Xiaodong Zhang

Carcinoma of unknown primary (CUP) is a rare malignancy characterized by metastatic disease without an identifiable primary tumor, even after extensive diagnostic evaluation. This case report described a 70-year-old female patient with squamous cell CUP (SCCUP) who initially presented with elevated carbohydrate antigen 19–9 and a diaphragmatic mass. Despite comprehensive workup, including ¹⁸ F-fluorodeoxyglucose positron emission tomography–computed tomography and a 90-gene expression assay, the primary site remained unclear. The patient underwent surgical resection followed by two cycles of systematic therapy and achieved a disease-free survival of 14 months. This case underscores the limitations of the current diagnostic tools and the potential role of multimodal therapy in the management of CUP. The discordance between molecular testing and the clinical findings further emphasizes the perplexing nature of CUP. This report also reviews the literature on diagnosis and therapeutic options. Due to the absence of standardized regimens, future international collaboration and comprehensive genomic profiling are warranted to advance the understanding of this heterogeneous disease.

Objectives: Cancer screening aims to detect and treat malignant lesions at an early stage and to prolong patients’ lifetime. There is still a lack of effective cancer screening programs in China. We initiated a screening project in 2018 and this study presented the cancer screening status in China. Methods: We conducted a cross-sectional study in one cancer-care medical center of China. The screening program included routine blood tests, plasma tumor markers, gastric endoscopy, colonoscopy, ultrasound, and computed tomography (CT) scans. Screening results were presented as sensitivity, specificity and positive predictive values (PPVs). Results: Twenty-three (1.46%) out of 1,576 participants were eventually diagnosed with malignant tumors or high-grade intraepithelial neoplasia (HGIN). A family history of malignancy (78.26% in diagnosed cancer and HGIN vs. 46.36% in the others) was the only statistically significant parameter associated with cancer detection (p = 0.002). None of the common tumor markers were associated with the cancers screened. Except for colonoscopy (50.00%) and ultrasound for renal cancer (66.67%), the sensitivities of most screening methods were 100%. The specificities of all the screening means were above 96%. Most PPVs ranged from 30–60%. Conclusion: We emphasized risk stratification for early cancer screening, such as a family history of cancer. The survey illustrated that gastric endoscopy, colonoscopy, ultrasound, and lung CT for early cancer screening had high specificity, reasonable sensitivity, and PPV. We anticipated this report would motivate larger-sample studies to estimate the risk-to-benefit ratio of cancer screening and urge the establishment of a native Chinese screening project and even guidelines.

Background: Esophageal squamous cell carcinoma (ESCC) is a serious threat to human health and life. The National Center for Biotechnology Information Gene Expression Omnibus (NCBI-GEO) database provides valuable information on genes related to the pathogenesis and prognosis of ESCC, which helps us to make in-depth understanding about the disease and improve its prognosis. Methods: Four microarray profiles [GSE77861 (African Americans), GSE26886 (Germans), GSE17351 (Americans), and GSE45670 (Chinese)] from the NCBI-GEO including 49 ESCC tissues and 41 corresponding normal tissues were collected. Integrated bioinformatics methods, including protein-protein interaction (PPI) network analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and Kaplan-Meier plotter were applied to determine the differentially expressed genes (DEGs) in ESCC together with their core functions and relationship with survival. Results: A total of 220 upregulated and 112 downregulated genes were identified as DEGs in ESCC, of which, 40 upregulated genes were core function genes. The DEGs were mostly involved in DNA replication and cell cycle pathways. Survival analysis and Bonferroni adjustment showed kinesin family member 18A (KIF18A) and TTK protein kinase (TTK) to be related to prognosis in ESCC. Conclusions: The findings of the present study verified the previously proposed association between TTK and patient survival in ESCC, and identified KIF18A as ESCC prognosis-related gene markers for the first time. The underlying mechanism needs to be further investigated using larger sample size studies and biological experiments in future.

Purpose: Esophageal squamous cell carcinoma (ESCC) is a critical threat to health and life. More than half of ESCC patients have recurrent or metastatic disease. Most late-stage patients undergo first-line treatment but experience further progression. Many of these patients have good performance status and are able to receive second-line therapy and even further treatments rather than best supportive care. Our analysis aimed to explore whether multiple lines of active treatment are beneficial in ESCC patients. Methods: We conducted a retrospective cohort study. Univariate and multivariate survival analyses were used to identify whether the number of active treatment lines was related to prognosis. All analyses and the corresponding survival curves were based on the Cox proportional hazard regression model and the Kaplan–Meier method. Comparisons between groups were conducted using the t-test, chi-square test, and Fisher’s exact test, as applicable. Results: Of a total of 138 patients with recurrent or metastatic disease, 66 (61.1%) received one line of active treatment, and 42 (38.9%) patients received two and more lines. Multiple lines of active therapy were statistically significantly associated with better prognosis (crude hazard ratio (HR) (95% confidence interval (CI))=0.21 (0.06– 0.73)), even after adjusting for relevant confounders (adjusted HR (95% CI)=0.19 (0.04– 0.86)). More grade 3– 4 hepatotoxicity patients were observed in the multiple-line treatment group (p=0.033). A small number of patients were cured by palliative management; these patients were more likely to have received both systematic and local treatment than other patients with repeated progression (9/15 versus 40/117, p=0.051). Conclusion: Multiple lines of active treatment are related to prolonged survival in recurrent and metastatic ESCC patients, and adverse effects are acceptable. Comprehensive therapy modalities are recommended.

An accurate estimation of prognosis of the esophageal carcinoma patients after surgery is urgently needed. Clinical nomogram has been developed to quantify risk by incorporating prognostic factors for individual patient. Based on the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2013, a total of 4566 patients were selected. Of those, 3198 patients were assigned to training set to construct the nomogram, which incorporated age, gender, histology, grade, T stage, N stage, nodes examined, radiation and chemotherapy. The calibration curve for probability of survival showed good agreement between prediction by nomogram and actual observation. The C-index of the nomogram was 0.71(95%CI 0.70-0.72), which was statistically higher than the TNM staging system. The results were then validated using bootstrap resampling and a validation set of 1368 patients in the SEER database. Besides, in the esophageal squamous cell carcinoma and esophageal adenocarcinoma subgroups, the nomogram discrimination was superior to the TNM staging system. It is likely that these results would play a supplementary role in the current staging system and help to identify the high risk population after surgery.

A characteristic of the epithelial-to-mesenchymal transition in cancer cells is the upregulation of mesenchymal markers. Fibroblast activation protein α (FAPα) is predominantly expressed by stromal fibroblasts. Previous studies have demonstrated that FAPα is also expressed by certain epithelium-derived cancer cells and is involved in the regulation of certain signaling pathways. One of our previous studies showed that FAPα promoted the proliferation of breast cancer cells via the phosphatidylinositol-3-kinase (PI3K) signaling pathway. In the present study, the A549 adenocarcinoma (AC) and SK-MES-1 squamous cell carcinoma (SCC) lung cancer cell lines were transfected with FAPα. The FAPα-expressing SK-MES-1 cells exhibited an increased growth rate, whereas the FAPα-expressing A549 cells exhibited a similar growth rate, compared with respective empty vector‑transfected control cells. Electric cell-substrate impedance sensing (ECIS)-based attachment and wound-healing assays showed that the overexpression of FAPα markedly increased the adhesive and migratory properties of the SK-MES-1 cells but not those of the A549 cells. Additionally, inhibitors of focal adhesion kinase, agonist-induced phospholipase C, neural Wiskott‑Aldrich syndrome protein, extracellular signal‑regulated kinase, Rho-associated protein kinase, PI3K, and sonic hedgehog (SHH) were used to evaluate the interaction between FAPα and signaling pathways. Only the inhibitors of SHH and PI3K inhibited the increased motility of the FAPα‑expressing SK-MES-1 cells. Western blot analysis confirmed the activation of PI3K/AKT and SHH/GLI family zinc finger 1 signaling in the FAPα-expressing SK-MES-1 cells. These results revealed that FAPα promoted the growth, adhesion and migration of lung SCC cells. In addition, FAPα regulated lung cancer cell function, potentially via the PI3K and SHH pathways. Further investigations are required to examine the role of FAPα in lung AC cells.

Patients with inoperable esophageal squamous cell carcinoma (ESCC) were not homogeneous and their outcomes were widely divergent. There was a lack of identified clinical factors related to prognosis; and there were no previous studies constructing prognosis score to predict survival and guide treatment. In this retrospective cohort study, twelve clinical characteristics of one hundred and twenty inoperable ESCC patients were collected at diagnosis and analyzed by Cox regression model. Various methods including univariate analysis, confounding adjusted multivariate analysis and model selection were applied to determine factors associated with poor prognosis; and prognosis score was built on established factors. Four characters were identified as poor prognosis factors, including mid- and low-thoracic tumor (aHR = 2.20, 95% CI = 1.03, 4.72), abdominal and retroperitoneal lymph node metastasis (aHR = 1.62, 95% CI = 1.00, 2.64), albumin no more than 39g/L (aHR = 2.81, 95% CI = 1.24, 6.41) and hematogenous metastasis (aHR = 1.61, 95% CI = 0.97, 2.69). Patients were stratified into three groups by prognosis score, that was, good survival with none of four identified factors (score zero), poor survival with three to four factors (score three to four) and median with one to two factors (score one to two), survival of three groups were statistically different (p_trend = 0.020). Prognosis score based on selected clinical characteristics could predict survival among inoperable ESCC patients, which was critical for individualized treatment and central of precise medicine.

Nimotuzumab (N) is a humanized anti‐epidermal growth factor receptor monoclonal antibody. This prospective, single‐armed, open label phase II study was conducted to evaluate the efficacy and safety of the combination of paclitaxel (T)/cisplatin (P) with nimotuzumab (N) as first‐line treatment in advanced esophageal squamous cell carcinoma (ESCC). Patients with pathologic confirmed unresectable locally advanced or metastatic ESCC were treated with the TPN regimen: nimotuzumab 200 mg weekly, paclitaxel 175 mg/m² on day 1 and cisplatin 30 mg/m² on days 1 and 2; repeat cycle every 3 weeks for six cycles. Radiotherapy was allowed to be admitted after four cycles of TPN treatment. The primary endpoint was the objective response rate (ORR). The secondary endpoint was the overall survival (OS), duration of disease control (DDC) and toxicities. From March 2011 to April 2013, a total of 59 patients were enrolled and 56 were eligible for the final analysis. Overall RR was 51.8% and disease control rate (DCR) (CR + PR + SD) was 92.9%. Local treatment (radiotherapy or surgery) followed by chemotherapy improved the duration of disease control for patients with metastatic disease and local‐regional advanced disease to 8.2 months and more than 23 months, respectively. The OS for patients with metastatic disease was 14.0 months (95% CI: 6.8–21.2 months). The most common G3/4 toxicities were neutropenia (46.4%), nausea (48.3%), alopecia (78.6%), anorexia (42.8%), vomiting (55.4%), arthralgia (62.5%) and anorexia (5%). Adding nimotuzumab to the standard TP regiment was safe, and well tolerated. The TPN regimen is an effective combination as the first‐line chemotherapy for the patients with advanced ESCC, and appears more active than current standard regimens.

The esophageal squamous cell carcinoma (ESCC) is the predominant pathological type and accounts for more than 80 % of esophageal cancer in China. The successful use of anti-epidermal growth factor receptor (EGFR) treatment in head and neck squamous cell carcinoma provides the rationale for introducing anti-EGFR targeting treatment in ESCC. One of our prospective phase II clinical trials analyzed the efficacy of nimotuzumab, an anti-EGFR agent, combined with chemotherapy (paclitaxel and cisplatin) to treat unresectable ESCC.