Yasuhiro Tsubosa

PURPOSE: Cisplatin plus fluorouracil (CF) has long been a standard of care for metastatic esophageal cancer. This study aimed to demonstrate the superiority of docetaxel administered once every 2 weeks plus CF (bDCF) over CF in terms of overall survival (OS). PATIENTS AND METHODS: We conducted a multicenter, randomized controlled phase III study. Patients age 20-75 years with metastatic or recurrent esophageal squamous cell carcinoma or adenocarcinoma who had not received systemic therapy for metastatic disease were included in this study. Patients were randomly assigned to the CF arm (cisplatin 80 mg/m ² once on day 1 and fluorouracil 800 mg/m ² continuously on days 1-5, every 28 days) or bDCF arm (docetaxel 30 mg/m ² once on days 1 and 15 in addition to CF, once every 28 days). The primary end point was OS. RESULTS: Overall, 240 patients were randomly assigned to bDCF (n = 121) or CF (n = 119). The median follow-up period was 15.3 months (IQR, 8.9-26.2). The median OS was 16.2 (95% CI, 13.8 to 20.4) and 14.8 (95% CI, 11.6 to 18.3) months in the bDCF and CF arms, respectively (hazard ratio [HR], 0.90 [95% CI, 0.68 to 1.19]; P = .23). The median progression-free survival was 6.0 and 5.2 months in the bDCF and CF arms, respectively (HR, 0.68 [95% CI, 0.52 to 0.88]). Major grade 3 or 4 adverse events observed in the bDCF and CF arms were neutropenia (45 [38%] and 32 [27%]), anorexia (30 [25%] and 19 [16%]), fatigue (12 [10%] and 18 [15%]), and hyponatremia (16 [13%] and 16 [14%]). There were no treatment-related deaths. CONCLUSION: Docetaxel added to CF once every 2 weeks did not improve OS when used as first-line chemotherapy in patients with metastatic or recurrent esophageal cancer.

Background: Esophageal carcinosarcoma (ECS) is a relatively rare malignancy, accounting for < 1% of all esophageal cancers. Its etiopathogenesis remains unknown. This study analyzed the genomic abnormalities in sarcomatous tumors from two patients undergoing subtotal esophagectomy using whole genome sequencing to elucidate the key characteristics of ECS. Case presentation: We identified TP53 driver mutations, copy number gains in 11q13 (including CCND1), and Apolipoprotein B mRNA editing enzyme catalytic polypeptide (APOBEC) signature enrichment in both ECS patients. Along with common genetic abnormalities, we identified CDKN2A driver mutations in case 1 and RAC1, NOTCH1, and TTC28 as novel fusion gene partners of MECOM in case 2. Notably, we detected germline pathogenic variant in Fanconi anemia (FA) complementation group I (FANCI) and group G (FANCG), which are involved in repairing DNA double-strand breaks by homologous recombination, for the first time, in ECS blood samples. These germline variants were truncating-type, Lys1221fs of FANCI (rs1567179036) for case 1 and Gln365Ter of FANCG (rs121434426) for case 2. We also identified somatic changes in cancer-associated pathways, such as PI3K/Akt/mTOR, cell cycle, and NOTCH signaling pathways, and structural chromosomal defects such as chromosome doubling. Conclusions: Our findings indicate that therapeutic drugs targeting the activation signal or FA pathway might be effective in treating ECS, however, their therapeutic significance should be elucidated in future studies.

Background There is no clear evidence on the prevention of postoperative delirium with pharmacotherapy in elderly patients with esophageal cancer. This retrospective study aimed to evaluate the efficacy of ramelteon and suvorexant in preventing postoperative delirium in this patient group. Methods Data on 251 patients who received radical esophagectomy for thoracic esophageal cancer were collected from January 2010 to September 2021. In total, 74 patients did not receive preventive intervention, and 177 received ramelteon and suvorexant. After propensity score matching, the rate of postoperative delirium was compared between the two groups. Results Seventy-two well-balanced patients in each group demonstrated similar clinical and pathological characteristics. The mean ages of the intervention and control groups were 70.8 and 70.3 years, respectively. All the patients underwent McKeown esophagectomy, and in the volume of intraoperative blood loss or operative time did not significantly differ between the two groups. The incidence rates of postoperative hyperactive delirium were 7% (5/72) in the intervention group and 32% (23/72) in the control group (p < 0.001). No severe adverse event potentially attributable to the intervention drug was observed. The multivariate analysis showed that the use of ramelteon and suvorexant was the only independent protective factor against postoperative delirium (hazard ratio 0.157, 95% CI 0.055–0.448, p < 0.001). Conclusions Ramelteon and suvorexant may play an important role in reducing postoperative delirium in elderly patients with esophageal cancer.

The need for prophylactic supraclavicular lymph node dissection during esophagectomy with radical lymphadenectomy remains controversial. A randomized phase III trial was launched in August 2022 to confirm the non-inferiority of esophagectomy with D2 lymphadenectomy except for supraclavicular lymph node dissection to standard D2 lymphadenectomy in terms of overall survival for patients with resectable upper or middle thoracic esophageal cancer. This study will enroll 480 patients from 54 Japanese institutions over 5 years. The primary endpoint includes overall survival, and the secondary endpoints include relapse-free survival, perioperative and late complication incidences, supraclavicular lymph node recurrence, salvage cervical treatment incidence, synchronous cervical and abdominal procedure proportion, operation time and the number of operating surgeons. This trial has been registered at the Japan Registry of Clinical Trials under study number jRCT1030220248.

Summary of WGS, methylation and expression data.

Probes for genes with specific expression alterations in malignant GISTs with KIT Δ557–558.

Genes for expression signatures.

SNVs/Indels identified in the 30 GIST cases in our study cohort.

Expression data of probes used for the volcano plot comparing between malignant GISTs carrying KIT Δ557–558 and other GISTs.