RESUMO
Recent sequencing analyses have shed light on heterogeneous patterns of genomic aberrations in human gastric cancers (GCs). To explore how individual genetic events translate into cancer phenotypes, we established a biological library consisting of genetically engineered gastric organoids carrying various GC mutations and 37 patient-derived organoid lines, including rare genomically stable GCs. Phenotype analyses of GC organoids revealed divergent genetic and epigenetic routes to gain Wnt and R-spondin niche independency. An unbiased phenotype-based genetic screening identified a significant association between CDH1/TP53 compound mutations and the R-spondin independency that was functionally validated by CRISPR-based knockout. Xenografting of GC organoids further established the feasibility of Wnt-targeting therapy for Wnt-dependent GCs. Our results collectively demonstrate that multifaceted genetic abnormalities render human GCs independent of the stem cell niche and highlight the validity of the genotype-phenotype screening strategy in gaining deeper understanding of human cancers.
Assuntos
Adenocarcinoma/patologia , Organoides/patologia , Neoplasias Gástricas/patologia , Estômago/patologia , Trombospondinas/metabolismo , Proteínas Wnt/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Animais , Antígenos CD/genética , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Caderinas/genética , Carcinogênese , Proliferação de Células , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mutação , Organoides/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Trombospondinas/genética , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genética , Proteínas Wnt/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Neoadjuvant therapy is the standard treatment for patients with locally advanced oesophageal squamous cell carcinoma (OSCC). However, the prognosis remains poor and more intensive neoadjuvant treatment might be needed to improve patient outcomes. We therefore aimed to compare the efficacy and safety of neoadjuvant doublet chemotherapy, triplet chemotherapy, and doublet chemotherapy plus radiotherapy in patients with previously untreated locally advanced OSCC. METHODS: In this randomised, open-label, phase 3 trial, patients aged 20-75 years with previously untreated locally advanced OSCC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were recruited from 44 centres across Japan. Patients were randomly assigned (1:1:1) centrally via a web-based system to receive neoadjuvant doublet chemotherapy (two courses of fluorouracil [800 mg/m2 per day intravenously on days 1-5] and cisplatin [80 mg/m2 per day on day 1] separated by an interval of 3 weeks [NeoCF]), triplet chemotherapy (three courses of fluorouracil [750 mg/m2 per day on days 1-5], cisplatin [70 mg/m2 per day on day 1], and docetaxel [70 mg/m2 per day on day 1] repeated every 3 weeks [NeoCF+D]), or doublet chemotherapy (two courses of fluorouracil [1000 mg/m2 per day on days 1-4] and cisplatin [75 mg/m2 per day on day 1] separated by an interval of 4 weeks) plus 41·4 Gy radiotherapy [NeoCF+RT]) followed by oesophagectomy with regional lymph node dissection. Randomisation was stratified by T stage and institution. Participants, investigators, and those assessing outcomes were not masked to group assignment. The primary endpoint was overall survival, analysed by intention to treat. Analysis of safety included all patients who received at least one course of chemotherapy, and analysis of surgical complications included those who also underwent surgery. This study is registered with the Japan Registry of Clinical Trials, jRCTs031180202, and the trial is complete. FINDINGS: A total of 601 patients (529 male individuals and 72 female individuals) were randomly assigned between Dec 5, 2012, and July 20, 2018, with 199 patients in the NeoCF group, 202 patients in the NeoCF+D group, and 200 patients in the NeoCF+RT group. Compared with the NeoCF group, during a median follow-up period of 50·7 months (IQR 23·8-70·7), the 3-year overall survival rate was significantly higher in the NeoCF+D group (72·1% [95% CI 65·4-77·8] vs 62·6% [55·5-68·9]; hazard ratio [HR] 0·68, 95% CI 0·50-0·92; p=0·006) but not in the NeoCF+RT group (68·3% [61·3-74·3]; HR 0·84, 0·63-1·12; p=0·12). Grade 3 or higher febrile neutropenia occurred in two (1%) of 193 patients in the NeoCF group, 32 (16%) of 196 patients in the NeoCF+D group, and nine (5%) of 191 patients in the NeoCF+RT group. Treatment-related adverse events leading to termination of neoadjuvant therapy were more common in the NeoCF+D group (18 [9%] of 202 participants) than in the NeoCF+RT group (12 [6%] of 200) and NeoCF group (eight [4%] of 199). There were three (2%) treatment-related deaths during neoadjuvant therapy in the NeoCF group, four (2%) deaths in the NeoCF+D group, and two (1%) deaths in the NeoCF+RT group. Grade 2 or higher postoperative pneumonia, anastomotic leak, and recurrent laryngeal nerve paralysis were reported in 19 (10%), 19 (10%), and 28 (15%) of 185 patients, respectively, in the NeoCF group; 18 (10%), 16 (9%), and 19 (10%) of 183 patients, respectively, in the NeoCF+D group; and 23 (13%), 23 (13%), and 17 (10%) of 178 patients, respectively, in the NeoCF+RT group. The in-hospital deaths following surgery included three deaths in the NeoCF group, two deaths in the NeoCF+D group, and one in the NeoCF+RT group. INTERPRETATION: Neoadjuvant triplet chemotherapy followed by oesophagectomy resulted in a statistically significant overall survival benefit compared with doublet chemotherapy and might be the new standard of care for locally advanced OSCC who are in good condition in Japan. Neoadjuvant doublet chemotherapy plus radiotherapy did not show significant improvement of survival compared with doublet chemotherapy. FUNDING: Japan Agency for Medical Research and Development and National Cancer Center Research and Development Fund.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Cisplatino , Docetaxel , Neoplasias Esofágicas , Fluoruracila , Terapia Neoadjuvante , Humanos , Pessoa de Meia-Idade , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/mortalidade , Masculino , Feminino , Terapia Neoadjuvante/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Idoso , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Docetaxel/administração & dosagem , Docetaxel/uso terapêutico , Adulto , Carcinoma de Células Escamosas do Esôfago/terapia , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/mortalidade , Quimiorradioterapia/métodos , EsofagectomiaRESUMO
OBJECTIVE: To assess the effect of antimicrobial prophylaxis with ampicillin-sulbactam (ABPC/SBT) compared with cefazolin (CEZ) on the short-term outcomes after esophagectomy. BACKGROUND: CEZ is widely used for antimicrobial prophylaxis in esophagectomy without procedure-specific evidence, whereas ABPC/SBT is preferred in some hospitals to target both aerobic and anaerobic oral bacteria. METHODS: Data of patients who underwent esophagectomy for cancer between July 2010 and March 2019 were extracted from a nationwide Japanese inpatient database. Overlap propensity score weighting was conducted to compare the short-term outcomes [including surgical site infection (SSI), anastomotic leakage, and respiratory failure] between antimicrobial prophylaxis with CEZ and ABPC/SBT after adjusting for potential confounders. Sensitivity analyses were also performed using propensity score matching and instrumental variable analyses. RESULTS: Among 17,772 eligible patients, 16,077 (90.5%) and 1695 (9.5%) patients were administered CEZ and ABPC/SBT, respectively. SSI, anastomotic leakage, and respiratory failure occurred in 2971 (16.7%), 2604 (14.7%), and 2754 patients (15.5%), respectively. After overlap weighting, ABPC/SBT was significantly associated with a reduction in SSI [odds ratio 0.51 (95% CI: 0.43-0.60)], anastomotic leakage [0.51 (0.43-0.61)], and respiratory failure [0.66 (0.57-0.77)]. ABPC/SBT was also associated with reduced respiratory complications, postoperative length of stay, and total hospitalization costs. The proportion of Clostridioides difficile colitis and noninfectious complications did not differ between the groups. Propensity score matching and instrumental variable analyses demonstrated equivalent results. CONCLUSIONS: The administration of ABPC/SBT as antimicrobial prophylaxis for esophagectomy was associated with better short-term postoperative outcomes compared with CEZ.
Assuntos
Anti-Infecciosos , Insuficiência Respiratória , Humanos , Cefazolina/uso terapêutico , Japão , Pacientes Internados , Fístula Anastomótica , Esofagectomia , Ampicilina/uso terapêutico , Sulbactam/uso terapêutico , Infecção da Ferida Cirúrgica/epidemiologia , Infecção da Ferida Cirúrgica/prevenção & controle , Infecção da Ferida Cirúrgica/tratamento farmacológicoRESUMO
BACKGROUND: Overall survival is considered as one of the most important endpoints of treatment efficacy but often requires long follow-up. This study aimed to determine the validity of recurrence-free survival as a surrogate endpoint for overall survival in patients with surgically resectable advanced oesophageal squamous cell carcinoma (OSCC). METHODS: Patients with OSCC who received neoadjuvant cisplatin and 5-fluorouracil, or docetaxel, cisplatin and 5-fluorouracil, at 58 Japanese oesophageal centres certified by the Japan Esophageal Society were reviewed retrospectively. The correlation between recurrence-free and overall survival was assessed using Kendall's τ. RESULTS: The study included 3154 patients. The 5-year overall and recurrence-free survival rates were 56.6 and 47.7% respectively. The primary analysis revealed a strong correlation between recurrence-free and overall survival (Kendall's τ 0.797, 95% c.i. 0.782 to 0.812) at the individual level. Subgroup analysis showed a positive relationship between a more favourable pathological response to neoadjuvant chemotherapy and a higher τ value. In the meta-regression model, the adjusted R2 value at the institutional level was 100 (95% c.i. 40.2 to 100)%. The surrogate threshold effect was 0.703. CONCLUSION: There was a strong correlation between recurrence-free and overall survival in patients with surgically resectable OSCC who underwent neoadjuvant chemotherapy, and this was more pronounced in patients with a better response to neoadjuvant chemotherapy.
Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/cirurgia , Cisplatino/uso terapêutico , Terapia Neoadjuvante , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/cirurgia , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica , Resultado do Tratamento , Biomarcadores , Fluoruracila/uso terapêuticoRESUMO
BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) for superficial esophageal cancer is a multistep treatment involving several endoscopic processes. Although analyzing each phase separately is worthwhile, it is not realistic in practice owing to the need for considerable manpower. To solve this problem, we aimed to establish a state-of-the-art artificial intelligence (AI)-based system, specifically, an automated phase-recognition system that can automatically identify each endoscopic phase based on video images. METHODS: Ninety-four videos of ESD procedures for superficial esophageal cancer were evaluated in this single-center study. A deep neural network-based phase-recognition system was developed in an automated manner to recognize each of the endoscopic phases. The system was trained with the use of videos that were annotated and verified by 2 GI endoscopists. RESULTS: The overall accuracy of the AI model for automated phase recognition was 90%, and the average precision, recall, and F value rates were 91%, 90%, and 90%, respectively. Two representative ESD videos predicted by the model indicated the usability of AI in clinical practice. CONCLUSIONS: We demonstrated that an AI-based automated phase-recognition system for esophageal ESD can be established with high accuracy. To the best of our knowledge, this is the first report on automated recognition of ESD treatment phases. Because this system enabled a detailed analysis of phases, collecting large volumes of data in the future may help to identify quality indicators for treatment techniques and uncover unmet medical needs that necessitate the creation of new treatment methods and devices.
RESUMO
Esophageal cancer is common worldwide, including in Japan, and its major histological subtype is squamous cell carcinoma. However, there are some rare esophageal cancers, including neuroendocrine neoplasm, gastrointestinal stromal tumor, carcinosarcoma and malignant melanoma. The biological and clinical features of these cancers differ from those of esophageal squamous cell carcinoma. Therefore, different treatment strategies are needed for these cancers but are based on limited evidence. Neuroendocrine neoplasm is mainly divided into neuroendocrine tumor and neuroendocrine carcinoma by differentiation and the Ki-67 proliferation index or mitotic index. Epidemiologically, the majority of esophageal neuroendocrine neoplasms are neuroendocrine carcinoma. The treatment of neuroendocrine carcinoma is similar to that of small cell lung cancer, which has similar morphological and biological features. Gastrointestinal stromal tumor is known to be associated with alterations in the c-KIT and platelet-derived growth factor receptor genes and, if resectable, is treated in accordance with the modified Fletcher classification. Carcinosarcoma is generally resistant to both chemotherapy and radiotherapy and requires multimodal treatments such as surgery plus chemotherapy to achieve cure. Primary malignant melanoma is resistant to cytotoxic chemotherapy, but immune checkpoint inhibitors have recently demonstrated efficacy for malignant melanoma of the esophagus. This review focuses on the current status and future perspectives for rare cancer of the esophagus.
Assuntos
Carcinoma Neuroendócrino , Carcinossarcoma , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Tumores do Estroma Gastrointestinal , Melanoma , Humanos , Neoplasias Esofágicas/patologia , Carcinossarcoma/patologiaRESUMO
BACKGROUND: Minimal data was reported regarding the characteristics, risks of lymph node metastasis, and prognostic factors in esophageal cancer patients who achieved remarkable response in the primary lesion to neoadjuvant treatment (NAT). METHODS: This study evaluated the nationwide data of esophageal squamous cell carcinoma (ESCC) patients who underwent surgery following NAT in Japan. Of 4484 patients, 300 (6.7%) had ypT0 following NAT and curative esophagectomy. Factors associated with lymph node metastasis and prognosis were analyzed. RESULTS: Neoadjuvant chemotherapy (NAC) and neoadjuvant chemoradiotherapy (NACRT) were administered in 260 (86.2%) and 40 (13.8%) patients, respectively. Pathologically, 72 (24.0%) had lymph node metastasis (residual nodal disease; RND), and pretherapeutic lymph node metastasis was the independent risk factor for RND (odd ratio [OR]: 3.21; 95% confidence interval [CI]: 1.44-8.20; P = 0.008). The 5-year overall and relapse-free survivals were significantly longer in patients with pathological complete response (pCR) than in those with RND (both P < 0.001). Pretherapeutic cT3 or T4a tumors (hazard ratio [HR]: 1.71; 95% CI: 1.02-2.88; P = 0.043), RND (HR: 3.30; 95% CI: 1.98-5.50; P < 0.001), and operative blood loss (Liter, HR: 1.53; 95% CI: 1.07-2.19; P = 0.021) were independent risk factors affecting relapse-free survival in multivariable analysis. CONCLUSIONS: Of patients with ypT0 after NAT, 24.0% had RND, and pretherapeutic lymph node metastasis was the risk factor. In addition, pretherapeutic cT3, or T4a tumors, RND, and operative blood loss were the poor prognosticators in patients with ypT0 after NAT.
Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/patologia , Neoplasias Esofágicas/patologia , Japão , Estudos de Coortes , Carcinoma de Células Escamosas/patologia , Terapia Neoadjuvante , Metástase Linfática , Perda Sanguínea Cirúrgica , Estadiamento de Neoplasias , Recidiva Local de Neoplasia/patologia , Resposta Patológica CompletaRESUMO
INTRODUCTION: There remains a lack of evidence regarding the optimal abdominal approach, including laparoscopy, hand-assisted, and open laparotomy for minimally invasive thoracoscopic esophagectomy. We aimed to compare the incidence of postoperative complications, particularly pulmonary complications, between laparoscopy and open laparotomy for minimally invasive thoracoscopic esophagectomy using nationwide Japanese databases. METHODS: Data from patients in the National Clinical Database (NCD) who underwent thoracoscopic esophagectomy for esophageal cancer were analyzed. The incidence of pulmonary complications was compared between abdominal laparoscopy and laparotomy after matching the propensity scores (PS) from preoperative factors to account for confounding bias. Laparoscopic-assisted surgery (LAS) was also compared to hand-assisted laparoscopic surgery (HALS). RESULTS: Of the 24,790 patients who underwent esophagectomy between 2018 and 2021, data from 12,633 underwent thoracoscopic procedure. The proportion of patients who experienced pulmonary complications did not significantly differ between the laparoscopy group and the laparotomy group after matching (664/3195 patients, 20.8% versus 702/3195 patients, 22.0%; P = 0.25). No difference in the incidence of pulmonary complications was observed among patients treated using the laparoscopic approach (508/2439 patients, 20.8% in the LAS group versus 498/2439 patients, 20.4% in the HALS group; P = 0.72). CONCLUSIONS: We observed no significant difference in the incidence of postoperative pulmonary complications between laparoscopy and laparotomy for thoracoscopic esophagectomy. Short-term outcomes were similar between the laparoscopic-assisted approach and the hand-assisted approach. This study provides valuable insights into the optimal abdominal approach for thoracoscopic esophagectomy using data from a nationwide database that reflect real-world clinical practice.
Assuntos
Neoplasias Esofágicas , Laparoscopia , Laparotomia , Humanos , Neoplasias Esofágicas/cirurgia , Esofagectomia , Incidência , Japão , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Laparotomia/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Toracoscopia/métodosRESUMO
BACKGROUND: Multiple development of squamous cell carcinoma (SCC) in the upper aerodigestive tract has been explained by the 'field cancerization phenomenon' associated with alcohol drinking. Squamous dysplastic lesion is clinically visualised as a Lugol-voiding lesion (LVL) by chromoendoscopy. Whether cessation or reduction of alcohol drinking improves multiple LVL and reduces the risk of field cancerization has not been elucidated. METHODS: We analysed 330 patients with newly diagnosed superficial esophageal SCC (ESCC) enrolled in the cohort study. The grade of LVL was assessed in all patients every 6 months. We instructed the patients to stop smoking and drinking and recorded their drinking and smoking status every 6 months. RESULTS: Among 330 patients, we excluded 98 with no LVL or no drinking habit. Of the remaining 232 patients, 158 continuously ceased or reduced their drinking habit. Patients who ceased or reduced their drinking habit significantly showed improvement in the grade of LVL. Multivariate analysis showed that continuous cessation or reduction of drinking habit improved the grade of LVL (hazard ratio [HR] = 8.5, 95% confidence interval [CI] 1.7-153.8, p = 0.0053). Higher grade of LVL carried a high risk of multiple ESCC and head and neck SCC (HNSCC) (HR = 3.7, 95% CI 2.2-6.4, p < 0.0001). Improvement in LVL significantly decreased the risk of multiple ESCC and HNSCC (HR = 0.2, 95% CI 0.04-0.7, p = 0.009). CONCLUSIONS: This is the first report indicating that field cancerization was reversible and cessation or reduction of drinking alcohol could prevent multiple squamous dysplastic lesion and multiple ESCC and HNSCC development. CLINICAL TRIALS REGISTRY NUMBER: UMIN000001676.
Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Neoplasias de Cabeça e Pescoço , Humanos , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço , Estudos de Coortes , Fatores de Risco , Carcinoma de Células Escamosas/patologia , EsofagoscopiaRESUMO
In Japan, standard of care of the patients with resectable esophageal cancer is neoadjuvant chemotherapy (NAC) followed by esophagectomy. Patients unfitted for surgery or with unresectable locally advanced esophageal cancer are generally indicated with definitive chemoradiotherapy (CRT). Local disease control is undoubtful important for the management of patients with esophageal cancer, therefore endoscopic evaluation of local efficacy after non-surgical treatments must be essential. The significant shrink of primary site after NAC has been reported as a good indicator of pathological good response as well as favorable survival outcome after esophagectomy. And patients who could achieve remarkable shrink to T1 level after CRT had favorable outcomes with salvage surgery and could be good candidates for salvage endoscopic treatments. Based on these data, "Japanese Classification of Esophageal Cancer, 12th edition" defined the new endoscopic criteria "remarkable response (RR)", that means significant volume reduction after treatment, with the subjective endoscopic evaluation are proposed. In addition, the finding of local recurrence (LR) at primary site after achieving a CR was also proposed in the latest edition of Japanese Classification of Esophageal Cancer. The findings of LR are also important for detecting candidates for salvage endoscopic treatments at an early timing during surveillance after CRT. The endoscopic evaluation would encourage us to make concrete decisions for further treatment indications, therefore physicians treating patients with esophageal cancer should be well-acquainted with each finding.
Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Humanos , Neoplasias Esofágicas/cirurgia , Neoplasias Esofágicas/tratamento farmacológico , Endoscopia , Quimiorradioterapia , Carcinoma de Células Escamosas/patologiaRESUMO
OBJECTIVE: This study aimed to validate the prognostic significance of stratification using pathological stage and response to neoadjuvant chemotherapy with a nationwide database from an authorized institute by the Japan Esophageal Society. BACKGROUND: We proposed the combined criteria using pStage and pathological response. Conducting a validation study using an expanded cohort in the clinical setting would be valuable since it was developed using retrospective data collection. METHODS: Patients with esophageal squamous cell carcinoma who underwent subtotal esophagectomy at 85 authorized institutes were retrospectively reviewed for esophageal cancer between 2010 and 2015. The prognostic value of the pathological response was evaluated within the same pStage. Moreover, risk stratification was developed to predict cancer-specific survival (CSS). RESULTS: The pathological response showed significant stratification of CSS in 3761 patients included in this analysis. We classified the patients into 7 groups as survival was significantly different between responders and nonresponders under the stratification with pStage, excluding pStage I comprising pStage 0-I/II responder/II nonresponder/III responder/III nonresponder/IV responder/IV nonresponder with the 5-year CSS of 83.7%/75.8%/68.9%/59.8%/44.4%/40.7%/23.1%, respectively. Furthermore, the area under the curve was significantly higher under the new classification than in the pStage alone ( P <0.001). CONCLUSIONS: The prognostic value of classification using pStage and the pathological response was successfully validated using real-world data in Japan. This result would guide appropriate treatment for patients with esophageal squamous cell carcinoma who received neoadjuvant chemotherapy followed by esophagectomy.
Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/cirurgia , Prognóstico , Neoplasias Esofágicas/tratamento farmacológico , Estudos Retrospectivos , Carcinoma de Células Escamosas/tratamento farmacológico , Terapia Neoadjuvante , Resultado do Tratamento , Estadiamento de Neoplasias , Esofagectomia/efeitos adversosRESUMO
OBJECTIVE: We aimed to evaluate the efficacy of neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy over cisplatin and 5-fluorouracil (CF) in patients with surgically resectable advanced esophageal squamous cell carcinoma (ESCC), using real-world data from 85 esophageal centers. BACKGROUND: JCOG1109 trial, which assessed the superiority of DCF over CF, and the superiority of chemoradiotherapy with CF over CF alone demonstrated the significant survival advantage of neoadjuvant DCF in overall survival (OS) over CF for ESCC. METHODS: The ESCC patients who received neoadjuvant CF or DCF at 85 Japanese esophageal centers certified by the Japan Esophageal Society were retrospectively reviewed. After propensity score (PS) matching, the OS and recurrence-free survival were compared between CF and DCF. RESULTS: We initially enrolled 4781 patients. After data cleaning and PS matching using pretreatment variables, 1074 patients for each group were selected for subsequent analysis. There was no significant difference in the incidence of postoperative pneumonia and anastomotic leakage. In the survival analysis, OS was significantly longer in DCF group than CF group (hazard ratio, 0.868; 95% confidence interval, 0.770-0.978; P =0.02), as well as recurrence-free survival (hazard ratio, 0.850; 95% confidence interval, 0.761-0.949; P =0.004). The survival advantage of DCF was not observed in patients with 76 years old or older. CONCLUSIONS: Neoadjuvant DCF therapy showed a remarkable survival advantage in surgically resectable ESCC patients, especially in patients who were 75 years old or younger. The current real-world evidence will encourage recommendations for DCF as a standard regimen in neoadjuvant chemotherapy-based treatment strategy for ESCC.
Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Idoso , Carcinoma de Células Escamosas do Esôfago/cirurgia , Neoplasias Esofágicas/cirurgia , Neoplasias Esofágicas/tratamento farmacológico , Cisplatino/uso terapêutico , Docetaxel/uso terapêutico , Terapia Neoadjuvante , Fluoruracila/efeitos adversos , Pontuação de Propensão , Japão/epidemiologia , Estudos Retrospectivos , Resultado do Tratamento , Taxoides , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
OBJECTIVE: To examine the association of BMI with mortality and related outcomes after oncologic esophagectomy. SUMMARY BACKGROUND DATA: Previous studies showed that high BMI was a risk factor for anastomotic leakage and low BMI was a risk factor for respiratory complications after esophagectomy. However, the association between BMI and in-hospital mortality after oncologic esophagectomy remains unclear. METHODS: Data for patients who underwent esophagectomy for esophageal cancer between July 2010 and March 2019 were extracted from a Japanese nationwide inpatient database. Multivariate regression analyses and restricted cubic spline analyses were used to investigate the associations between BMI and short-term outcomes, adjusting for potential confounders. RESULTS: Among 39,406 eligible patients, in-hospital mortality, major complications, and multiple complications (≥2 major complications) occurred in 1069 (2.7%), 14,824 (37.6%), and 3621 (9.2%), respectively. Compared with normal weight (18.5-22.9 kg/m 2 ), severe underweight (<16.0 kg/m 2 ), mild/moderate underweight (16.0-18.4 kg/m 2 ), and obese (≥27.5 kg/m 2 )were significantly associated with higher in-hospital mortality [odds ratio 2.20 (95% confidence interval 1.65-2.94), 1.25 (1.01-1.49), and 1.48 (1.05-2.09), respectively]. BMI showed U-shaped dose-response associations with mortality, major complications, and multiple complications. BMI also showed a reverse J-shaped association with failure to rescue (death after major complications). CONCLUSIONS: Both high BMI and low BMI were associated with mortality, major complications and multiple complications after esophagectomy for esophageal cancer. Patients with low BMI were more likely to die once a major complication occurred. The present results can assist with risk stratification in patients undergoing oncologic esophagectomy.
Assuntos
Neoplasias Esofágicas , Sobrepeso , Humanos , Índice de Massa Corporal , Sobrepeso/complicações , Sobrepeso/cirurgia , Magreza/complicações , Magreza/cirurgia , Mortalidade Hospitalar , Pacientes Internados , Esofagectomia/efeitos adversos , Japão/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos RetrospectivosRESUMO
OBJECTIVE: To assess the effect of preoperative prophylactic corticosteroid use on short-term outcomes after oncologic esophagectomy. BACKGROUND: Previous studies have shown that prophylactic corticosteroid use may decrease the risk of respiratory failure following esophagectomy by attenuating the perioperative systemic inflammation response. However, its effectiveness has been controversial, and its impact on mortality remains unknown. METHODS: Data of patients who underwent oncologic esophagectomy between July 2010 and March 2019 were extracted from a Japanese nationwide inpatient database. Stabilized inverse probability of treatment weighting, propensity score matching, and instrumental variable analyses were performed to investigate the associations between prophylactic corticosteroid use and short-term outcomes, such as in-hospital mortality and respiratory failure, adjusting for potential confounders. RESULTS: Among 35,501 eligible patients, prophylactic corticosteroids were used in 22,620 (63.7%) patients. In-hospital mortality, respiratory failure, and severe respiratory failure occurred in 924 (2.6%), 5440 (15.3%), and 2861 (8.1%) patients, respectively. In stabilized inverse probability of treatment weighting analyses, corticosteroids were significantly associated with decreased in-hospital mortality [odds ratio (OR)=0.80; 95% confidence interval (CI): 0.69-0.93], respiratory failure (OR=0.84; 95% CI: 0.79-0.90), and severe respiratory failure (OR=0.87; 95% CI: 0.80-0.95). Corticosteroids were also associated with decreased postoperative length of stay and total hospitalization costs. The proportion of anastomotic leakage did not differ with the use of Propensity score matching and instrumental variable analysis demonstrated similar results. CONCLUSIONS: Prophylactic corticosteroid use in oncologic esophagectomy was associated with lower in-hospital mortality as well as decreased respiratory failure and severe respiratory failure, suggesting a potential benefit for preoperative corticosteroid use in esophagectomy.
Assuntos
Neoplasias Esofágicas , Insuficiência Respiratória , Humanos , Mortalidade Hospitalar , Estudos Retrospectivos , Pacientes Internados , Esofagectomia/efeitos adversos , Japão/epidemiologia , Corticosteroides/uso terapêutico , Neoplasias Esofágicas/cirurgia , Insuficiência Respiratória/epidemiologia , Insuficiência Respiratória/prevenção & controleRESUMO
BACKGROUND: Although imaging surveillance after esophagectomy is required to achieve long-term survival for patients with esophageal cancer, the optimal surveillance timing and interval remain unclear. This study was designed to investigate the differences in oncological outcomes based on the detection method for recurrence and surveillance interval in patients with recurrence detected by routine imaging examination after esophagectomy. METHODS: A total of 527 patients who underwent thoracic esophagectomy for esophageal cancer with R0 resection between 2003 and 2021 in our department were enrolled in this study. Postoperative, routine surveillance was conducted at an outpatient clinic every 3 months, thoracoabdominal computed tomography (CT) every 4-6 months, and esophagogastroduodenoscopy every 6 months. The detection method and optimal interval of imaging surveillance also were investigated. RESULTS: Of all patients, 161 patients developed recurrence during surveillance; 110 (68.3 %) by routine surveillance and 37 (23.0%) not detected by routine surveillance. Among patients who were diagnosed with recurrence following routine surveillance, patients with pStage IV disease on imaging surveillance by thoracoabdominal CT at an interval of ≤ 5 months had a better survival rate than those with an interval of 6 months (P = 0.004), whereas no significant difference among different intervals was observed in patients with pStage I-III disease. CONCLUSIONS: Recurrence may have been detectable by our routine surveillance in approximately 70% of patients who developed recurrence. These findings demonstrate the necessity of different imaging surveillance intervals for different pStages of esophageal cancer.
Assuntos
Neoplasias Esofágicas , Esofagectomia , Humanos , Esofagectomia/métodos , Neoplasias Esofágicas/diagnóstico por imagem , Neoplasias Esofágicas/cirurgia , Tomografia Computadorizada por Raios X , Estudos Retrospectivos , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: Neoadjuvant treatment has become the standard of care for patients with advanced esophageal cancer. However, few studies have elucidated the clinical factors that predict response to neoadjuvant therapy in a large multicenter cohort. We aimed to develop a predictive model of therapeutic effect in patients with esophageal squamous cell carcinoma (SCC) who received neoadjuvant treatment. METHODS: This nationwide study included 4078 patients from 85 institutions. Patients who received neoadjuvant treatment followed by surgery for esophageal SCC were eligible. We developed a logistic regression model to predict good pathological therapeutic effects, and a predictive nomogram was generated by applying the logistic regression formula. RESULTS: Among neoadjuvant regimens, cisplatin plus 5-fluorouracil (CF) was the most frequently used (60.2%), followed by docetaxel plus CF (DCF, 27.4%), CF with radiotherapy (CF-RT, 4.5%), adriamycin plus CF (3.6%), nedaplatin plus 5-fluorouracil (0.9%), and DCF-RT (0.5%). Multivariable analysis revealed that male sex, advanced cT category, and increased pretherapeutic SCC antigen level were independently associated with not achieving a good therapeutic effect. Moreover, intensified neoadjuvant regimens were independently associated with favorable therapeutic effects; DCF-RT elicited the best therapeutic effect, followed by CF-RT and DCF. A predictive model including nine commonly measured preoperative variables was generated, and the area under the curve was 0.679 (95% confidence interval: 0.658-0.700). This nomogram was also adequately validated internally. CONCLUSIONS: The model developed in this study was validated and predicts the therapeutic effect in patients with esophageal SCC who received neoadjuvant treatment. This model might contribute to individualized treatment strategies.
Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Masculino , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Neoplasias Esofágicas/patologia , Terapia Neoadjuvante , Estudos Retrospectivos , Japão , Taxoides , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino , Docetaxel , FluoruracilaRESUMO
BACKGROUND: We previously reported that endoscopic response evaluation can preoperatively predict the prognosis and distribution of residual tumors after neoadjuvant chemotherapy (NAC). In this study, we developed artificial intelligence (AI)-guided endoscopic response evaluation using a deep neural network to discriminate endoscopic responders (ERs) in patients with esophageal squamous cell carcinoma (ESCC) after NAC. METHOD: Surgically resectable ESCC patients who underwent esophagectomy following NAC were retrospectively analyzed in this study. Endoscopic images of the tumors were analyzed using a deep neural network. The model was validated with a test data set using 10 newly collected ERs and 10 newly collected non-ER images. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the endoscopic response evaluation by AI and endoscopists were calculated and compared. RESULTS: Of 193 patients, 40 (21%) were diagnosed as ERs. The median sensitivity, specificity, PPV, and NPV values for ER detection in 10 models were 60%, 100%, 100%, and 71%, respectively. Similarly, the median values by the endoscopist were 80%, 80%, 81%, and 81%, respectively. CONCLUSION: This proof-of-concept study using a deep learning algorithm demonstrated that the constructed AI-guided endoscopic response evaluation after NAC could identify ER with high specificity and PPV. It would appropriately guide an individualized treatment strategy that includes an organ preservation approach in ESCC patients.
Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/cirurgia , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/cirurgia , Terapia Neoadjuvante/métodos , Inteligência Artificial , Estudos Retrospectivos , Redes Neurais de Computação , EsofagoscopiaRESUMO
BACKGROUND: Detecting pathological complete response (pCR) before surgery would facilitate nonsurgical approach after neoadjuvant chemotherapy (NAC). We developed an artificial intelligence (AI)-guided pCR evaluation using a deep neural network to identify pCR before surgery. METHODS: This study examined resectable esophageal squamous cell carcinoma (ESCC) patients who underwent esophagectomy after NAC. The same number of histological responders without pCR and non-responders were randomly selected based on the number of pCR patients. Endoscopic images were analyzed using a deep neural network. A test dataset consisting of 20 photos was used for validation. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of AI and four experienced endoscopists' pCR evaluations were calculated. For pathological response evaluation, Japanese Classification of Esophageal Cancer was used. RESULTS: The study enrolled 123 patients, including 41 patients with pCR, the same number of histological responders without pCR, and non-responders [grade 0, 5 (4%); grade 1a, 36 (30%); grade 1b, 21 (17%); grade 2, 20 (16%); grade 3, 41 (33%)]. In 20 models, the median values of sensitivity, specificity, PPV, NPV, and accuracy for endoscopic response (ER) detection were 60%, 81%, 77%, 67%, and 70%, respectively. Similarly, the endoscopists' median of these was 43%, 90%, 85%, 65%, and 66%, respectively. CONCLUSIONS: This proof-of-concept study demonstrated that the AI-guided endoscopic response evaluation after NAC could identify pCR with moderate accuracy. The current AI algorithm might guide an individualized treatment strategy including nonsurgical approach in ESCC patients through prospective studies with careful external validation to demonstrate the clinical value of this diagnostic approach including primary tumor and lymph node.
RESUMO
BACKGROUND: Although neoadjuvant treatment has become the standard of care for patients with locally advanced esophageal cancer, previous studies comparing neoadjuvant chemotherapy (NAC) and neoadjuvant chemoradiotherapy (NACRT) have demonstrated inconclusive results. METHODS: Our study cohort included 3978 patients from 85 institutions. Those who underwent NAC or NACRT followed by surgery for esophageal squamous cell carcinoma (ESCC) were eligible for inclusion. We used the inverse probability of treatment weighting (IPTW) method to compare the outcomes between NAC and NACRT. RESULTS: Among the 3978 patients, 3777 (94.9%) received NAC and 201 (5.1%) received NACRT. After IPTW adjustment, the NACRT group had more patients with pathologically downstaged diseases and significantly better pathological response compared with the NAC group (p < 0.001); however, 5-year overall survival (OS), recurrence-free survival (RFS), and regional recurrence-specific survival (RRSS) were comparable between the groups. Subgroup analysis stratifying patients according to cT category showed that among cT1-2 patients, those in the NACRT group had significantly longer 5-year OS, RFS, and RRSS than those in the NAC group (P = 0.024, < 0.001, and 0.020, respectively). In contrast, no significant differences were observed among cT3-4a patients. The competing risks regression model showed comparable subdistribution hazard ratios for 10-year cancerous and noncancerous deaths between the NAC and NACRT groups. CONCLUSIONS: Compared with NAC, NACRT for ESCC did not promote better survival despite better therapeutic effects and did not increase noncancerous deaths.
Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Terapia Neoadjuvante , Neoplasias Esofágicas/patologia , População do Leste Asiático , Quimiorradioterapia , Estudos RetrospectivosRESUMO
BACKGROUND: To guide appropriate treatment strategy, an accurate tumor monitoring modality that reflects tumor burden during neoadjuvant treatment is required for esophageal squamous cell carcinoma (ESCC). We aimed to investigate the clinical utility of circulating tumor DNA (ctDNA) in plasma in patients who received neoadjuvant chemotherapy (NAC) followed by esophagectomy. PATIENTS AND METHODS: Longitudinally collected plasma samples for ctDNA combined with genomic DNA from primary lesions were obtained from patients with histologically confirmed ESCC who underwent NAC followed by subtotal esophagectomy. Next-generation sequencing was performed to identify mutations from the plasma and the primary tumor. The relationships between changes in ctDNA and the pathological response and recurrence were assessed in patients with locally advanced ESCC. RESULTS: In pretreatment samples from 13 patients, multiple concordant mutations in ctDNA and primary tumors were observed in 11 patients (85%), who were classified as ctDNA positive before treatment. The ctDNA positive rate after NAC correlated with the pathological response (responders, 25%; nonresponders, 100%; p = 0.007). The risk of recurrence increased significantly in patients with positive ctDNA after surgery in analysis of 16 patients; the 1-year recurrence-free survival rates were 90 and 0% in ctDNA-negative and ctDNA-positive groups, respectively (p = 0.0008). In two patients with postoperative recurrence, ctDNA was detected approximately 5.5 months earlier than the diagnosis using radiographical imaging. CONCLUSIONS: ctDNA is a promising biomarker for predicting pathological response and postoperative recurrence in ESCC. To demonstrate the external validity, we are currently preparing a multicenter prospective study.