: The curability of endoscopic resection for superficial pharyngeal squamous cell carcinoma (SPSCC) has not been fully elucidated, particularly for lesions invading the subepithelial layer, which carry the risk of metastasis. The aim of this study was to evaluate the curative potential of endoscopic resection for SPSCC invading the subepithelial layer. PATIENTS AND METHODS: From June 2002 to July 2010, 198 SPSCCs in 176 consecutive patients were treated by endoscopic resection at two tertiary referral centers. Selection criteria were initial endoscopic resection, histologically proven squamous cell carcinoma invading the subepithelial layer, no lymph node or distant metastasis before endoscopic resection, and no prior treatment for pharyngeal squamous cell carcinoma. Endoscopic resection was performed under general anesthesia. Long-term survival and clinical outcomes were retrospectively evaluated. RESULTS: Among 176 consecutive patients, 50 lesions in 47 patients (all male; median age 64 years) were histologically diagnosed from endoscopic resection specimens as having subepithelial invasion. Median tumor thickness was 1000 µm (range 200 - 10 000 µm). Six patients developed local recurrence (13 %; 95 % confidence interval [CI] 3.1 % - 22.4 %), and all were cured with organ-preserving intervention. After a median follow-up period of 71 months (range 27 - 116 months), one patient (2 %; 95 %CI 0 - 6.3 %) developed neck lymph node metastasis. A total of 14 patients (30 %) were followed for 5 years or more, and 5-year overall survival and disease-specific survival rates were 84.5 % (95 %CI 73 % - 96 %) and 100 %, respectively. CONCLUSIONS: Endoscopic resection has curative potential as a minimally invasive treatment option for SPSCC that invades the subepithelial layer.

Narrow-band imaging for the head and neck region and the upper gastrointestinal tract.

Endoscopy is essential for the diagnosis and treatment of cancers derived from the gastrointestinal tract. However, a conventional white-light image has technical limitations in detecting small or superficial lesions. Narrow-band imaging, especially with magnification, allows visualization of microstructure patterns and microvascular patterns on the mucosal surface. These technical breakthroughs enable endoscopists to easily detect small pre-neoplastic and neoplastic lesions and to make a differential diagnosis of these lesions. Appropriate diagnosis with narrow-band imaging contributes to minimally invasive endoscopic resection.

Multiple Gastric Neuroendocrine Tumors Associated with Long-term Use of a Proton Pump Inhibitor and a Potassium-competitive Acid Blocker.

A 52-year-old man who had been using a proton pump inhibitor (PPI) and a potassium-competitive acid blocker (P-CAB) for 14 years underwent esophagogastroduodenoscopy and was found to have three neuroendocrine tumors (NETs) in the gastric body. Following detailed examinations, parietal cell dysfunction was excluded, and the NETs did not meet the criteria for the Rindi classification types I-III. The lesions were ultimately considered to be associated with the long-term use of the PPI and P-CAB. We performed endoscopic submucosal dissection of the lesions, with no recurrence or new lesions noted after discontinuation of the PPI and P-CAB.

Usefulness of endoscopic radial incision and cutting method for refractory esophagogastric anastomotic stricture (with video).

BACKGROUND: There is no effective treatment for gastroesophageal anastomotic strictures that are refractory to repeated endoscopic balloon dilation (EBD). However, EBD is still selected worldwide to manage such refractory strictures. To relieve the symptoms of dysphagia and keep a wide lumen, we developed a new incisional treatment, radial incision and cutting (RIC). OBJECTIVE: To evaluate the efficacy and safety of the RIC method for the treatment of refractory anastomotic strictures. DESIGN: Retrospective cohort study. SETTING: National Cancer Center and University Hospital. PATIENTS: This study involved 54 consecutive patients with refractory anastomotic stricture after esophagogastric surgery. INTERVENTION: RIC. MAIN OUTCOME MEASUREMENTS: The safety and clinical success of RIC and the long-term patency after RIC compared with those of continued EBD. RESULTS: The median procedure time of RIC was 14 minutes (range, 4-40 minutes). No serious adverse events associated with RIC were observed. Immediately after RIC, 81.3% (26/32) of patients were able to eat solid food without symptoms of dysphagia. As a short-term effect, the dysphagia improved after RIC in 93.8% (30/32) of the patients. As a long-term effect, 63% (17/27) and 62% (13/21) of patients were able to eat solid food 6 and 12 months after RIC, respectively. The 6-month and 12-month patency rates were significantly different between the RIC group and the continued EBD group (65.3% vs 19.8%, P < .005; 61.5% vs 19.8%, P < .005). LIMITATIONS: Nonrandomized retrospective study. CONCLUSIONS: RIC is an effective and safe method. The demonstration of the validity of this method may place RIC as a new medical treatment for patients with refractory stricture after surgical resection for esophagogastric diseases.

Bile acid-induced expression of activation-induced cytidine deaminase during the development of Barrett's oesophageal adenocarcinoma.

Activation-induced cytidine deaminase (AID) induces somatic mutations in various host genes of non-lymphoid tissues, thereby contributing to carcinogenesis. We recently demonstrated that Helicobacter pylori infection and/or proinflammatory cytokine stimulation triggers aberrant AID expression in gastric epithelial cells, causing mutations in the tumour-suppressor TP53 gene. The findings of the present study provide evidence of ectopic AID expression in Barrett's oesophagus and Barrett's oesophageal adenocarcinoma, a cancer that develops under chronic inflammatory conditions. Immunoreactivity for endogenous AID was observed in 24 of 28 (85.7%) specimens of the columnar cell-lined Barrett's oesophagus and in 20 of 22 (90.9%) of Barrett's adenocarcinoma, whereas weak or no AID protein expression was detectable in normal squamous epithelial cells of the oesophagus. We validated these results by analysing tissue specimens from another cohort comprising 16 cases with Barrett's oesophagus and four cases with Barrett's adenocarcinoma. In vitro treatment of human non-neoplastic oesophageal squamous-derived cells with sodium salt deoxycholic acid induced ectopic AID expression via the nuclear factor-kappaB activation pathway. These findings suggest that aberrant AID expression occurs in a substantial proportion of Barrett's epithelium, at least in part due to bile acid stimulation. Considering the genotoxic activity of AID, our current findings suggest that aberrant AID expression might enhance the susceptibility to genetic alterations in Barrett's columnar-lined epithelial cells, leading to cancer development.

Long-term outcome of transoral organ-preserving pharyngeal endoscopic resection for superficial pharyngeal cancer.

BACKGROUND: Early detection of pharyngeal cancer has been difficult. We reported that narrow-band imaging (NBI) endoscopy can detect superficial pharyngeal cancer, and these lesions can be treated endoscopically. OBJECTIVE: To assess the safety and long-term efficacy of transoral organ-preserving pharyngeal endoscopic resection (TOPER) for superficial pharyngeal cancer. DESIGN AND SETTING: Retrospective 2-center cohort study. PATIENTS: The study included 104 consecutive patients with superficial pharyngeal cancer. INTERVENTION: TOPER with the patients under general anesthesia. MAIN OUTCOME MEASUREMENTS: Safety of the procedure, long-term survival, clinical outcome. RESULTS: A total of 148 consecutive lesions were resected in 104 patients. There was no severe adverse event. Temporary tracheostomy was required in 17 patients (16%) to prevent airway obstruction. The median fasting period and hospital stay after TOPER were 2 days (range 1-20 days) and 8 days (range 3-58 days), respectively. Ninety-six patients (92%) had no local recurrence or distant metastases. Local recurrence at the primary site developed in 6 patients, but all were resolved by repeat TOPER. With a median follow-up period of 43 months (range 3-96 months), the overall survival rate at 5 years was 71% (95% CI, 59-82). Cause-specific survival rate at 5 years was 97% (95% CI, 93-100). The cumulative development rate of multiple cancers in pharyngeal mucosal sites at 5 years was 22% (95% CI, 12-33). The pharynx was preserved in all patients, and they experienced no loss of function. LIMITATION: Retrospective design. CONCLUSIONS: Peroral endoscopic resection of superficial pharyngeal cancer is a feasible and effective treatment with curative intent.

Efficacy of preventive endoscopic balloon dilation for esophageal stricture after endoscopic resection.

BACKGROUND AND AIM: We earlier reported that mucosal defect involving over three-fourths of the circumference of the esophagus after endoscopic mucosal resection (EMR) is a risk factor for the development of the stricture. Although endoscopic balloon dilation (EBD) is a useful procedure to relieve the stricture, there is no standard strategy for preventing development of the stricture. The aim of this study was to evaluate the efficacy and the safety of preventive EBD. METHODS: From 1993 to 2008, 41 consecutive patients with extensive mucosal defect involving over three-fourths of the esophageal circumference after EMR or endoscopic submucosal dissection (ESD) were investigated. Preventive EBD was carried out for 29 cases within 1 week just after EMR/ESD and was repeated once a week until the mucosal defect was completely healed. The remaining 12 cases were not underwent preventive EBD and used as a historic control. If postEMR/ESD stricture developed regardless of preventive EBD, conventional EBD was given repeatedly until the stricture was completely relieved. RESULTS: Preventive EBD decreased the incidence of stricture (59% vs. 92%, P =0.04), reduced the severity of stricture [(≤2 mm; >2 mm and ≤5 mm; >5 mm)=(1; 2; 14) vs. (4; 4; 3), P = 0.01] and shortened the duration required for resolving the stricture (29 d vs. 78 d, P =0.04) even when stricture developed. There was no complication associated with preventive EBD procedure. CONCLUSIONS: Preventive EBD is an effective procedure to prevent postEMR/ESD stricture. Preventive EBD should be considered when EMR/ESD results in a mucosal defect with a circumference greater than three-fourths of the esophageal lumen.

Multicenter prospective in vivo study of an endocytoscope system (ECS) for superficial esophageal cancer.

BACKGROUND: Endocytoscope systems (ECS) can visualize cellular nuclei of the mucosa of the gastrointestinal tract and are predicted to provide real-time microscopic diagnosis. However, their practical diagnostic performance remains unclear. Therefore, we conducted a multicenter prospective study to evaluate the visualization of superficial esophageal neoplasm in vivo using an ECS, and its diagnostic capability. METHODS: The study target was histologically confirmed squamous cell carcinoma (SCC) and high-grade intraepithelial neoplasia (HGIN). An integrated ECS was used to obtain ECS images. In each patient, three ECS images of cancerous and corresponding noncancerous regions were selected for evaluation. A pathological review board of five certified pathologists made the final diagnosis of the images. The primary endpoint was the sensitivity of ECS diagnosis by pathologists. RESULTS: ECS images of 68 patients were assessed: 42 lesions were mucosal SCC, 13 were submucosal SCC, and 13 were HGIN. The rate of assessable images was 96% (95% CI 87.6-99.1). The sensitivity of ECS diagnosis by pathologists was 88% (95% CI 77.2-94.5). CONCLUSIONS: ECS can provide high-quality images of cancerous lesions and a high diagnostic accuracy by pathologists, and could be useful for real-time endoscopic histological diagnosis of SCC and HGIN. TRIAL REGISTRATION: The UMIN Clinical Trials Registry Identification Number: 000004218.

Improving visualization techniques by narrow band imaging and magnification endoscopy.

Endoscopy plays an important role in the early detection of gastrointestinal tract neoplasms. Using conventional white light or dye-based image enhanced endoscopy, it has been difficult to assess pre-malignant and early neoplastic lesions precisely. However, narrow band imaging (NBI) dramatically improves the detection of these lesions, particularly in combination with magnifying endoscopy. This allows the endoscopist to accomplish accurate diagnosis. Such enhanced detection of pre-malignant and early neoplastic lesions in the gastrointestinal tract should allow better targeting of biopsy, improved and more appropriate treatment, and thereby contribute to optimal quality of life and patient survival.

The Distribution of Phosphatidylcholine Species in Superficial-Type Pharyngeal Carcinoma.

Objectives. Superficial-type pharyngeal squamous cell carcinoma (STPSCC) is defined as carcinoma in situ or microinvasive squamous cell carcinoma without invasion to the muscular layer. An exploration of the biological characteristics of STPSCC could uncover the invasion mechanism of this carcinoma. Phosphatidylcholine (PC) in combination with fatty acids is considered to play an important role in cell motility. Imaging mass spectrometry (IMS) is especially suitable for phospholipid analysis because this technique can distinguish even fatty acid compositions. Study Design. IMS analysis of frozen human specimens. Methods. IMS analysis was conducted to elucidate the distribution of PC species in STPSCC tissues. STPSCC tissue sections from five patients were analyzed, and we identified the signals that showed significant increases in the subepithelial invasive region relative to the superficial region. Results. Three kinds of PC species containing arachidonic acid, that is, PC (16:0/20:4), PC (18:1/20:4), and PC (18:0/20:4), were increased in the subepithelial invasive region. Conclusion. These results may be associated with the invasion mechanism of hypopharyngeal carcinoma.

The prospect of endoscopic submucosal dissection for early anal canal squamous cell carcinoma.

Squamous cell carcinoma (SCC) of the anal canal is seldom diagnosed at an early stage. Chemoradiation therapy is a standard in Europe and the United States, though in squamous cell carcinoma there is no evidence-based therapy. In Japan, endoscopic submucosal dissection (ESD) is the standard minimally invasive treatment for early stage cancer of the digestive tract, including the colorectum. Therefore, if the lesion is diagnosed at an early stage, ESD may be selected for anal canal lesions. We experienced two cases of early stage anal canal cancer in which the diagnosis and the extent of the lesions were confirmed using magnifying endoscopy with narrow-band imaging (NBI), as well as performing ESD. Pathological examination showed the resected specimen to be SCC in situ; the horizontal and vertical margins were free of tumor; and in one case there was no lymphovascular invasion. In the other case it showed the tumor was contained within the epithelium; horizontal and vertical margins were free of tumor; The follow-up period is not long enough to assert that ESD for anal canal squamous cell carcinoma may be an option of minimally invasive therapy. However, if there is a possibility of lymphatic invasion as in one of our cases, we need to give serious consideration to ESD for these lesions, and careful follow-up is necessary even if the lesion is in situ.

Voice Outcome in Patients Treated With Endoscopic Laryngopharyngeal Surgery for Superficial Hypopharyngeal Cancer.

OBJECTIVES: Endoscopic laryngopharyngeal surgery (ELPS) is a minimally invasive transoral surgery that was developed to treat superficial larygo-pharyngeal cancer, in which a mucosal lesion is resected transorally while preserving deeper structures by subepithelial injection. The purpose of this retrospective study is to evaluate voice outcome in patients who underwent ELPS for superficial hypopharyngeal cancer. As important structures in producing voice, such as intrinsic laryngeal muscles, their fascia, and recurrent laryngeal nerve, are located in the medial side of the piriform sinus and the postcricoid region of the hypopharynx, we focused on patients with cancer lesions involving these regions. METHODS: From April 2010 to March 2011, 25 consecutive patients with superficial laryngopharyngeal cancer were treated with ELPS at Kyoto University Hospital. Among the 25 patients, 11 patients with cancer lesions on the medial side of the piriform sinus or the postcricoid area were studied. Preoperative and postoperative voice functions including maximum phonation time (MPT), mean flow rate (MFR), jitter, shimmer, soft phonation index (SPI), and noise-to-harmonic ratio (NHR), were compared retrospectively. RESULTS: Five of 11 cancer lesions had submucosal invasion and no lesion had invaded the muscular layer pathologically. T stage was classified as Tis in 5 cases, T1 in 4 cases, and T2 in 2 cases. All lesions involved the medial side of the piriform sinus and 2 also involved the postcricoid area. Vocal fold movement was normal in all cases after the surgery. Average preoperative and postoperative values for MPT, MFR, jitter, shimmer, SPI, and NHR, were 22.7 seconds and 23.4 seconds, 165 mL/sec and 150 mL/sec, 1.53% and 1.77%, 3.82% and 5.17%, 35.5 and 36.6, and 0.13% and 0.14%, respectively. There was no statistical difference between preoperative and postoperative data for all values examined. CONCLUSION: ELPS is useful in preserving voice function in the treatment of superficial hypopharyngeal cancer. Preserving the deeper structures including intrinsic muscles and their fascia may be important for preserving voice function as long as the lesions are superficial.