Systemic treatment of advanced esophageal squamous cell carcinoma (ESCC) mainly consists of cytotoxic agents, aiming to palliate symptoms and prolong survival. Cisplatin and 5-fluorouracil have been ...considered standard treatment for several decades. Efforts to develop more effective treatment have led to clinical trials testing triplet, irinotecan-based, oxaliplatin-based and paclitaxel-based regimens. Molecular-targeting agents, mainly anti-EGFR inhibitors including gefitinib, panitumumab and nimotuzumab, have been investigated; however, no molecular-targeting agents demonstrate the clinical utility in Phase 3 trials so far. Negative results from Phase 3 trials testing gefitinib and panitumumab suggest the importance of identifying predictive biomarkers of responses to molecular-targeting agents. On the basis of results from Phase 3 trials testing PD-1 inhibitors, nivolumab and pembrolizumab, are anticipated to be the standard treatment for patients with ESCC. Dual immune checkpoint inhibition and immunotherapy in combination with cytotoxic agents are under study. Recent advances in next-generation sequencing technologies provide comprehensive catalogues of genetic alterations in ESCC which may lead to therapeutic breakthroughs in a personalized manner. Here, we review the existing clinical data and discuss future perspectives with a focus on the systemic treatment of advanced ESCC.
Abstract
The tumor–node metastasis (TNM) classification, originally developed in 1943 and subsequently adopted by the Union for International Cancer Control and the American Joint Committee on ...Cancer, is regularly updated based on new information and developments. The TNM classification system is the main tool used for both clinical and pathological staging of cancers worldwide. The 8th edition of the TNM classification for esophageal and esophagogastric junction (EGJ) cancer, released in 2017, was updated from the 7th edition based on additional data supplied by the Worldwide Esophageal Cancer Collaboration group. We summarize the main changes between the 7th and 8th editions of this TNM classification. Notable changes included separate clinical, pathological and pathological prognostic staging for adenocarcinomas and squamous cell carcinomas. Pathological prognostic staging was also improved by updating the T- and N-factors regarding histopathological differentiation and tumor location, respectively. The definition of EGJ cancer was changed from tumors centered within 5 cm to tumors within 2 cm of the EGJ. These updates to the TNM classification will help to improve the personalized management and treatment of patients with esophageal and EGJ cancers.
Bladder cancer is the 9th leading cause of cancer death worldwide. The major problem in bladder cancer is primarily the high recurrence rate after drug treatment and resection. Although conventional ...screening methods, such as cystoscopy, urinary cytology and ultrasound sonography, have become widely used in clinical settings, the diagnostic performance of these modalities is unsatisfactory due to low accuracy or high invasiveness. Because circulating micro RNA (miRNA) profiles have recently been reported as an attractive tool for liquid biopsy in cancer screening, here, we performed global miRNA profiling of 392 serum samples of bladder cancer patients with 100 non‐cancer samples and 480 samples of other types of cancer as controls. We randomly classified the bladder cancer and control samples into 2 cohorts, a training set (N = 486) and a validation set (N = 486). By comparing both controls, we identified specific miRNA, such as miR‐6087, for diagnosing bladder cancer in the training and validation sets. Furthermore, we found that a combination of 7 miRNA (7‐miRNA panel: miR‐6087, miR‐6724‐5p, miR‐3960, miR‐1343‐5p, miR‐1185‐1‐3p, miR‐6831‐5p and miR‐4695‐5p) could discriminate bladder cancer from non‐cancer and other types of tumors with the highest accuracy (AUC: .97; sensitivity: 95%; specificity: 87%). The diagnostic accuracy was high, regardless of the stage and grade of bladder cancer. Our data demonstrated that the 7‐miRNA panel could be a biomarker for the specific and early detection of bladder cancer.
The present study selected 7 miRNA expression levels among bladder cancer, non‐cancer and other cancer samples. A diagnostic index was calculated and plotted in the dot plot among 12 different cancers. An index score ≥0 indicated the presence of bladder cancer and an index score <0 indicated the absence of bladder cancer.
A major obstacle to improving prognoses in ovarian cancer is the lack of effective screening methods for early detection. Circulating microRNAs (miRNAs) have been recognized as promising biomarkers ...that could lead to clinical applications. Here, to develop an optimal detection method, we use microarrays to obtain comprehensive miRNA profiles from 4046 serum samples, including 428 patients with ovarian tumors. A diagnostic model based on expression levels of ten miRNAs is constructed in the discovery set. Validation in an independent cohort reveals that the model is very accurate (sensitivity, 0.99; specificity, 1.00), and the diagnostic accuracy is maintained even in early-stage ovarian cancers. Furthermore, we construct two additional models, each using 9-10 serum miRNAs, aimed at discriminating ovarian cancers from the other types of solid tumors or benign ovarian tumors. Our findings provide robust evidence that the serum miRNA profile represents a promising diagnostic biomarker for ovarian cancer.
Background: Dialysis patients have strong intracoronary calcification, accelerated by secondary hyperparathyroidism as well as atherosclerosis. We evaluated the association of intact parathyroid ...hormone (iPTH) level with intracoronary calcification evaluated by intravascular ultrasound (IVUS), and its impact on both stent expansion after percutaneous coronary intervention (PCI) and long-term clinical outcomes, in dialysis patients with coronary artery disease (CAD).Methods and Results: A total of 116 patients on dialysis, who underwent PCI with IVUS guidance between March 2012 and December 2020, were enrolled. Patients were divided into 2 groups based on their median iPTH level. The degree of intracoronary calcification was evaluated by calcification score using grayscale IVUS in the target lesions. Preprocedural calcification scores were significantly higher in the high iPTH group compared with the low iPTH group (2.9±1.1 vs. 2.1±0.7, P<0.001). After PCI, the high iPTH group had a significantly lower stent expansion index (0.6±0.2 vs. 0.7±0.1, P<0.001) and stent symmetry index (0.5±0.1 vs. 0.7±0.1, P<0.001) compared with the low iPTH group. The incidence of major adverse cardiac or cerebrovascular events within 3 years was significantly higher in the high iPTH group (log-rank P<0.05).Conclusions: High iPTH level is likely to increase intracoronary calcification, and cause inadequate stent expansion, which may be associated with increased risk of future adverse events in dialysis patients with CAD requiring PCI.
The excited‐state dynamics of the photostable luminescent organic radical (3,5‐dichloro‐4‐pyridyl)bis(2,4,6‐trichlorophenyl)methyl (PyBTM) doped in a host crystal was investigated by using optically ...detected magnetic resonance (ODMR) and time‐resolved emission spectroscopies. In the radical system, the unpaired electron can be used as the probe for studying the electronic state and its dynamics. The mixed crystal with a high concentration of the radical showed excimer emission, together with the monomer emission. The ODMR signals were observed with opposite signs for monitoring the monomer and the excimer emissions. Based on their temperature and concentration dependencies, the excited‐state dynamics on the doped crystal and the mechanism of the excimer formation and the ODMR signal generation are discussed with the help of the quantum mechanical simulation of the excited‐state spin dynamics. The initial process of excimer formation has been clarified for the first time from the viewpoint of the spin‐dynamics.
The excited‐state dynamics of a photostable luminescent organic radical doped in a host crystal was investigated by using optically detected magnetic resonance (ODMR) and time‐resolved emission spectroscopies. The initial process in excimer formation was clarified for the first time from the viewpoint of the spin dynamics.
Patients with advanced esophageal cancer have a poor prognosis and limited treatment options after first-line chemotherapy.
In this open-label, phase III study, we randomly assigned (1:1) 628 ...patients with advanced/metastatic squamous cell carcinoma or adenocarcinoma of the esophagus, that progressed after one prior therapy, to pembrolizumab 200 mg every 3 weeks for up to 2 years or chemotherapy (investigator's choice of paclitaxel, docetaxel, or irinotecan). Primary end points were overall survival (OS) in patients with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 10, in patients with squamous cell carcinoma, and in all patients (one-sided α 0.9%, 0.8%, and 0.8%, respectively).
At final analysis, conducted 16 months after the last patient was randomly assigned, OS was prolonged with pembrolizumab versus chemotherapy for patients with CPS ≥ 10 (median, 9.3
6.7 months; hazard ratio HR, 0.69 95% CI, 0.52 to 0.93;
= .0074). Estimated 12-month OS rate was 43% (95% CI, 33.5% to 52.1%) with pembrolizumab versus 20% (95% CI, 13.5% to 28.3%) with chemotherapy. Median OS was 8.2 months versus 7.1 months (HR, 0.78 95% CI, 0.63 to 0.96;
= .0095) in patients with squamous cell carcinoma and 7.1 months versus 7.1 months (HR, 0.89 95% CI, 0.75 to 1.05;
= .0560) in all patients. Grade 3-5 treatment-related adverse events occurred in 18.2% of patients with pembrolizumab versus 40.9% in those who underwent chemotherapy.
Pembrolizumab prolonged OS versus chemotherapy as second-line therapy for advanced esophageal cancer in patients with PD-L1 CPS ≥ 10, with fewer treatment-related adverse events.
Low‐dose cisplatin and 5‐fluorouracil (LDPF) chemotherapy with daily radiotherapy (RT) is used as an alternative chemoradiotherapy regimen for locally advanced esophageal carcinoma. We evaluated ...whether RT plus LDPF chemotherapy had an advantage in terms of survival and/or toxicity over RT plus standard‐dose cisplatin and 5‐fluorouracil (SDPF) chemotherapy in this study. This multicenter trial included esophageal cancer patients with clinical T4 disease and/or unresectable regional lymph node metastasis. Patients were randomly assigned to receive RT (2 Gy/fraction, total dose of 60 Gy) with SDPF (arm A) or LDPF (arm B) chemotherapy. The primary endpoint was overall survival (OS). A total of 142 patients (arm A/B, 71/71) from 41 institutions were enrolled between April 2004 and September 2009. The OS hazard ratio in arm B versus arm A was 1.05 (80% confidence interval, 0.78–1.41). There were no differences in toxicities in either arm. Arm B was judged as not promising for further evaluation in the phase III setting. Thus, the Data and Safety Monitoring Committee recommended that the study be terminated. In the updated analyses, median OS and 3‐year OS were 13.1 months and 25.9%, respectively, for arm A and 14.4 months and 25.7%, respectively, for arm B. Daily RT plus LDPF chemotherapy did not qualify for further evaluation as a new treatment option for patients with locally advanced unresectable esophageal cancer. This study was registered at the UMIN Clinical Trials Registry as UMIN000000861.
LDPF‐RT vs SDPF‐RT for thoracic EC
Chemoradiotherapy has been clinically indicated for patients with resectable esophageal squamous cell carcinoma who refuse surgical resection and in locally advanced unresectable esophageal squamous ...cell carcinoma patients. Concurrent chemoradiotherapy prolongs survival than radiation therapy alone when given as definitive treatment. Therefore, chemoradiotherapy is recognized as the standard non-invasive treatment for patients with localized esophageal cancer who opt for non-surgical treatment. JCOG9906 showed promising outcomes for stage II/III ESCC patients. But there are some problems about chemoradiotherapy for esophageal squamous cell carcinoma. Late toxicities are sometimes lethal for patients who achieved complete response even after years. Salvage treatment for residual or recurrent disease is unestablished. Modified Radiation Therapy Oncology Group regimen at the dose of 50.4 Gy reduced late toxicities without reducing efficacy. Optimal timings and procedure of salvage surgery and endoscopic therapy is evaluated in JCOG0909. Strategy including salvage therapy after chemoradiotherapy should be considered at the time of starting the treatment. Targeted therapy has not shown adding effect for chemoradiotherapy for esophageal squamous cell carcinoma yet. New agents, such as immune checkpoint inhibitors, are expected to show synergistic effect with chemoradiotherapy for esophageal squamous cell carcinoma. Further investigation is needed.
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