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Locally recurrent nasopharyngeal carcinoma (NPC) presents substantial challenges in clinical management. Although postoperative re-irradiation (re-RT) has been acknowledged as a potential treatment option, standardized guidelines and consensus regarding the use of re-RT in this context are lacking. This article provides a comprehensive review and summary of international recommendations on postoperative management for potentially resectable locally recurrent NPC, with a special focus on postoperative re-RT. A thorough search was conducted to identify relevant studies on postoperative re-RT for locally recurrent NPC. Controversial issues, including resectability criteria, margin assessment, indications for postoperative re-RT, and the optimal dose and method of re-RT, were addressed through a Delphi consensus process. The consensus recommendations emphasize the need for a clearer and broader definition of resectability, highlighting the importance of achieving clear surgical margins, preferably through an en bloc approach with frozen section margin assessment. Furthermore, these guidelines suggest considering re-RT for patients with positive or close margins. Optimal postoperative re-RT doses typically range around 60 Gy, and hyperfractionation has shown promise in reducing toxicity. These guidelines aim to assist clinicians in making evidence-based decisions and improving patient outcomes in the management of potentially resectable locally recurrent NPC. By addressing key areas of controversy and providing recommendations on resectability, margin assessment, and re-RT parameters, these guidelines serve as a valuable resource for clinical experts involved in the treatment of locally recurrent NPC., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: I declare no competing interests.

Emerging evidence suggests that cancer cells may disseminate early, prior to the formation of traditional macro-metastases. However, the mechanisms underlying the seeding and transition of early disseminated cancer cells (DCCs) into metastatic tumors remain poorly understood. Through single-cell RNA sequencing, we show that early lung DCCs from esophageal squamous cell carcinoma (ESCC) exhibit a trophoblast-like 'tumor implantation' phenotype, which enhances their dissemination and supports metastatic growth. Notably, ESCC cells overexpressing GPRC5A demonstrate improved implantation and persistence, resulting in macro-metastases in the lungs. Clinically, elevated GPRC5A level is associated with poorer outcomes in a cohort of 148 ESCC patients. Mechanistically, GPRC5A is found to potentially interact with WWP1, facilitating the polyubiquitination and degradation of LATS1, thereby activating YAP1 signaling pathways essential for metastasis. Importantly, targeting YAP1 axis with CA3 or TED-347 significantly diminishes early implantation and macro-metastases. Thus, the GPRC5A/WWP1/LATS1/YAP1 pathway represents a crucial target for therapeutic intervention in ESCC lung metastases., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The use of immune checkpoint inhibitors (ICIs) in cancer treatment has shown promise but can also have unintended consequences, such as reactivating latent tuberculosis (TB). To develop treatments that address ICIs-related adverse events, it is essential to understand cellular heterogeneity across healthy and pathological tissues. We performed cross-tissue multiplexed staining analysis on samples from two patients with TB reactivation during pembrolizumab treatment for metastatic nasopharyngeal carcinoma. CD8+ T cells, rather than CD4+ T cells, accumulated preferentially in the tuberculoma and were associated with increased production of IFNγ and expression of CD137. Additionally, CD137 enrichment played a role in the spatial organization of the tuberculoma, with specific interaction limited to spatial proximal cells between IFNγ+ CD137+ CD8+ T cells and IL12+ CD137+ type-1 macrophages. This unique feature was not observed in non-tumoral or tumoral tissues. Our analysis of public transcriptomic datasets supported the notion that this cellular interaction was more prominent in patients with durable ICI responses compared to those with non-ICI-related TB. We suggest that shifts towards CD137-rich immune niches are correlated with both off-target immune-related adverse events and anti-tumor efficacy. Targeting the tumor microenvironment through conditional activation of anti-CD137 signaling in combination with ICIs can modulate the reactivity of T cells and macrophages for localized tumor killing without the potential off-target immune-related risks associated with ICIs alone.

Importance: Esophageal squamous cell carcinoma (ESCC) is a deadly disease with frequent recurrence. There are unmet needs for prognostic biomarkers for dynamically monitoring disease progression and detecting minimal residual disease., Objective: To examine whether circulating tumor DNA is clinically useful as a prognostic biomarker for ESCC recurrence and patient survival., Design, Setting, and Participants: This single-center, population-based cohort study consecutively enrolled 147 patients receiving curative (n = 74) or palliative (n = 73) treatment at the surgery and clinical oncology departments of Queen Mary Hospital in Hong Kong from August 1, 2016, to September 31, 2021. Patients were followed up for 2 years. Plasma samples were collected at different longitudinal time points for a prospective circulating tumor DNA (ctDNA) next-generation sequencing profiling study of 77 actionable genes., Intervention: Patients were treated with up-front surgery, neoadjuvant chemoradiotherapy plus surgery with or without adjuvant therapy, or palliative chemotherapy (CT)., Main Outcomes and Measures: Detection of circulating tumor DNA (ctDNA), progression-free survival (PFS), and overall survival (OS)., Results: A total of 478 serial plasma samples from 147 patients with locoregional or metastatic ESCC were prospectively analyzed. Among the 74 patients in the curative group (median [range] age, 66 [46-85] years; 56 [76.0%] male), 44 (59.5%) relapsed and 36 (48.6%) died. For patients receiving curative surgical treatment, a high ctDNA level (hazard ratio [HR], 7.84; 95% CI, 1.87-32.97; P = .005) and ctDNA alterations (HR, 5.71; 95% CI, 1.81-17.97; P = .003) at 6 months postoperation were independently associated with poor OS. Among patients receiving neoadjuvant chemoradiotherapy, postneoadjuvant ctDNA alterations were associated with poor PFS (HR, 3.16; 95% CI, 1.17-8.52; P = .02). In the 73 patients in the palliative group (median [range] age, 63 [45-82] years; 63 [86.0%] male), 71 (97.3%) had disease relapse and 68 (93.2%) died. Detectable pre-CT NFE2L2 alterations were independently associated with PFS (HR, 2.99; 95% CI, 1.35-6.61; P = .007) and OS (HR, 28.39; 95% CI, 7.26-111.03; P = 1.52 × 10-6), whereas high ctDNA levels (HR, 2.41; 95% CI, 1.18-4.95; P = .02) and alterations in pre-cycle III ctDNA (HR, 1.99; 95% CI, 1.03-3.85; P = .04) showed weaker associations with PFS. Alterations in pre-CT ctDNA were independently associated with OS (HR, 4.46; 95% CI, 1.86-10.69; P = 7.97 × 10-4)., Conclusions and Relevance: The findings of this cohort study indicate that prognostic models incorporating ctDNA features are useful in ESCC. Both ctDNA level and NFE2L2 alterations pre-CT and before cycle III were found to be important prognostic factors in palliative groups, and ctDNA alterations after treatment and at 6 months after surgery may define high-risk groups for recurrence in the curative group. High-risk patients can benefit by a timely switch to the next therapeutic options.

Background: The strategy of dual blockade of TGF-β and PD-L1 pathways has not been previously tested in platinum-refractory recurrent or metastatic nasopharyngeal cancer (R/M NPC) patients. This study aimed to evaluate the safety and efficacy of bintrafusp alfa in refractory R/M NPC patients., Methods: In this single-arm, single-centre phase II clinical trial, 38 histologically confirmed R/M NPC patients were enrolled and administered with bintrafusp alfa every 2 weeks. Primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety., Findings: Thirty-eight patients were accrued (33 men; median age, 54 years). ORR was 23.7% (complete response, n = 2; partial response, n = 7). The median DOR was 19.2 months, median PFS was 2.3 months, median OS was 17.0 months, and 1-year OS rate was 63.2%. Unfortunately, 25 patients (65.7%) progressed within 8 weeks of treatment, 15 patients (39.5%) and 8 patients (21.1%) developed hyper-progressive disease (HPD) per RECIST v1.1 and tumor growth rate (TGR) ratio respectively. Sixteen patients (42.4%) experienced ≥ grade 3 treatment-related adverse events (TRAEs), most commonly anemia (n = 9, 23.7%) and secondary malignancies (n = 4, 10.5%). TRAEs led to permanent treatment discontinuation in 7 patients. Patients with strong suppression of plasma TGFβ1 level at week 8 were unexpectedly associated with worse ORR (9.1% vs 44.4%, P  = 0.046) and development of HPD. There was no correlation between PD-L1 expression and ORR., Interpretation: Bintrafusp alfa demonstrated modest activity in R/M NPC but high rates of HPD and treatment discontinuation secondary to TRAEs are concerning., Funding: The project was supported by Alice Ho Miu Ling Nethersole Charity Foundation Professorship Endowed Fund and Merck KGaA., Competing Interests: All the authors declare no potential conflicts of interest., (© 2023 The Author(s).)

Background: The meta-analysis of chemotherapy for nasopharynx carcinoma (MAC-NPC) collaborative group previously showed that the addition of adjuvant chemotherapy to concomitant chemoradiotherapy had the highest survival benefit of the studied treatment regimens in nasopharyngeal carcinoma. Due to the publication of new trials on induction chemotherapy, we updated the network meta-analysis., Methods: For this individual patient data network meta-analysis, trials of radiotherapy with or without chemotherapy in patients with non-metastatic nasopharyngeal carcinoma that completed accrual before Dec 31, 2016, were identified and updated individual patient data were obtained. Both general databases (eg, PubMed and Web of Science) and Chinese medical literature databases were searched. Overall survival was the primary endpoint. A frequentist network meta-analysis approach with a two-step random effect stratified by trial based on hazard ratio Peto estimator was used. Global Cochran Q statistic was used to assess homogeneity and consistency, and p score to rank treatments, with higher scores indicating higher benefit therapies. Treatments were grouped into the following categories: radiotherapy alone, induction chemotherapy followed by radiotherapy, induction chemotherapy without taxanes followed by chemoradiotherapy, induction chemotherapy with taxanes followed by chemoradiotherapy, chemoradiotherapy, chemoradiotherapy followed by adjuvant chemotherapy, and radiotherapy followed by adjuvant chemotherapy. This study is registered with PROSPERO, CRD42016042524., Findings: The network comprised 28 trials and included 8214 patients (6133 [74·7%] were men, 2073 [25·2%] were women, and eight [0·1%] had missing data) enrolled between Jan 1, 1988, and Dec 31, 2016. Median follow-up was 7·6 years (IQR 6·2-13·3). There was no evidence of heterogeneity (p=0·18), and inconsistency was borderline (p=0·10). The three treatments with the highest benefit for overall survival were induction chemotherapy with taxanes followed by chemoradiotherapy (hazard ratio 0·75; 95% CI 0·59-0·96; p score 92%), induction chemotherapy without taxanes followed by chemoradiotherapy (0·81; 0·69-0·95; p score 87%), and chemoradiotherapy followed by adjuvant chemotherapy (0·88; 0·75-1·04; p score 72%), compared with concomitant chemoradiotherapy (p score 46%)., Interpretation: The inclusion of new trials modified the conclusion of the previous network meta-analysis. In this updated network meta-analysis, the addition of either induction chemotherapy or adjuvant chemotherapy to chemoradiotherapy improved overall survival over chemoradiotherapy alone in nasopharyngeal carcinoma., Funding: Institut National du Cancer and Ligue Nationale Contre le Cancer., Competing Interests: Declaration of interests AA reports payment to her institution by MSD France for the participation on a data safety monitoring board or advisory board. P-YH reports grants from JunShi Pharm, outside the submitted work. CP reports a fellow grant from Fondation de France, outside the submitted work. LZ reports research grants from Hengrui Pharm, Beigen Pharm, and Eli Lilly. JMo reports a grant from the US National Cancer Institute to SWOG Statistics and Data Management Center. RKCN reports consulting fees from Pfizer, Novartis, Sanofi, AstraZeneca, Eli Lilly, MSD, Zai Lab, Roche, Eisai, and Merck; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Novartis, AstraZeneca, Sanofi, Pfizer, Zai Lab, Eisai, Eli Lilly, and MSD; support for attending meetings or travel from Pfizer, Astellas, Novartis, MSD, Roche, Eisai, Merck, Sanofi, Bristol Myers Squibb (BMS), and ZaiLab; payment to his institution from Nuance for participation on a data safety monitoring board or advisory board. GF reports payment from Novartis for an advisory role, and stock or stock options from Genprex, Daiichi Sankyo, Ariad, RFL Holdings, and Formycon. ATCC reports grants to his institution from Merck Serono, MSD, Novartis, Pfizer, and Eli Lilly; consulting fees from MSD, Merck Serono, and Cullinan Management; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Beigene, Springer, Merck, and Pfizer; support for attending meetings or travel from BMS, MSD, Pfizer, Roche, Novartis, and AstraZeneca; participation on a data safety monitoring board or advisory board from MSD and Tessa Therapeutics; and other non-financial interests from Immunomic Therpeutics, Angene Biotechnology, and Owlstone Medical. JB reports consulting fees from Merck, MSD, Roche, BMS, and Nanobiotix. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

We aim to reveal the clinical significance and potential usefulness of dynamic monitoring of CTCs to track therapeutic responses and improve survival for advanced ESCC patients. Peripheral blood (PB) ( n = 389) and azygos vein blood (AVB) ( n = 13) samplings were recruited prospectively from 88 ESCC patients undergoing curative surgery from 2017 to 2022. Longitudinal CTC enumeration was performed with epithelial (EpCAM/pan-cytokeratins/MUC1) and mesenchymal (vimentin) markers at 12 serial timepoints at any of the pre-treatment, all of the post-treatments/pre-surgery, post-surgery follow-ups for 3-year, and relapse. Longitudinal real-time CTC analysis in PB and AVB suggests more CTCs are released early at pre-surgery and 3-month post-surgery into the circulation from the CTRT group compared to the up-front surgery group. High CTC levels at pre-treatments, 1-/3-month post-surgery, unfavorable changes of CTC levels between all post-treatment/pre-surgery and 1-month or 3-month post-surgery (Hazard Ratio (HR) = 6.662, p < 0.001), were independent prognosticators for curative treatment. The unfavorable pre-surgery CTC status was independent prognostic and predictive for neoadjuvant treatment efficacy (HR = 3.652, p = 0.035). The aggressive CTC clusters were more frequently observed in AVB compared to PB. Its role as an independent prognosticator with relapse was first reported in ESCC (HR = 2.539, p = 0.068). CTC clusters and longitudinal CTC monitoring provide useful prognostic information and potential predictive biomarkers to help guide clinicians in improving disease management.

Objective: This study aims at constructing a staging system incorporating tumor regression grade and ypN-category (TRG-N) in patients with neoadjuvant therapy before esophagectomy. It is hypothesized that this would prognosticate better than the current American Joint Committee on Cancer (AJCC) postneoadjuvant therapy (ypTNM) stage groups., Background: Conventional pathological T-category is defined by the depth of invasion, and may lose prognostic relevance after neoadjuvant therapy. TRG defines treatment response by the degree of tumor regression, and when combined with ypN-category may be more prognostic than AJCC postneoadjuvant therapy (ypTNM) stage groups., Methods: A training cohort of 210 patients with esophageal squamous cell carcinoma and who had had neoadjuvant therapy before esophagectomy were studied. A validation cohort comprised 107 patients from another hospital. Resected esophagi were assessed by ypT-category and TRG, the latter assigned according to the Becker 4-tier system. These categories were grouped with ypN-category into a TRG-N system. Patients' survival was compared between the current AJCC postneoadjuvant therapy (ypTNM) stage groups and this TRG-N system., Results: In the training cohort, 5-year survival rates according to ypTNM stage I, II, IIIA, IIIB, and IVA were 53%, 39.4%, 47%, 18.3%, and 0%, respectively. For TRG-N stages I, II, III, and IV, the respective figures were 59.6%, 43.5%, 23.8%, and 15.6%. TRG-N stage showed better fit in survival than ypTNM stage groups, indicated by lower Akaike Information Criteria (AIC) and Bayesian Information Criterion values. Similar results were found in the validation cohort. Multivariate analysis showed that TRG-N stage ( P =0.02), age ( P =0.006), and sex ( P =0.005) were independent prognostic factors., Conclusion: TRG-N stage shows better prognostication than the AJCC postneoadjuvant therapy (ypTNM) stage groups., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To investigate the dosimetric variations and radiobiological impacts as a consequence of delivering treatment plans of 3D nature in 4D manner based on the 4D Monte Carlo treatment planning framework implemented on Cyberknife., Methods and Materials: Dose distributions were optimized on reference 3D images at end of exhale phase of a 4DCT dataset for twenty-five lung cancer patients treated with 60 Gy / 3Fx or 48 Gy / 4Fx. Deformable image registrations (DIR) between individual 3DCT images to the reference 3DCT image in the 4DCT study were performed to interpolate doses calculated on multiple anatomical geometries back on to the reference geometry to compose a 4D dose distribution that included the tracking beam motion and organ deformation. The 3D and 4D dose distributions that were initially calculated with the equivalent path-length (EPL) algorithm (3D EPL dose and 4D EPL dose) were recalculated with the Monte Carlo algorithm (3D MC dose and 4D MC dose). Dosimetric variations of V 60Gy / 48Gy and D 99 of GTV, mean doses to the lung and the heart and maximum dose (D 1 ) of the spinal cord as a consequence of tracking beam motion in deforming anatomy, dose calculation algorithm, and both were quantified by the relative change from 4D MC to 3D MC doses, from 4D MC to 4D EPL doses, and from 4D MC to 3D EPL doses, respectively., Results: Comparing 4D MC to 3D EPL plans, V 60Gy / 48Gy and D 99 of GTV decreased considerably by 13 ± 22% (mean ± 1SD) and 9.2 ± 5.5 Gy but changes of normal tissue doses were not more than 0.5 Gy on average. The generalized equivalent uniform dose (gEUD) and tumor control probability (TCP) were reduced by 14.3 ± 8.8 Gy and 7.5 ± 5.2%, and normal tissue complication probability (NTCP) for myelopathy and pericarditis were close to zero and NTCP for radiation pneumonitis was reduced by 2.5 ± 4.1%. Comparing 4D MC to 4D EPL plans found decreased V 60Gy / 48Gy and D 99 by 12.3 ± 21.6% and 7.3 ± 5.3 Gy, the normal tissues doses by 0.5 Gy on average, gEUD and TCP by 13.0 ± 8.6 Gy and 7.1 ± 5.1%. Comparing 4D MC to 3D MC doses, V 60Gy / 48Gy and D 99 of GTV was reduced by 5.2 ± 8.8 %and 2.6 ± 3.3 Gy, and normal tissues hardly changed from 4D MC to 3D MC doses. The corresponding decreases of gEUD and TCP were 2.8 ± 4.0 Gy and 1.6 ± 2.4%., Conclusion: The large discrepancy between original 3D EPL plan and benchmarking 4D MC plan is predominately due to dose calculation algorithms as the tracking beam motion and organ deformation hardly influenced doses of normal tissues and moderately decreased V 60Gy / 48Gy and D 99 of GTV. It is worth to make a thoughtful weight of the benefits of full 4D MC dose calculation and consider 3D MC dose calculation as a compromise of 4D MC dose calculation considering the multifold computation time. This article is protected by copyright. All rights reserved., (This article is protected by copyright. All rights reserved.)

Purpose: The current recommendation for patients with locoregionally advanced nasopharyngeal carcinoma (NPC) is cisplatin-based induction chemotherapy (IC) or adjuvant chemotherapy (AC) plus concurrent chemoradiotherapy (CRT). However, data on the optimal platinum doses for each phase of combined regimens are lacking., Experimental Design: 742 patients with NPC in the NPC-0501 trial treated with CRT plus IC/AC and irradiated with intensity-modulated radiotherapy (IMRT) were analyzed. The optimal platinum dose to achieve the best overall survival (OS) in the concurrent and induction/adjuvant phases was studied., Results: Evaluation of the whole series shows the optimal platinum dose was 160 mg/m2 in the concurrent and 260 mg/m2 in the induction/adjuvant phase. Repeating the analyses on 591 patients treated with cisplatin throughout (no replacement by carboplatin) confirmed the same results. The cohort with optimal platinum doses in both phases had better OS than the cohort suboptimal in both phases (stage III: 90% vs. 75%; stage IVA-B: 80% vs. 56%, at 5-year). Multivariable analyses confirmed optimal platinum doses in both phases versus suboptimal dose in each phase are significant independent factors for OS, with HR of 0.61 [95% confidence interval (CI), 0.41-0.91] and 0.67 (95% CI, 0.48-0.94), respectively. Treatment sequence was statistically insignificant after adjusting for platinum doses., Conclusions: Both concurrent and IC/AC are needed for locoregionally advanced NPC, even for patients irradiated by IMRT; the concurrent platinum dosage could be set at ≥160 mg/m2 when coupled with adequate induction/adjuvant dosage at ≥260 mg/m2 (or at least ≥240 mg/m2). To achieve these optimal dosages, IC-CRT at conventional fractionation is favored., (©2022 American Association for Cancer Research.)

Purpose: To propose a refined M1 classification in de novo metastatic nasopharyngeal carcinoma (NPC) based on pooled data from two academic institutions., Methods: Previously untreated de novo M1 NPC patients prospectively treated at The University of Hong Kong (N = 69) and Fujian Cancer Hospital (N = 114) between 2007 and 2016 were recruited and randomized in a 2:1 ratio to generate training (N = 120) and validation (N = 63) cohorts, respectively. Multivariable analysis (MVA) was performed for the training and validation cohorts to identify anatomic prognostic factors for overall survival (OS). Recursive partitioning analysis (RPA) was performed which incorporated the anatomic prognostic factors identified in the MVA to derive Anatomic-RPA groups which stratified OS in the training cohort, and were then validated in the validation cohort., Results: Median follow-up for the training and validation cohorts was 27.2 and 30.2 months with 3-year OS of 51.6% and 51.1%, respectively. MVA revealed that co-existing liver-bone metastases was the only factor prognostic for OS in both the training and validation cohorts. Anatomic-RPA separated M1 disease into M1a (no co-existing liver-bone metastases) and M1b (co-existing liver-bone metastases) with median OS 39.5 and 23.7 months, respectively (p = 0.004) in the training cohort. RPA for the validation cohort also confirmed good segregation with co-existing liver-bone metastases with median OS 47.7 and 16.0 months, respectively (p = 0.008)., Conclusion: Our proposal to subdivide de novo M1 NPC into M1a (no co-existing liver-bone metastases) vs. M1b (co-existing liver-bone metastases) provides better OS segregation., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Most patients with well-differentiated thyroid cancers (WDTC) are adequately treated with surgery, radioactive iodine, and TSH suppression by thyroxine. External radiotherapy (ERT) is reserved for selected cases and for older patients. Some of the indications for ERT to neck include adjuvant treatment for gross or microscopic disease after surgery, palliation of locally advanced unresectable tumor, or as salvage for recurrent disease which is not amenable to surgery or does not uptake radioactive iodine. High radiation dose of at least 60Gy is required for locoregional control of gross or microscopic residual disease. As even patients with recurrent or metastatic disease can have long survival, it is important to minimize late radiation-induced morbidity without compromising local control. Modern ERT technique like intensity-modulated radiotherapy allows high radiation dose to be delivered to the large, complex target volume while protecting the adjacent critical normal structures like the trachea, larynx, esophagus, and cervical spinal cord., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Radioactive iodine is given after total thyroidectomy for remnant ablation or treatment of residual/metastatic disease. The decision and dose of radioactive iodine should be in a personalized and patient-specific approach, taking account the clinical-pathological features, risk stratification, patient's preference, and facilities of the institutions. We review the principles and use of radioactive iodine in differentiated thyroid cancer., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Patients with radioactive iodine (RAI) refractory locally advanced or metastatic differentiated thyroid cancer have a poor prognosis. This article reviews the definition of RAI-refractory thyroid cancer and the management approach. Watchful waiting should be considered for patients with asymptomatic and non-progressive disease, while oral targeted agent with tyrosine kinase inhibitors can be considered for patients who are symptomatic or whose disease would cause irreversible complications if treatment has not been initiated. Since these targeted agents only improve disease-free survival and are associated with adverse events, physicians should assess both clinical and tumor factors carefully to decide on the right timing of start of palliative treatment., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Chemotherapy, when added to radiotherapy, improves survival in locally advanced nasopharyngeal carcinoma (NPC). This article presents the second update of the Meta-Analysis of Chemotherapy in NPC., Methods: Published or unpublished randomized trials assessing radiotherapy (±a second chemotherapy timing) with/without chemotherapy in non-metastatic NPC patients were identified. Updated data were sought for studies included in the previous rounds of the meta-analysis. The primary endpoint was overall survival. All trials were analyzed following the intent-to-treat principle using a fixed-effects model. Treatments were classified in five subsets according to chemotherapy timing. The statistical analysis plan was pre-specified., Results: Eighteen new trials were identified. Individual patient data were available for seven. In total, the meta-analysis now included 26 trials and 7,080 patients. The addition of chemotherapy reduced the risk of death, with a hazard ratio (HR) of 0.79 (95% confidence interval (CI) [0.73; 0.85]), and an absolute survival increase at 5 and 10 years of 6.1% [+3.9; +8.3] and + 8.4% [+5.7; +11.1], respectively. The largest effect was observed for concomitant + adjuvant, induction (with concomitant in both arms) and concomitant chemotherapy, with respective HR [95%CI] of 0.68 [0.59; 0.79] (absolute survival increase at 5 years: 12.3% (7.0%;17.6%)), 0.73 [0.63; 0.86] (6.0% (2.5%;9.5%)) and 0.81 [0.70; 0.92] (5.2% (0.8%;9.6%)). The benefit of chemotherapy was also demonstrated by improvement in progression-free survival, cancer mortality, locoregional control and distant control. There was a significant interaction between patient age and chemotherapy effect., Conclusion: This updated meta-analysis confirms the benefit of concomitant chemotherapy and concomitant + adjuvant chemotherapy, and suggests that addition of induction or adjuvant chemotherapy to concomitant chemotherapy improves tumor control and survival. The benefit of chemotherapy decreases with increasing patient age., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Objective: This study compared the efficacy of PF-based and CROSS-based neoadjuvant chemoradiotherapy for ESCC., Background: PF-based regimen has been a standard regimen for ESCC, but it has been replaced by the CROSS regimen in the past few years, despite no prospective head-to-head comparative study has been performed., Methods: This is a single center retrospective study. Records of all ESCC patients who have received neoadjuvant PF with 40 Gy radiotherapy in 20 daily fractions (PFRT Group) or CROSS with 41.4 Gy radiotherapy in 23 daily fractions (CROSS Group) during the period 2002 to 2019 were retrieved. Propensity score matching (1:1) was performed to minimize baseline differences. The primary and secondary endpoints were overall survival and clinicopathological response. Subgroup analysis ("CROSS Eligibility") was performed based on tumor length, cT-stage, cM-stage, age, and performance status., Results: One hundred (out of 109) patients (CROSS group) and propensity score matched 100 (out of 210) patients (PFRT group) were included. Esophagectomy rates in CROSS and PFRT group were 69% and 76%, respectively (P = 0.268). R0 resection rates were 85.5% and 81.6% (P = 0.525) and the pathological complete remission rates were 24.6% and 35.5% (P = 0.154). By intention-to-treat, the median survival was 16.7 and 32.7 months (P = 0.083). For "CROSS Eligible subgroup," the median survival of the CROSS and PFRT group was 21.6 versus 44.9 months (P = 0.093)., Conclusions: There is no statistically difference in survival or clinicopathological outcome between both groups, but the trend favors PFRT. Prospective head-to-head comparison and novel strategies to improve the outcomes in resectable ESCC are warranted.

Background and Purpose: Nasopharyngeal carcinoma (NPC) is one of the most common cancers in southern China and the first-line treatment is radiotherapy. Intensity-modulated radiation therapy (IMRT) can deliver high dose to cancer and low dose to normal tissue, but xerostomia is still one of the complications after IMRT. However, how the concentration of saliva electrolytes be affected by IMRT and the effects on the quality of life are still unknown. In this prospective study, 76 NPC patients were recruited from hospitals in Hong Kong to identify the change of saliva electrolytes and xerostomia-related quality of life before and after IMRT., Methods and Materials: Saliva and questionnaire were collected before IMRT, 1 month, 3 months, 6 months and 12 months after IMRT. The concentration of saliva electrolytes was detected using inductively coupled plasma-optical emission spectroscopy (ICP-OES)., Results: Saliva flow rate significantly decreased after IMRT. Decrease in the mean value of pH was observed but the difference is not statistically significant. The concentrations of potassium, iodine, and calcium decreased and chloride concentration increased after IMRT, while the concentrations of sodium, magnesium, copper or zinc were kept at the same level before and after treatment. Xerostomia-related quality of life was adversely affected by IMRT, but partially recovered after 1 year., Conclusions: Our study revealed the change of saliva electrolytes and xerostomia-related quality of life in patients undergone IMRT for NPC., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Preoperative chemoradiation (CROSS regimen) has been widely adopted worldwide. The survival advantage imparted is especially impressive for oesophageal squamous cell carcinoma (OSCC). This study aimed at investigating the efficacy of the CROSS regimen in real-world scenario., Methods: This is a retrospective study of all patients with OSCC intended for preoperative treatment using the CROSS regimen during 2012-2017. Patients were divided into two groups: those within the selection criteria in the CROSS trial and those beyond criteria, namely age > 75 years old, tumour length > 8 cm or clinical M1 stage of lymph node involvement (AJCC 6th edition). Clinical outcome and survival data were compared., Results: Eighty-eight patients were included. There were 46 patients in the "CROSS eligible" group and 42 in the "CROSS ineligible" group. By intention-to-treat, the estimated median survival was 24.2 months vs. 12.7 months, respectively (p = 0.047). The results were much inferior compared to that published in the original CROSS trial. Univariable and multivariable analyses showed tumour length and resectability as independent variables affecting survival., Discussion: In a real-world scenario, the clinical outcome remains suboptimal and the excellent results in the trial setting were not reproducible in this Asian cohort. Patient selection is one key element accountable for the difference. The efficacy of the CROSS regimen may not be adequate for patients with more advanced disease. The optimal multimodal therapy for this group of patients remains undefined.

Background: A current recommendation for the treatment of patients with locoregionally advanced nasopharyngeal carcinoma (NPC) is conventional fractionated radiotherapy (RT) with concurrent cisplatin followed by adjuvant cisplatin and 5-fluorouracil (PF). This randomized NPC-0501 trial evaluated the therapeutic effect of changing to an induction-concurrent sequence or accelerated-fractionation sequence, and/or replacing 5-fluorouracil with capecitabine (X)., Methods: Patients with American Joint Committee on Cancer/International Union Against Cancer stage III to stage IVB NPC initially were randomly allocated to 1 of 6 treatment arms (6-arm full-randomization cohort). The protocol was amended in 2009 to permit centers to opt out of randomization regarding fractionation (3-arm chemotherapy cohort)., Results: A total of 803 patients were accrued (1 of whom was nonevaluable) from 2006 to 2012. Based on the overall comparisons, neither changing the chemotherapy sequence nor accelerated fractionation improved treatment outcome. However, secondary analyses demonstrated that when adjusted for RT parameters and other significant factors, the induction-concurrent sequence, especially the induction-PX regimen, achieved significant improvements in progression-free survival (PFS) and overall survival. Efficacy varied among different RT groups: although no impact was observed in the accelerated-fractionation group and the 3-arm chemotherapy cohort, a comparison of the induction-concurrent versus concurrent-adjuvant sequence in the conventional-fractionation group demonstrated a significant benefit in PFS (78% vs 62% at 5 years; P = .015) and a marginal benefit in overall survival (84% vs 72%; P = .042) after adjusting for multiple comparisons. Comparison of the induction-PX versus the adjuvant-PF regimen demonstrated better PFS (78% vs 62%; P = .027) without an increase in overall late toxicity., Conclusions: For patients irradiated using conventional fractionation, changing the chemotherapy sequence from a concurrent-adjuvant to an induction-concurrent sequence, particularly using induction cisplatin and capecitabine, potentially could improve efficacy without an adverse impact on late toxicity. However, further validation is needed for confirmation of these findings., (© 2020 American Cancer Society.)

(1) Background: Early predictive markers to track treatment responses are needed for advanced esophageal squamous cell carcinoma (ESCC) patients. We examined the prognostication and risk stratification role of liquid biopsy serial monitoring for this deadly cancer. (2) Methods: Circulating tumor cells (CTCs) and plasma cell-free DNA (cfDNA) were isolated from 60 ESCC patients treated by chemotherapy (CT) at five serial timepoints: baseline (CTC1/cfDNA1), CT pre-cycle III (CTC2/cfDNA2), CT post-cycle IV, end of CT and relapse. (3) Results: In 45/57 ESCC patients with evaluable CTC counts at CT pre-cycle III, positive CTC2 (≥3 CTCs) is independently associated with response at interim reassessment and progression-free survival (PFS) in multivariate analysis. In 42/57 ESCC patients with changes of CTC1/CTC2 and cfDNA1/cfDNA2, patients categorized into four risk groups based on the number of favorable and unfavorable changes of CTC1/CTC2 and cfDNA1/cfDNA2, were independently associated with overall survival (OS) by multivariate analysis. (4) Conclusions: CTC counts at pre-cycle III are independently associated with response at interim reassessment and PFS. Combined changes of CTC counts and cfDNA levels from baseline to pre-cycle III are independently associated with OS. Longitudinal liquid biopsy serial monitoring provides complementary information for prediction and prognosis for CT responses in advanced ESCC.

Nasopharyngeal carcinoma is an Epstein-Barr virus (EBV)-related malignancy. Recently, we found that the EBV-encoded miRNA BART2-5p was increased in the serum of patients with preclinical nasopharyngeal carcinoma and that the copy number positively correlated with disease progression. In this study, we established its role in nasopharyngeal carcinoma progression and explored underlying mechanisms and clinical significance. BART2-5p was an independent unfavorable prognostic factor for progression-free survival and its circulating abundance positively associated with distant metastasis. Ectopic expression of BART2-5p promoted migration and invasion of EBV-negative nasopharyngeal carcinoma cells, whereas genetic downregulation of BART2-5p in EBV-positive nasopharyngeal carcinoma cells decreased aggressiveness. Mechanistically, BART2-5p targeted RND3 , a negative regulator of Rho signaling. Downregulation of RND3 phenocopied the effect of BART2-5p and reconstitution of RND3 rescued the phenotype. By suppressing RND3, BART2-5p activated Rho signaling to enhance cell motility. These findings suggest a novel role for EBV miRNA BART2-5p in promoting nasopharyngeal carcinoma metastasis and its potential value as a prognostic indicator or therapeutic target. SIGNIFICANCE: This study shows that EBV-encoded BART2-5p miRNA suppresses expression of the RND3 Rho family GTPase, consequently promoting ROCK signaling, cell motility, and metastatic behavior of NPC cells., (©2020 American Association for Cancer Research.)

Purpose: Despite being the most common pediatric solid tumors, incidence and outcome of CNS tumors in Chinese children have not been systematically reported. We addressed this knowledge gap by comparing the epidemiology of pediatric CNS tumors in Hong Kong and the United States., Patients and Methods: Data between 1999 and 2016 from a population-based cancer registry in Hong Kong, China, on patients < 18 years old with CNS tumors (Hong Kong cohort) and from the US SEER Program (Asian/Pacific Islander and all ethnicities) were compared. Incidence and overall survival (OS) by histology were evaluated., Results: During the study period, 526 children were newly diagnosed with CNS tumors in Hong Kong (crude incidence rate, 2.47 per 100,000; 95% CI, 2.26 to 2.69). Adjusted incidences were significantly lower in the Hong Kong (2.51; 95% CI, 2.30 to 2.74) than in the SEER (Asian/Pacific Islander: 3.26; 95% CI, 2.97 to 3.57; P < .001; all ethnicities: 4.10 per 100,000; 95% CI, 3.99 to 4.22; P < .001) cohorts. Incidences of germ cell tumors (0.57 v 0.24; P < .001) were significantly higher, but those of glial and neuronal tumors (0.94 v 2.61; P < .001), ependymomas (0.18 v 0.31; P = .005), and choroid plexus tumors (0.08 v 0.16; P = .045) were significantly lower in Hong Kong compared with SEER (all ethnicities) cohorts. Compared with the SEER (Asian/Pacific Islander) cohort, histology-specific incidences were similar except for a lower incidence of glial and neuronal tumors in Hong Kong (0.94 v 1.74; P < .001). Among cohorts, OS differed only for patients with glial and neuronal tumors (5-year OS: Hong Kong, 52.5%; SEER [Asian/Pacific Islander], 73.6%; SEER [all ethnicities], 79.9%; P < .001)., Conclusion: We identified important ethnic differences in the epidemiology of CNS tumors in Chinese children. These results will inform the development of pediatric neuro-oncology services in China and aid further etiologic studies.

With more understanding of the tumor biology, esophageal squamous cell carcinoma (ESCC) and adenocarcinoma are increasingly recognized as different disease entities and are managed with different treatment approaches. Most patients with ESCC need systemic treatment at some point of their disease course, but only until recently, the progress in systemic treatment has been relatively stagnant compared with its adenocarcinoma counterpart. Platinum-based regimens remain the standard of care, while taxanes have been increasingly used upfront and in later lines of treatment. The attempts to personalize treatment for ESCC with various target therapies have been futile. Immune checkpoint inhibitors are now coming into play with promising activity and potentials to combine with different treatment modalities. The current chapter overviews the systemic treatment for ESCC and highlights the recent development.

Esophageal squamous cell carcinoma (ESCC) is an aggressive disease. Many patients have locally advanced disease or already have distant metastasis at presentation. Radiotherapy plays an important role in the treatment of esophageal squamous cell carcinoma. Neoadjuvant chemoradiotherapy improves the survival and surgical outcome compared to surgery alone. Definitive radiotherapy (RT) with or without chemotherapy is used in patients who decline surgery or are medically inoperable. Palliative radiotherapy using external beam radiotherapy or intraluminal brachytherapy is effective for dysphagia and pain control.d.

Cervical esophageal carcinoma (CEC) is rare, accounting for 2-10% of esophageal cancers and is mostly squamous cell carcinoma. Because of the anatomical proximity of CEC to larynx, surgical treatment would involve pharyngo-laryngo-esophagectomy (PLE) with inherent high mortality and morbidity. Laryngeal preservation is an important consideration, and definitive chemoradiotherapy is the recommended treatment. Treatment strategy of CEC can be more akin to treatment for head and neck cancers than to thoracic esophageal cancers. Since the exact location, extent of primary and nodal metastasis varies between patients, radiotherapy treatment needs to be individualized. The optimal radiation dose for CEC is uncertain, but retrospective data suggests that higher radiation dose of at least 60 Gy is associated with better local control and survival. Advanced radiotherapy technique, like intensity modulated radiotherapy, is usually required to achieve high dose to tumor while protecting normal tissues from excessive radiation.

Gastric cancers are highly prevalent in both the East and the West, although they differ in aetiology and prognostic outcome. Management of gastric cancer from screening to definitive treatment varies substantially between Eastern and Western countries and regions, owing to numerous factors, including government incentives to carry out population-wide screening programmes to detect early disease, differences in clinical and biological tumour behaviours and responsiveness to treatment, patient accessibility to effective treatment, etc. This review highlights and contrasts the differences in tumour aetiology and histology, as well as the management approaches between the East and the West, which gives important insights and inspirations on future international multicentre research collaboration to combat this dreadful malignancy., (Copyright © 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Managing head and neck cancers is an excellent example of the importance of teamwork, with head and neck surgeons, clinical oncologists, radiologists, pathologists and other allied health professionals specialised in this disease site working together. The reliable imaging and dedicated pretreatment work-up entailing the comprehensive anatomical description of tumour involvement by the radiologists, the expertise of surgeons in performing en-bloc gross tumour resection, the uneventful speedy postoperative rehabilitation and recovery by the speech therapists and nutritionists, as well as the dedicated treatment planning of clinical oncologists in delivering precise preoperative or postoperative (chemo)radiotherapy to maximise the therapeutic potentials are the pillars of treatment success. A multidisciplinary tumour board involving all of these key players is essential to provide the highest level of recommendation based on evidence-based medicine and to bring patients new hopes and the best chance of cure. This review illustrates the seamless collaborative teamwork within a well-established multidisciplinary tumour board in managing one of the most intractable cancers in the East, taking enlightenment and inspiration from the West., (Copyright © 2019. Published by Elsevier Ltd.)

Magnesium (Mg) has been known to play vital roles in regulating growth and various metabolic processes. In recent years, the association between Mg and tumorigenesis has raised more and more attention. However, the effects of Mg on the progression of head and neck carcinoma (HNC), as well as the mechanism behind it, remain undefined. In this study, the roles of Mg in tumorigenic activities were tested in CAL27 and FaDu cells as well as in a xenograft tumor model in nude mice. We demonstrated that a moderate increase in extracellular Mg contributed to the proliferation, migration, and invasion of 2 HNC cell lines, while the addition of Mg in drinking water promoted the growth of xenograft tumors in mice without altering their serum Mg levels. Moreover, TRPM7, a major Mg transporter, was shown to be essential for the tumorigenic activities of HNC and the Mg-induced promotive effects on HNC cells and was further shown to be associated with the activation of AKT/mTOR (mammalian target of rapamycin) signaling. In a preliminary clinical study, we determined the Mg ion concentrations in the stimulated saliva from 72 patients with nasopharynx carcinoma and 12 healthy individuals. Our data revealed that the salivary Mg levels of subjects with nasopharynx carcinoma were significantly higher than those of the healthy controls. This is correlated with our finding showing TRPM7 to be overexpressed in tumor tissues harvested from 9 patients with HNC. Therefore, we can conclude that salivary Mg level, within a certain range, could act as a risk factor for the progression of HNC, which involves the activation of AKT/mTOR signaling pathways through the TRPM7 channel. The control of salivary Mg level and the intervention of TRPM7 should not be ignored during the study of HNC.

Gastric cancer displays marked molecular heterogeneity with aggressive behavior and treatment resistance. Therefore, good in vitro models that encompass unique subtypes are urgently needed for precision medicine development. Here, we have established a primary gastric cancer organoid (GCO) biobank that comprises normal, dysplastic, cancer, and lymph node metastases (n = 63) from 34 patients, including detailed whole-exome and transcriptome analysis. The cohort encompasses most known molecular subtypes (including EBV, MSI, intestinal/CIN, and diffuse/GS, with CLDN18-ARHGAP6 or CTNND1-ARHGAP26 fusions or RHOA mutations), capturing regional heterogeneity and subclonal architecture, while their morphology, transcriptome, and genomic profiles remain closely similar to in vivo tumors, even after long-term culture. Large-scale drug screening revealed sensitivity to unexpected drugs that were recently approved or in clinical trials, including Napabucasin, Abemaciclib, and the ATR inhibitor VE-822. Overall, this new GCO biobank, with linked genomic data, provides a useful resource for studying both cancer cell biology and precision cancer therapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To evaluate, in a phase 2 study, whether induction docetaxel, cisplatin, and fluorouracil (TPF) followed by weekly docetaxel and cetuximab in concurrence with intensity modulated radiation therapy can improve the treatment outcome for patients with advanced locally recurrent nasopharyngeal carcinoma (rNPC)., Methods and Materials: Thirty-three patients with rNPC (T3-T4, N0-N1, M0) were recruited. Of these, 19 patients (57.6%) had stage rT3 recurrence, and the rest had stage rT4. Eight patients also had rN1 at the time of relapse. Treatment outcomes and safety were evaluated., Results: Among these 33 patients, 1 died after 1 cycle of TPF, 5 patients withdrew from the study during the induction period because of grade ≥3 toxicities; 27 patients completed the whole course of treatment, but 1 died before any assessment could be made. The median follow-up period was 28.5 months. The progression-free survival and overall survival at 3 years for the whole group were 35.7% and 63.8%, respectively. Among the 26 patients who could be assessed after treatment, the complete response rate was 30.8%, and the locoregional control rate at 3 years was 49.2%. Temporal lobe necrosis (TLN) developed in 8 cases. The rates of grade ≥3 hearing loss, soft tissue necrosis, dysphagia, and trismus were 30.8%, 15.4%, 11.5%, and 19.2%, respectively. Overall, 5 patients died owing to acute (1 after cycle 1 TPF and 1 after completion of bio-chemoradiotherapy) or late (2 epistaxis and 1 TLN) treatment-related complications., Conclusions: The proposed salvage treatment regimen for advanced locally recurrent NPC could achieve a better treatment outcome than seen in previous studies. However, poor tolerability of induction TPF and the high rate of TLN limit its applicability outside clinical trials., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To evaluate treatment outcomes, failure patterns and late toxicities in patients with nasopharyngeal carcinoma (NPC) treated by intensity modulated radiotherapy (IMRT) in 6 public hospitals in Hong Kong over a 10-year period from 2001 to 2010., Material and Methods: Eligible patients were identified through the Hong Kong Cancer Registry data base. Clinical information was retrieved and verified by oncologists working in the individual centers. Treatment details, survival outcomes and late toxicities were analyzed., Results: A total of 3328 patients were recruited. The median follow-up time was 80.2 months. The 8-year actuarial overall survival (OS), local failure-free survival (LFFS), regional failure-free survival (RFFS), distant failure free survival (DFFS), progression-free survival (PFS) for the whole group was 68.5%, 85.8%, 91.5%, 81.5% and 62.6% respectively. Male gender, older age, advanced T and N stage were adverse prognostic factors for OS, DFFS and PFS, whereas use of chemotherapy in form of concurrent chemo-irradiation (CRT), neoadjuvant + CRT, or CRT + adjuvant chemotherapy were favorable prognostic factors for OS and PFS. The local control was adversely affected by advanced T stage. N stage remained as the single adverse prognostic factor for regional control. Distant metastasis was the commonest site of failure., Conclusion: IMRT is an effective treatment for NPC with excellent overall loco-regional control. Distant metastasis is the major site of failure. Concurrent chemotherapy with cisplatin has an established role in NPC patients treated by IMRT., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Esophageal and esophagogastric junction adenocarcinoma is a distinct entity from esophageal squamous cell carcinoma with respect to etiology and biology despite sharing the same anatomical location. While most international treatment guidelines recommend a similar management strategy for both esophageal squamous and adenocarcinoma histologies, the evidence for treating adenocarcinoma are indeed more often extrapolated from that of gastric carcinoma. In this chapter, the best evidences for the management of this distinct disease with chemotherapy in both curative and palliative clinical settings are presented.

Adenocarcinomas occur in distal esophagus and often involve esophagogastric junction. Radiotherapy plays a key role in treatment, often in combination with chemotherapy and surgery in multi-modalities management. For resectable esophageal primaries, neoadjuvant chemoradiotherapy plus surgery can downstage disease and improve outcome over surgery alone. For patients with unresectable primaries or medically unfit for surgery, definitive chemoradiotherapy was found to improve survival over radiotherapy alone. For patients who had residual disease or involved margins after primary surgery, adjuvant chemoradiotherapy in postoperative setting was shown to improve local control and survival. Palliative radiotherapy can also be used to relieve local symptoms like dysphagia or bleeding. Careful radiotherapy planning is required to ensure adequate dose to target volumes without overdose to normal organs.

Adenocarcinoma of the esophagus is a deadly disease and median survival of patients with metastatic disease is around 1 year only. There is an unmet need to personalize treatment by identifying molecular targets and respective target therapy in esophageal adenocarcinoma. There has been success in targeting the human epidermal growth factor receptor 2 (HER2) and vasoendothelial growth factor (VEGF) pathway while more failures were encountered in the clinical studies targeting epidermal growth factor (EGFR), mammalian target of rapamycin (mTOR), and mesenchymal-epithelial transition (MET). Studies using immune-checkpoint inhibitors have shown early success, and we await mature data for clinical application. In the chapter, the target therapy and novel treatment strategy will be reviewed. In the future, it is hoped that advances in translational research in targeted therapy against esophageal adenocarcinoma will bring about new progress in clinical practice.

Calcium-binding protein (CAB39) is a key regulator of a group of sterile 20 kinases. Here, we report that CAB39 was frequently up-regulated in hepatocellular carcinoma (HCC), which was significantly associated with tumor metastasis (P = 0.000), poorer disease-free survival rate (P = 0.027), and poor prognosis (P = 0.000). Ectopic expression of CAB39 in immortalized human liver cell line LO2 and HCC cell lines QGY-7703 and BEL-7402 could increase foci formation, colony formation in soft agar, tumor formation in nude mice, and cell motility. Silencing CAB39 expression in two HCC cell lines, Huh7 and MHCC97H, with short hairpin RNA could effectively abolish its oncogenic function. Further study found that CAB39 contributed to extracellular signal-regulated kinase (ERK) pathway activation, and mutations of the key sites of CAB39 markedly decrease the level of phosphorylated ERK. In addition, CAB39 could promote epithelial-mesenchymal transition by up-regulating N-cadherin and Fibronectin and down-regulating E-cadherin and α-E-catenin. As a result, β-catenin nuclear translocation was increased and its downstream target gene, matrix metalloproteinase-9, was up-regulated., Conclusion: Taken together, our findings suggested that CAB39 played very important oncogenic roles in HCC pathogenesis and progression by activating the ERK signaling pathway. Better understanding of CAB39 may lead to its clinical application as a biomarker for a prognosis predictor and a novel therapeutic target. (Hepatology 2017;66:1529-1545)., (© 2017 by the American Association for the Study of Liver Diseases.)