Ken Hatogai

Photodynamic therapy for esophageal cancer

Photodynamic therapy (PDT) is a treatment that uses a photosensitizing drug that is administered to the patient, localized to a tumor, and then activated with a laser to induce a photochemical reaction to destroy the cell. PDT using porfimer sodium followed by excimer dye laser irradiation is approved as a curative treatment for superficial esophageal cancer in Japan. While endoscopic submucosal dissection (ESD) is currently more popular for esophageal cancer, there is evidence to support PDT as an alternative treatment and as a salvage treatment for local failure after chemoradiotherapy (CRT). A photosensitizing agent has also been developed that requires a shorter sun shade period after administration, and studies are currently underway to establish an esophageal cancer indication for this next-generation PDT in Japan.

Comprehensive immunohistochemical analysis of tumor microenvironment immune status in esophageal squamous cell carcinoma.

Immunotherapy with anti-PD-1 antibody preliminarily showed promising efficacy for treating esophageal squamous cell carcinoma (ESCC). Herein, we used tissue microarrays and immunohistochemically analyzed PD-L1 and various tumor infiltrating immune cells (TIICs) in specimens from 196 ESCC patients who had undergone curative resection without preoperative therapy. PD-L1 expressions in tumor cells (TCs) and TIICs, as well as infiltration of lymphocytes (CD4+, CD8+, FOXP3+, and PD- 1+) and macrophages (CD68+ and CD204+), were evaluated. PD-L1 was expressed in TCs of 18.4% and in TIICs of 83.3% of these patients. PD-L1 expressions in TCs and TIICs were associated with significant infiltration of various TIIC types, especially CD8+ cells. PD-L1 expressions in both TCs and TIICs were significantly associated with favorable overall survival, and combining their levels enhanced prognostic accuracy. Prognostic impacts of PD-L1 expressions in TCs and TIICs, abundant PD-1+ cell infiltration, a high CD8+/FOXP3+ ratio, and the CD8+/CD204+ ratio remained significant after adjusting for clinicopathological factors. In conclusion, PD-L1 expression reflects anti-tumor immunity, and PD-1/PD-L1 expression and the ratio of infiltrating effector to immune suppressor cells have prognostic value. Therapeutic strategies inhibiting the PD-1/PD-L1 signal and immune suppressor cells are anticipated in ESCC patients.

Prognostic significance of tumor regression grade for patients with esophageal squamous cell carcinoma after neoadjuvant chemotherapy followed by surgery

To clarify prognostic factors for the patients with esophageal squamous cell carcinoma (ESCC) through an assessment of surgically resected specimens modified by neoadjuvant chemotherapy (nCT).

Large-scale comprehensive immunohistochemical biomarker analyses in esophageal squamous cell carcinoma

BackgroundEsophageal squamous cell carcinoma (ESCC) is a heterogeneous disease in the sense that the biological behavior is regulated by the activation of various signaling pathways. The aim of this study was to investigate the relationships between the expressions of various targetable proteins and the clinicopathological characteristics of ESCC patients.MethodsA total of 286 patients with ESCC who had undergone curative surgical resection without neoadjuvant therapy were enrolled in this study. The protein expressions of EGFR, HER2, MET, IGF1R, FGFR2, p53, and PD-L1 were immunohistochemically evaluated in a tissue microarray analysis. The relationships between the expression statuses of each of the above molecules, and the PD-L1 expression status as well as the clinicopathological characteristics, including the survival outcome were assessed.ResultsThe expression frequencies of EGFR, HER2, MET, IGF1R, FGFR2, p53, and PD-L1 were as follows: 90.9, 1.0, 2.4, 71.0, 16.1, 62.9 and 23.4%. The overlapping expressions of two or more receptor tyrosine kinases were observed in 72.0%. MET expression was the only poor prognostic factor of recurrence-free survival [hazard ratio (HR) 1.89, 95% confidence interval (CI) 1.15–3.11]; in contrast, PD-L1 was the only favorable prognostic factor for both recurrence-free survival (HR 0.57, 95% CI 0.38–0.87) and overall survival (HR 0.56, 95% CI 0.35–0.89). No correlation was observed between the expressions of PD-L1 and the other molecules.ConclusionsThis large cohort study demonstrated that multiple molecules were co-expressed in most of the ESCC cases, suggesting that combining molecular targeted agents for these co-expressed molecules should be considered.

Unexpected endoscopic full-thickness resection of a duodenal neuroendocrine tumor

A 57-year-old man underwent endoscopy for investigation of a duodenal polyp. Endoscopy revealed a hemispheric submucosal tumor, about 5 mm in diameter, in the anterior wall of the duodenal bulb. Endoscopic biopsy disclosed a neuroendocrine tumor histologically, therefore endoscopic mucosal resection was conducted. The tumor was effectively and evenly elevated after injection of a mixture of 0.2% hyaluronic acid and glycerol at a ratio of 1:1 into the submucosal layer. A small amount of indigo-carmine dye was also added for coloration of injection fluid. The lesion was completely resected en bloc with a snare after submucosal fluid injection. Immediately, muscle-fiber-like tissues were identified in the marginal area of the resected defect above the blue-colored layer, which suggested perforation. The defect was completely closed with a total of 9 endoclips, and no symptoms associated with peritonitis appeared thereafter. Histologically, the horizontal and vertical margins of the resected specimen were free of tumor and muscularis propria was also seen in the resected specimen. Generally, endoscopic mucosal resection is considered to be theoretically successful if the mucosal defect is colored blue. The blue layer in this case, however, had been created by unplanned injection into the subserosal rather than the submucosal layer.

Salvage endoscopic resection (ER) after chemoradiotherapy for esophageal squamous cell carcinoma: What are the risk factors for recurrence after salvage ER?

Salvage endoscopic resection (ER) is among the curative treatments for superficial local failure after chemoradiotherapy (CRT) for esophageal squamous cell carcinoma (ESCC). The present study aimed to clarify risk factors for recurrence after salvage ER.

Pathological tumor regression grade of metastatic tumors in lymph node predicts prognosis in esophageal cancer patients

Tumor regression grade of the primary tumor (TRG‐PT) and residual lymph node metastasis have been pathologically determined in esophageal squamous cell carcinoma (ESCC) patients who had received neoadjuvant chemotherapy (nCT) followed by surgery; however, TRG of the metastatic tumor involving lymph nodes (LN) has not yet been determined. The aim of the present study was to clarify the impact of TRG on the prognosis of ESCC patients. ESCC patients (n = 110) who had received nCT followed by surgery were enrolled. Dissected LN were classified into 2 categories: plausible positive metastatic LN (pp‐MLN) where viable and/or degenerated ESCC cells and/or tissue modifications were observed, and non‐metastatic LN (non‐MLN) where neither of them was observed. We defined nCT‐effective rate (CER) as the ratio of the number of pp‐MLN that showed tumor regression to the total number of pp‐MLN, and divided CER into low‐CER (LCER; ≥0% and <50%) and high‐CER (HCER; ≥50% and ≤100%). Relationships between CER and clinicopathological factors including prognosis were then examined. Multivariate analyses of 110 patients indicated that ypT3‐4 (P = .023, HR; 2.551), positive venous infiltration (P = .006, HR; 3.526), and LCER (P = .033, HR; 1.922) were independently associated with shorter recurrence‐free survival (RFS). Multivariate analyses of 43 patients with grade 0 TRG‐PT showed that ypT3‐4 (P = .033, HR; 3.397) and LCER (P = .008, HR; 3.543) were independently associated with shorter RFS. This study showed that CER was one of the prognostic factors for ESCC patients who had received nCT followed by surgery.

Concordance between PIK3CA mutations in endoscopic biopsy and surgically resected specimens of esophageal squamous cell carcinoma

BackgroundPIK3CA mutations are expected to be potential therapeutic targets for esophageal squamous cell carcinoma (ESCC). We aimed to clarify the concordance between PIK3CA mutations detected in endoscopic biopsy specimens and corresponding surgically resected specimens.MethodsWe examined five hotspot mutations in the PIK3CA gene (E542K, E545K, E546K, H1047R, and H1047L) in formalin-fixed and paraffin-embedded tissue sections of paired endoscopic biopsy and surgically resected specimens from 181 patients undergoing curative resection for ESCC between 2000 and 2011 using a Luminex technology-based multiplex gene mutation detection kit.ResultsMutation analyses were successfully performed for both endoscopic biopsy and surgically resected specimens in all the cases. A PIK3CA mutation was detected in either type of specimen in 13 cases (7.2%, 95% confidence interval: 3.9–12.0). The overall concordance rate, positive predictive value, and negative predictive value were 98.3% (178/181), 90.9% (10/11), and 98.8% (168/170), respectively. Among patients with a PIK3CA mutation detected in both types of specimens, the concordance between PIK3CA mutation genotypes was 100%. There were three cases with a discordant mutation status between the types of specimens (PIK3CA mutation in surgically resected specimen and wild-type in biopsy specimen in two cases, and the opposite pattern in one case), suggesting possible intratumoral heterogeneity in the PIK3CA mutation status.ConclusionsThe PIK3CA mutation status was highly concordant between endoscopic biopsy and surgically resected specimens from the same patient, suggesting that endoscopic biopsy specimens can be clinically used to detect PIK3CA mutations in patients with ESCC.