Exosomes in esophageal cancer: Promising nanocarriers in cancer progression, diagnosis, prognosis, and therapy.

Esophageal cancer (EC) is one of the most fatal cancers all over the world. Sensitive detection modalities for early-stage EC and efficient treatment methods are urgently needed for the improvement of the prognosis of EC. Exosomes are small vesicles for intercellular communication, mediating many biological responses including cancer progression, which are not only promising biomarkers for diagnosis and prognosis but also therapeutic tools for EC. This review provides an overview of the relationships between exosomes and EC progression, as well as the application of exosomes in the diagnosis, prognosis, and treatment of EC. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Endoscopic submucosal dissection vs. endoscopic mucosal resection in the treatment of early Barrett's neoplasia: Systematic review and meta-analysis.

OBJECTIVES: Endoscopic resection is the preferred approach to treat early Barrett's neoplasia, reducing the need for surgical interventions. However, the best choice between endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) remains unclear. The study aimed to compare the efficacy and safety of EMR vs. ESD for early Barrett's neoplasia. METHODS: An electronic search was conducted in MEDLINE, Central Cochrane, EMBASE, and LILACS until November 2023. Studies comparing ESD vs. EMR in the treatment of patients with early Barrett's neoplasia were included. This study was performed according to the Preferred Report Items for Systematic Reviews and Meta-Analyses guidelines. The ROBIN-I tool was used to analyze the risk of bias and GRADE to measure the quality of the evidence. RESULTS: A total of 9352 patients from 15 observational studies were included. Patients undergoing ESD had significantly higher rates of en-bloc (odds ratio [OR] 25.96, 95% confidence interval [CI] 13.82, 48.74; I2 = 52%; P < 0.00001) and R0 (OR 5.10, 95% CI 3.29, 7.91; I2 = 73%; P < 0.00001) with a higher risk of adverse events, including bleeding, stricture formation, and perforation. In a subgroup analysis of patients who did not receive radiofrequency ablation, ESD had a lower recurrence rate than EMR (OR 0.22, 95% CI 0.05, 0.94; I2 = 88%; P = 0.04). CONCLUSION: Endoscopic submucosal dissection is more effective than EMR in treating early Barrett's neoplasia at the expense of higher adverse events rates.

Phase III randomized trial comparing neoadjuvant paclitaxel+platinum to 5-fluorouracil+platinum in esophageal/GEJ squamous cell carcinoma.

PURPOSE: Standard neoadjuvant chemotherapy (NACT) for locally advanced esophageal/gastroesophageal junction squamous cancer (LAEGSC), 5-fluorouracil (5FU)+platinum, is toxic and logistically challenging; alternative regimens are needed. PATIENTS AND METHODS: Phase III randomized open-label non-inferiority trial at Tata Memorial Center, India, in resectable LAEGSC. Patients were randomized 1:1 to three cycles of 3-weekly platinum (cisplatin 75 mg/m2 or carboplatin AUC 6) with paclitaxel 175 mg/m2 (day 1) or 5FU 1000 mg/m2 continuous infusion (days 1-4), followed by surgery. RESULTS: Between August 2014 and June 2022, we enrolled 420 patients; 210 to each arm. Significantly more patients on paclitaxel + platinum (194 (92.3%)] received all 3 chemotherapy cycles than on 5FU+platinum (170 [85.9%]), P = .009. 5FU + platinum caused more grade ≥ 3 toxicities (124 [69.7%]) than paclitaxel + platinum (97 [51.9%]), P = .001. Surgery was performed in 131 (62.4%) patients on 5FU + platinum vs 139 (66.2%) on paclitaxel + platinum, P = .415. Paclitaxel + platinum resulted in higher pathologic primary tumor clearance (33 [25.8%]) vs 17 [15%]; P = .04), and pathologic complete responses in 21.9% compared to 12.4% from 5FU + platinum, P = .053. Median OS was 27.5 months (95% CI, 18.6-43.5) from paclitaxel + platinum, which was non-inferior to 27.1 months (95% CI, 18.8-40.7) from 5FU + platinum; HR, 0.89 (95% CI, 0.72-1.09); P = .346. CONCLUSION: Neoadjuvant paclitaxel + platinum chemotherapy is safer, and results in similar R0 resections, higher pathologic tumor clearance and non-inferior survival, compared to 5FU + platinum. Paclitaxel + platinum should replace 5FU + platinum as NACT for resectable LAEGSC. CLINICAL TRIALS REGISTRY INDIA NUMBER: CTRI/2014/04/004516.

FAM83D promotes the progression of 4NQO-induced esophageal carcinoma via inhibiting FBWX7.

The present study aimed to explore the expression and regulatory role of FAM83D in the different developmental stages of esophageal squamous cell carcinoma (ESCC) to determine the effect of FAM83D on the proliferation, migration, and invasion of ESCC cells and to elucidate its underlying molecular mechanism. Immunohistochemistry (IHC) analysis revealed that the expression of FAM83D was obviously elevated in ESCC tissues compared to adjacent normal tissues. Furthermore, the FAM83D levels was positively correlated with tumor size, TNM stage, T stage, and N stage, while it was negatively correlated with FBXW7 expression, Karnofsky Performance Status (KPS) score, and survival rate. Subsequently, ESCC cell lines with low FAM83D expression were constructed using RNA interference technology to investigate the impact of FAM83D on the biological behavior of ESCC cells. Silencing of FAM83D inhibited the proliferation and migration of ESCC cells but promoted apoptosis. Furthermore, a reduction in FAM83D expression may also induce cell cycle arrest at the G0/G1 phase and regulate the expression of proteins related to epithelial-mesenchymal transition (EMT), the cell cycle, and apoptosis. Further research indicated that silencing FAM83D led to the upregulation of FBXW7 expression. These results suggested that FAM83D may exert its effects on ESCC by downregulating FBXW7. Additionally, using a 4NQO solution in the drinking water to establish an ESCC mouse model, IHC analysis revealed that FAM83D expression levels were positively correlated with the pathological grade of esophageal lesions in the mice and negatively correlated with the expression levels of FBXW7 and E-cadherin. The above results demonstrated that FAM83D may facilitate the progression of ESCC by negatively regulating FBXW7 expression and that FAM83D could represent a promising therapeutic target for ESCC.

Predictive value of early postoperative blood lipid metabolism for anastomotic leakage after esophageal cancer surgery.

OBJECTIVE: To explore the clinical value of assessing early postoperative blood lipid metabolism levels in predicting anastomotic leakage (AL) after esophageal cancer (EC) surgery. METHODS: The clinical data of EC patients who underwent surgery at the Northern Jiangsu People's Hospital from May 2021 to May 2023 were retrospectively studied. Totally, 28 patients who developed AL were included in the AL group, while 110 patients who did not develop AL were included in the non-AL group. Outcomes compared between the two groups included clinical baseline data, total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels. Logistic regression analysis was performed to identify independent risk factors for postoperative AL. The predictive value of early postoperative blood lipid metabolism levels for AL was evaluated using Receiver Operating Characteristic (ROC) curves. RESULTS: The AL group exhibited significantly elevated levels of TC and LDL-C but significantly reduced HDL-C levels compared to the non-AL group (all P<0.05). However, there was no significant difference in triglyceride levels between the two groups (P>0.05). Logistic regression analysis revealed that low BMI (P=0.012; OR: 4.409; 95% CI: 1.391-13.976), comorbid hypertension (P=0.011; OR: 5.891; 95% CI: 1.492-23.259), comorbid diabetes (P=0.022; OR: 4.522; 95% CI: 1.238-16.521), low HDL-C (P=0.007; OR: 19.965; 95% CI: 2.293-173.809), and high LDL-C (P=0.012; OR: 4.321; 95% CI: 1.388-13.449) were independent risk factors for developing AL after EC surgery. The combined prediction model using TC, HDL-C, and LDL-C yielded an area under the curve (AUC) of 0.876, with a sensitivity of 79.09%, specificity of 85.71%, and overall accuracy of 80.44%, significantly outperforming individual lipid measurements. CONCLUSION: The combined assessment of TC, HDL-C, and LDL-C can effectively predict the occurrence of AL after EC surgery. For EC patients with relatively low BMI, hypertension, diabetes, relatively low HDL-C, and relatively high LDL-C, prioritizing weight management, hypertension and diabetes control, and lipid management can significantly reduce the risk of AL post-surgery.

Evaluation of the gastric conduit perfusion using indocyanine green in thoracoscopic esophagectomy for esophageal cancer.

Objective: Indocyanine green has been used in the assessment of the gastric conduit perfusion in thoracoscopic esophagectomy to prevent malperfusion-associated anastomotic leak. This study aims to evaluate the initial results of investigating the gastric conduit perfusion with indocyanine green in the surgical treatment of esophageal cancer. Patients and methods: This cross-sectional descriptive study was carried out on 54 esophageal cancer patients undergoing thoracoscopic esophagectomy and gastric conduit reconstruction. The blood flow in the gastric conduit was observed using an infrared camera and indocyanine green after completion of the conduit and after tunneling the conduit through the mediastinum to the neck. Results: The gastric conduit width and length were 5.2 ± 0.3 cm, and 31.5 ± 1.6 cm, respectively. The length of the gastric conduit from the junction between the right and left gastroepiploic to the point where the distal end of the gastric conduit still has a vascular pulse was 11.9 ± 4.3 cm. Seventeen patients (31.5%) had poor blood supply at the distal end of the gastric conduit, with indocyanine green appearance time ⩾ 60 s, in whom anastomotic leaks occurred in five patients (9.3%). The lack of connection between the right and left gastroepiploic vessels was associated with poor blood supply of the distal gastric conduit (p = 0.04). Multivariable logistic regression analysis showed association between the time of indocyanine green appearance at the distal gastric conduit and the risk of anastomotic leak (OR = 1.99, 95% CI = 1.10-3.60, p = 0.02). Conclusion: Investigation of gastric conduit perfusion using indocyanine green in gastric conduit reconstruction detected 31.5% of patients with poor blood supply at the distal end of the conduit, in whom 9.3% had anastomotic leak. The longer indocyanine green appearance time in the distal gastric conduit (segment BC), was associated with the higher rate of the anastomotic leak.

Salvage radiotherapy for locoregional recurrence of esophageal cancer after surgery.

OBJECTIVE: There is no consensus on the optimal treatment for patients with locoregional recurrence of esophageal cancer after surgery. The objective of this study was to investigate the outcomes and prognostic factors associated with salvage radiotherapy in patients with locoregional recurrence of esophageal cancer after surgery. METHODS: We reviewed 80 patients with locoregional recurrence of esophageal cancer after surgery who were treated with radiotherapy. The median dose was 60 Gy, and 29 patients (36%) received elective nodal irradiation. Fifty-three patients (66%) received concurrent chemotherapy (mostly 5-fluorouracil and cisplatin) during radiotherapy. Overall survival, progression-free survival and in-field recurrence rate were assessed. RESULTS: The median follow-up period was 17 months. Two-year overall survival, progression-free survival and in-field recurrence rate were 50.3%, 23.5% and 41.3%, respectively. On multivariate analysis, a maximum diameter of locoregional recurrence lesions <30 mm was associated with higher overall survival (P = 0.044). Disease-free interval between surgery and locoregional recurrence >14 months was associated with higher PFS (P = 0.003). Late grade 3 toxicities occurred in three patients (3.8%). No grade 4 or higher toxicity was observed. CONCLUSIONS: Salvage radiotherapy demonstrated efficacy in achieving in-field control with acceptable toxicity. However, the high rate of out-of-field metastases led to poor progression-free survival and overall survival, particularly in cases involving large lesions and a short disease-free interval. A prospective study is warranted to establish a treatment strategy, particularly considering the combined use of effective anti-cancer drugs.

Right Parasternal Approach for Aortic Valve Replacement After Presternal Gastropexy.

Due to bicuspid aortic valve aortic stenosis, a 78-year-old man with a history of esophagectomy and presternal gastric tube reconstruction required aortic valve replacement (AVR). AVR with a bioprosthetic valve was performed through a right parasternal thoracotomy. Despite the unfavorable conditions for conventional median sternotomy, AVR was successfully performed through an alternate approach. The right parasternal approach was excellent for AVR in patients with presternal gastric tube reconstruction for esophageal cancer (EC).

Pathologic response evaluation of localized or locally advanced esophageal carcinoma to induction chemotherapy followed by preoperative concurrent chemotherapy and hypofractionated radiotherapy: a clinical trial.

Objective: Esophageal cancer is a therapeutic challenge in most healthcare systems. Most patients present with locally advanced disease at diagnosis. Concurrent chemoradiotherapy (CRT) is the standard treatment for locally advanced esophageal carcinoma. Since achieving a complete pathological response in postoperative specimens following neoadjuvant therapy is associated with improved patient survival, this study was designed to evaluate the pathologic response of localized or locally advanced esophageal carcinoma to induction chemotherapy followed by preoperative concurrent chemotherapy and hypofractionated radiotherapy (HFR). Methods: This single-arm clinical trial (IRCT20210623051676N1) evaluated patients with squamous cell carcinoma or adenocarcinoma of the esophagus, stage cT2-T4a N0 M0 or cT1-T4a N+ M0. Patients received 3-5 cycles of weekly induction chemotherapy with the paclitaxel (50 mg/m2) and carboplatin (AUC=2) regimen, followed by weekly concurrent CRT with the same chemotherapy regimen. The radiation dose was 40 Gy, delivered over 16 fractions, 5 days per week (2.5 Gray/fraction). Patients underwent surgery 4-6 weeks after completion of CRT. The surgical specimens were evaluated for pathological response. A p-value of < 0.05 was considered significant in all analyses. Results: Out of 54 patients enrolled in this study, 45 completed the neoadjuvant protocol. Of these 45 patients, 32 underwent surgery and were finally analyzed. The mean age of the patients was 59.9 ± 8.6 years (range, 37-75 years). The location of the tumor was in the mid-thoracic esophagus in most patients (21, 65.6%) and the most common histological type was SCC (29, 90.6%). The median number of induction and concurrent chemotherapy cycles was 5 (4.8 ± 1.3 course, range, 1-10) and 3 (2.6 ± 0.8 course, range, 0-4), respectively. Among 45 patients who completed the neoadjuvant protocol, the most common toxicities were grade 3 neutropenia (15.6%), acute renal failure (4.4%), and odynophagia (37.8%). Nearly two-thirds of the patients experienced complete or near-complete responses (71.9%, 23 patients). Partial response was reported in 6 patients (18.8%) and poor response in 3 patients (9.4%). Conclusion: Preoperative induction chemotherapy followed by HFR with concurrent chemotherapy has low toxicity and side effects, good tolerance, and significant efficacy in the treatment of patients with esophageal cancer. Clinical trial registration: https://irct.behdasht.gov.ir/trial/59930, identifier NCT05745545.

Association between preoperative neutrophil-to-lymphocyte ratio and the survival outcomes of esophageal cancer patients underwent esophagectomy: a systematic review and meta-analysis.

Objectives: The purpose of this study was to assess the association between preoperative neutrophil-to-lymphocyte ratio (NLR) and the survival outcomes of esophageal cancer patients who underwent esophagectomy, the latest and comprehensive systematic review performed. Methods: Related literature retrieved from PubMed, Web of Science, Embase, and Cochrane before January 2024, according to the inclusion criteria. Outcomes measured were overall survival (OS), disease-free survival (DFS), relapse-free survival (RFS), and cancer-specific survival (CSS). Results: Eighteen studies with 6,119 esophageal cancer patients were retained for analysis. Meta-analysis demonstrated that OS (HR: 1.47; 95% CI: 1.29, 1.67; P < 0.00001), DFS (HR: 1.62; 95% CI: 1.29, 2.05; P < 0.0001), and CSS (HR: 1.62; 95% CI: 1.29, 2.05; P < 0.0001) were significantly shorter in the high NLR group compared with the low NLR group. In addition, meta-analysis revealed a similar RFS (HR: 1.47; 95% CI: 0.92, 2.35; P = 0.10) among the two groups. Subgroup analysis of OS and DFS based on mean/median age, NLR cutoff, and region found that all subgroups remained significant difference between two groups. Conclusion: Among esophageal cancer patients who underwent esophagectomy, preoperative NLR can be used as prognostic factor independently. High-preoperative NLR is associated with poor prognosis. More large-scale, multicenter prospective clinical studies are needed to further validate the relationship between preoperative NLR and prognosis of esophageal cancer.

The spatiotemporal associations between esophageal and gastric cancers provide evidence for its joint endoscopic screening in China: a population-based study.

BACKGROUND: The spatiotemporal epidemiological evidence supporting joint endoscopic screening for esophageal cancer (EC) and gastric cancer (GC) remains limited. This study aims to identify combined high-risk regions for EC and GC and determine optimal areas for joint and separate endoscopic screening. METHODS: We analyzed the association of incidence trends between EC and GC in cancer registry areas across China from 2006 to 2016 using spatiotemporal statistical methods. Based on these analyses, we divided different combined risk regions for EC and GC to implement joint endoscopic screening. RESULTS: From 2006 to 2016, national incidence trends for both EC and GC showed a decline, with an average annual percentage change of -3.15 (95% confidence interval [CI]: -5.33 to -0.92) for EC and -3.78 (95% CI: -4.98 to -2.56) for GC. A grey comprehensive correlation analysis revealed a strong temporal association between the incidence trends of EC and GC, with correlations of 79.00% (95% CI: 77.85 to 80.14) in males and 77.62% (95% CI: 76.50 to 78.73) in females. Geographic patterns of EC and GC varied, demonstrating both homogeneity and heterogeneity across different regions. The cancer registry areas were classified into seven distinct combined risk regions, with 33 areas identified as high-risk for both EC and GC, highlighting these regions as priorities for joint endoscopic screening. CONCLUSION: This study demonstrates a significant spatiotemporal association between EC and GC. The identified combined risk regions provide a valuable basis for optimizing joint endoscopic screening strategies for these cancers.

Treatment strategies for elderly patients with locally advanced esophageal cancer: a systematic review and meta-analysis.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) followed by surgery remains a standard of care for resectable esophageal cancer (EC), and definitive chemoradiotherapy (dCRT) is an alternative for unresectable diseases. However, it is controversial for the use of the two aggressive regimens in elderly patients. METHODS: We systematically searched multiple databases for studies comparing overall survival (OS) and/or progression-free survival (PFS) between dCRT and surgery (nCRT + surgery or surgery alone) or between dCRT and radiotherapy (RT) alone in elderly patients (age ≥ 65 years) until March 28, 2024. Statistical analysis was performed using random-effects model. RESULTS: Fourty-five studies with 33,729 patients were included. dCRT significantly prolonged OS (hazard ratio [HR] = 0.64, 95% confidence interval [CI]: 0.58-0.70) and PFS (HR = 0.67, 95% CI: 0.60-0.76) compared to RT alone for unresectable EC, and resulted in a worse OS compared to surgery for resectable cases (HR = 1.34, 95% CI: 1.23-1.45). Similar results of OS were also observed when the multivariate-adjusted HRs were used as the measure of effect (dCRT vs. RT alone: HR = 0.65, 95% CI: 0.58-0.73; dCRT vs. surgery: HR = 1.49, 95% CI: 1.28-1.74). Subgroup analyses according to age group (≥ 70, ≥ 75, or ≥ 80 years), study design, study region, histological type, radiation field, chemotherapy regimen revealed comparable results. CONCLUSIONS: nCRT + surgery is likely a preferred strategy for elderly patients with good physiological conditions; and dCRT is a better alternative for unresectable cases. Advanced age alone does not appear to be a key predictor for the tolerability of the two aggressive treatments.

Clinicopathologic features and surgical treatment prognosis of esophageal carcinosarcoma.

Background: Carcinosarcoma is a rare esophageal tumor, accounting for approximately 0.27-2.8% of malignant esophageal tumors. This study aims to investigate the clinical pathological characteristics, surgical treatment outcomes, and analysis of prognostic factors in esophageal carcinosarcoma (ECS). Methods: Clinical data from sixteen patients diagnosed with esophageal sarcomatoid carcinoma who underwent surgical interventions were retrospectively analyzed. Clinical and pathological features, treatment modalities, and postoperative outcomes were systematically examined. Results: Out of the 1261 patients who underwent surgical treatment for esophageal cancer, 16 cases were pathologically confirmed as carcinosarcoma. Among them, two underwent neoadjuvant chemotherapy, six received postoperative chemotherapy. Carcinosarcomas predominantly occurred in the middle (43.75%) and lower (50%) segments of the esophagus. Among the 16 cases, 10 presented as polypoid, 4 as ulcerative, and 2 as medullary types. Microscopic examination revealed coexistence and transitional transitions between sarcomatous and carcinoma components. Pathological staging showed 5 cases in stage T1, 2 in stage T2, and 9 in stage T3, with lymph node metastasis observed in 8 cases (50%). TNM staging revealed 2 cases in stage I, 9 in stage II, and 5 in stage III. The overall 1, 3, and 5-year survival rates were 86.67%, 62.5%, and 57.14%, respectively. Univariate analysis indicated that pathological N staging influenced survival rates, while multivariate analysis demonstrated that pathological N staging was an independent prognostic factor. Conclusions: Carcinosarcoma is a rare esophageal tumor, accounting for approximately 0.27-2.8% of malignant esophageal tumors. Histologically, the biphasic pattern is a crucial diagnostic feature, although the carcinomatous component may not always be evident, especially in limited biopsies, leading to potential misclassification as pure sarcoma or squamous cell carcinoma. Despite its large volume and cellular atypia, carcinosarcoma carries a favorable prognosis. Complete surgical resection of the tumor and regional lymph node dissection is the preferred treatment approach for esophageal carcinosarcoma.

Discovery of TK-642 as a highly potent, selective, orally bioavailable pyrazolopyrazine-based allosteric SHP2 inhibitor.

Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) is a promising therapeutic target for cancer therapy. In this work, we presented the structure-guided design of 5,6-fused bicyclic allosteric SHP2 inhibitors, leading to the identification of pyrazolopyrazine-based TK-642 as a highly potent, selective, orally bioavailable allosteric SHP2 inhibitor (SHP2WT IC50 = 2.7 nmol/L) with favorable pharmacokinetic profiles (F = 42.5%; t 1/2 = 2.47 h). Both dual inhibition biochemical assay and docking analysis indicated that TK-642 likely bound to the "tunnel" allosteric site of SHP2. TK-642 could effectively suppress cell proliferation (KYSE-520 cells IC50 = 5.73 µmol/L) and induce apoptosis in esophageal cancer cells by targeting the SHP2-mediated AKT and ERK signaling pathways. Additionally, oral administration of TK-642 also demonstrated effective anti-tumor effects in the KYSE-520 xenograft mouse model, with a T/C value of 83.69%. Collectively, TK-642 may warrant further investigation as a promising lead compound for the treatment of esophageal cancer.

Clinical Translation of a Deep Learning Model of Radiation-Induced Lymphopenia for Esophageal Cancer.

Purpose: Radiation-induced lymphopenia is a common immune toxicity that adversely impacts treatment outcomes. We report here our approach to translate a deep-learning (DL) model developed to predict severe lymphopenia risk among esophageal cancer into a strategy for incorporating the immune system as an organ-at-risk (iOAR) to mitigate the risk. Materials and Methods: We conducted "virtual clinical trials" utilizing retrospective data for 10 intensity-modulated radiation therapy (IMRT) and 10 passively-scattered proton therapy (PSPT) esophageal cancer patients. For each patient, additional treatment plans of the modality other than the original were created employing standard-of-care (SOC) dose constraints. Predicted values of absolute lymphocyte count (ALC) nadir for all plans were estimated using a previously-developed DL model. The model also yielded the relative magnitudes of contributions of iOARs dosimetric factors to ALC nadir, which were used to compute iOARs dose-volume constraints, which were incorporated into optimization criteria to produce "IMRT-enhanced" and "intensity-modulated proton therapy (IMPT)-enhanced" plans. Results: Model-predicted ALC nadir for the original IMRT (IMRT-SOC) and PSPT plans agreed well with actual values. IMPT-SOC showed greater immune sparing vs IMRT and PSPT. The average mean body doses were 13.10 Gy vs 7.62 Gy for IMRT-SOC vs IMPT-SOC for patients treated with IMRT-SOC; and 8.08 Gy vs 6.68 Gy for PSPT vs IMPT-SOC for patients treated with PSPT. For IMRT patients, the average predicted ALC nadir of IMRT-SOC, IMRT-enhanced, IMPT-SOC, and IMPT-enhanced was 281, 327, 351, and 392 cells/µL, respectively. For PSPT patients, the average predicted ALC nadir of PSPT, IMPT-SOC, and IMPT-enhanced was 258, 316, and 350 cells/µL, respectively. Enhanced plans achieved higher predicted ALC nadir, with an average improvement of 40.8 cells/µL (20.6%). Conclusion: The proposed DL model-guided strategy to incorporate the immune system as iOAR in IMRT and IMPT optimization has the potential for radiation-induced lymphopenia mitigation. A prospective clinical trial is planned.

Textbook outcome contributes to long-term prognosis in elderly patients with esophageal squamous cell carcinoma.

Purpose: Textbook outcome (TO) is a composite quality measurement of outcomes for evaluating surgical procedures. We investigated whether TO can be used to predict outcomes after curative resection for esophageal squamous cell carcinoma (ESCC) in elderly patients. Methods: We retrospectively analyzed 105 patients who underwent curative esophagectomy for ESCC from 2005 to 2020. In accordance with previous reports, TO consisted of 10 parameters. The patients were divided into two groups: those who achieved TO (TO) and those who failed to achieve TO (non-TO). We evaluated the association between TO and long-term survival. Results: TO was achieved in 28 (26%) patients. The patients in the TO group were significantly older (p = 0.02). The parameter with the lowest achievement rate was "No hospital stay ≥21 days". The patients in non-TO group had significantly shorter overall survival than those in TO group (p = 0.03). Multivariable Cox regression analyses of overall survival revealed that lymph node metastasis (hazard ratio [HR], 3.42; 95% confidence interval [CI], 1.73-6.78; p < 0.0002) and non-TO (HR, 2.37; 95% CI, 1.05-5.65; p = 0.03) were significantly associated with poor overall survival. Conclusion: TO can be used to predict outcomes after curative esophagectomy in elderly patients with ESCC.

Prognostic impact of dysphagia scores in patients with advanced resectable esophageal cancer who underwent radical esophagectomy after preoperative treatment.

BACKGROUND: Dysphagia caused by tumor strictures is a major symptom in patients with advanced esophageal cancer. However, the prognostic impact of dysphagia in resectable cases is insufficiently investigated. This study investigated the prognostic value of dysphagia scores in resectable advanced esophageal cancer who underwent radical esophagectomy after preoperative treatment. METHODS: This retrospective study enrolled 302 consecutive patients with advanced resectable esophageal cancer who received preoperative treatment. The preoperative dysphagia score was used to assess the relationship between tumor stricture and clinical outcomes. RESULTS: Almost half of the patients had dysphagia scores of 2-4 (n=152, 50.3%). A lower body mass index (BMI), circumferential tumors, and non-curative resection were significantly more as dysphagia scores worsened. Patients with dysphagia had significantly more advanced ypT stage and worse histopathological response than those without dysphagia. The 5-year disease-free survival rates for dysphagia scores 0-1, 2-3, and 4 were 52.9%, 35.3%, and 26.7% and for overall survival were 60.7%, 40.4%, and 26.7%, respectively. Multivariate analysis identified dysphagia score as an independent factor of overall survival, similar to surgical curability and ypN stage. The postoperative recurrence rate was significantly higher among patients with dysphagia scores of 2-3 (56%) and those of 4 (67%), compared to those with 0-1 (36%) (P<0.001 and 0.037, respectively). Furthermore, distant recurrence in dysphagia scores of 2-3 and 4 was higher than in 0-1 (26%, 46%, and 42%, respectively). CONCLUSION: Dysphagia score before initial treatment is associated with postoperative survival in patients with resectable advanced esophageal cancer.

Perioperative and mid-term outcomes of robotic-assisted versus video-assisted minimally invasive esophagectomy for esophageal cancer: a retrospective propensity-matched analysis of 842 patients.

Aim: Comparing the safety, effectiveness, and mid-term survival rates of robot-assisted minimally invasive esophagectomy (RAMIE) and video-assisted minimally invasive esophagectomy (VAMIE). Methods: A total of 842 patients undergoing minimally invasive esophagectomy were analyzed, including 694 patients in VAMIE group and 148 in RAMIE group. PSM analysis was applied to generate matched pairs for further comparison. Operative outcomes, postoperative complications and Mid-term outcomes were compared between all patients in matched groups. Results: After 1:4 PSM, 148 patients in the RAMIE and 592 patients in the VAMIE. Compared to VAMIE, RAMIE exhibited earlier removal of chest and neck drainage tubes, shorter postoperative hospital stays, and a higher number of lymph node dissections. However, the surgical duration of RAMIE was longer than that of VAMIE. Postoperative complications were no statistically significant between the RAMIE and VAMIE groups. There was no statistically significant difference in the 3-year OS and DFS between the two groups. Conclusion: Compared to VAMIE, RAMIE emerges as a viable and safe surgical approach and suggests RAMIE as a potential alternative to minimally invasive esophagectomy.

Impaired TGF-ß signaling via AHNAK family mutations elicits an esophageal cancer subtype with sensitivities to genotoxic therapy and immunotherapy.

BACKGROUND: Genome instability (GI) is a hallmark of esophageal squamous cell carcinoma (ESCC) while factors affecting GI remain unclear. METHODS: Here, we aimed to characterize genomic events representing specific mechanisms of GI based on 201 ESCC samples and validated our findings at the patient, single-cell and cancer cell-line levels, including a newly generated multi-omics dataset of the trial NCT04006041. RESULTS: A two-gene (AHNAK and AHNAK2) mutation signature was identified to define the "AHNAK1/2-mutant" cancer subtype. Single-cell-assisted multi-omics analysis showed that this subtype had a higher neoantigen load, active antigen presentation, and proficient CD8 + T cell infiltrations, which were validated at pan-cancer levels. Mechanistically, AHNAK1/2-mutant ESCC was characterized by impaired response of TGF-ß and the inefficient alternative end-join repair (Alt-EJ) that might promote GI. Knockdown of AHNAK in ESCC cell lines resulted in more Alt-EJ events and increased sensitivities to cisplatin. Furthermore, this two-gene signature accurately predicted better responses to DNA-damaging therapy in various clinical settings (HR ≈ 0.25). The two-gene signature predicted higher pCR rates in ESCCs receiving neoadjuvant immunotherapy-involved treatment. Finally, a molecular classification scheme was built and outperformed established molecular typing models in the prognosis stratification of ESCC patients. CONCLUSION: Our study extended our understanding of the AHNAK family in promoting GI and selecting treatment responders of ESCC.