Esophageal Squamous Cell Carcinoma

Tissue samples from individuals of the first set (n = 28) were obtained from the tumor bank of Charité Comprehensive Cancer Center. Gene expression was examined by whole-human-genome microarrays (Affymetrix, Santa Clara, CA, USA). Ten esophageal squamous cell carcinoma (ESCC) and 18 normal esophageal (NE) biopsies were randomly collected. Normal healthy esophageal biopsies were collected from patients with esophageal pain but diagnosed as normal squamous without pathological changes. Surgical specimens of chemotherapy-naïve patients with known ESCC of histological grading G1, UICC stage II and III, had undergone esophagectomy. Patients’ age ranged from 22 to 83 years, with a median age of 59 years.
A second panel (n = 71) consisting of ESCC (n = 25), NE (n = 11), esophageal adenocarcinoma (EAC) (n = 13), gastric adenocarcinoma (GAC) (n = 15) and colorectal cancers (CRC) (n = 7) was used for qRT-PCR validation. Patients’ age ranged from 24 to 79 years, with a median age of 63 years.
All samples were snap-frozen in liquid nitrogen and stored at −80°C. We obtained tissue specimens from all subjects with informed written consent (approved by the local ethics committee of the Charité-Universitätsmedizin, Berlin). Each single specimen included in this study was histopathologically approved according to grade and stage by an experienced pathologist ( MV, University Bayreuth).

The majority of cancer patients in eastern Golestan present first to the local general practitioners or to the medical and surgical specialists in the area, and only a small group of patients are first diagnosed in major cities outside the area. Before the study began, the investigators contacted all of the local medical practitioners and asked them to refer their patients with suspected GI tract cancers to the Atrak Clinic. From August 2001 to August 2003, 682 patients were referred to the Atrak Clinic. Based on the results of a recent cancer surveillance study and an ongoing cancer registration in Golestan Province, we have shown that approximately 70% of the incident cases of oesophageal cancer recorded in the eastern part of Golestan Province during the study period were referred to the Clinic (unpublished data), so the results of this report may be generalised to represent the experience of eastern Golestan Province.
All the 682 patients referred to the Atrak Clinic were suspected of having upper GI cancers. After signing an informed consent, the patients were interviewed by a physician using a structured questionnaire and underwent physical examination followed by oesophago-gastro-duodenal videoendoscopy. Intravenous Midazolam (5 mg) and 10% lidocaine spray to the pharynx were used as premedication. Local medical specialists, who had been given specific training, performed the endoscopies using Olympus GIF-XQ230 and Pentax EG-2900 video endoscopes. At least four biopsies were obtained from all of the tumours that were found during endoscopy and standard biopsies were taken from the antrum, the gastric body (lesser curvature), the cardia and the oesophagus in all patients. Two more biopsies were taken from columnar-lined distal oesophagus, if such tissue existed. The endoscopic data were entered on predesigned forms, and the location of the tumours was either captured and registered electronically (90% of the tumours), or precisely drawn on a specially designed form. An experienced endoscopist (R Malekzadeh) reviewed both the endoscopic reports and the captured images to confirm the exact site of the tumours. Biopsy specimens were oriented and spread on strips of filter paper and fixed immediately in 10% buffered formalin. The samples were sent to the DDRC, in Tehran, where they were embedded, sectioned and stained with haematoxylin and eosin and examined by experienced DDRC pathologists (M Sotoudeh and B Abedi).
The cancers were classified into four groups: oesophageal squamous cell carcinoma (ESCC), oesophageal adenocarcinoma (EAC), gastric cardia adenocarcinoma (GCA) and gastric noncardia adenocarcinoma (GNCA). Adenocarcinomas of the stomach were classified as intestinal or diffuse type using Lauren's classification criteria (Lauren, 1965 ). Gastric cardia tumours were defined as adenocarcinoma with an estimated point of origin within 1 cm proximal or 3 cm distal of the oesophago-gastric junction.
The study was reviewed and approved by the Institutional Review Boards of the DDRC and the US National Cancer Institute.

The target population of the study was patients with advanced or metastatic esophageal squamous cell carcinoma who previously failed to receive first-line chemotherapy. The patients were assigned to receive either camrelizumab or chemotherapy (docetaxel or irinotecan). A partitioned survival model was established to reflect the disease progression. The model included three states: progression-free disease (PFD), progressive disease (PD), and death. The three states are mutually exclusive. All patients were assumed to enter the model in the PFD state, and that they could maintain their designated health state or develop into another health state in each cycle (Figure 1). The relative 5-year survival rate is 8% or less for patients diagnosed with metastatic disease; thus, the time horizon of the model was set to 10 years (ASCO, 2020 ; Cancer Information Service, 2020 ). The model period was set to 1 month to facilitate model operation and parameter calculation. The main results of the model output were total cost, incremental cost-effectiveness ratio (ICER), and quality-adjusted life years (QALYs). ICER refers to the additional cost required for each additional QALY. Cost and utility were discounted at a rate of 5% (Liu, 2020 ). All costs were converted to USD, with an average RMB exchange rate of $1 to 6.8974 Yuan for the full year of 2020 (National Bureau of statistics of China, 2020 ). In addition, 1–3 times the national per capita GDP in 2020 ($10,503.52) was used as the willingness-to-pay (WTP) threshold (World Health Organization, 2011 ; Liu, 2020 ; National Bureau of statistics of China, 2020 ). The TreeAge Pro 2020 software package was used to build the model and conduct statistical analysis.

We searched studies in four databases including PubMed, Embase, the Cochrane Library, and CNKI on Dec 10, 2022. ALI was searched as “Advanced lung cancer inflammation index” OR “ALI” OR “BMI x ALB / NLR” OR “BMI x serum albumin / NLR” OR “body mass index x serum albumin / neutrophil-to lymphocyte”. As for gastrointestinal cancer, the search strategy was “gastrointestinal cancer” OR “gastrointestinal neoplasms” OR “colon cancer” OR “rectal cancer” OR “colorectal cancer” OR “rectum cancer” OR “colorectal neoplasm” OR “colon neoplasm” OR “rectal neoplasm” OR “rectum neoplasm” OR “colorectal carcinoma” OR “colon carcinoma” OR “rectum carcinoma” OR “rectal carcinoma” OR “CRC” OR “gastric cancer” OR “gastric carcinoma” OR “gastric neoplasms” OR “stomach cancer” OR “stomach carcinoma” OR “stomach neoplasms” OR “liver cancer” OR “hepatocellular carcinoma cancer” OR “esophageal cancer” OR “esophageal neoplasm” OR “esophagus cancer” OR “esophagus neoplasm” OR “esophageal squamous cell carcinoma” OR “cholangiocarcinoma” OR “extrahepatic cholangiocarcinoma” OR “gallbladder cancer” OR “gallbladder neoplasms” OR “bile duct cancer” OR “bile duct neoplasms” OR “pancreatic cancer” OR “pancreatic carcinoma”. The search scope was limited to titles and abstracts. Language and study design had no limitations.

Human esophageal cancer cell lines KYSE-30 and TE-1 were acquired from the department of experimental research center in Beijing Friendship Hospital (Beijing, China). These two human esophageal squamous cell carcinoma cells were cultured in Roswell Park Memorial Institute (RPMI)-1640 (Hyclone, Termo Scientifc, MA) supplemented with 10% FBS (fetal bovine serum; Biological Industries, Tel Aviv, Israel) and 1% penicillin/streptomycin (KeyGen, Nanjing, China) at 37 °C in a humidified atmosphere of 5% CO₂. Anlotinib and raltitrexed were kindly given as gifts by Chia Tai Tianqing Co., Ltd. (Nanjing, China). Anlotinib and raltitrexed were dissolved in dimethyl sulfoxide (DMSO, Sigma, St. Louis, USA) and stored at − 20 °C for in vitro studies, and diluted with medium before each test.