Comparison of the treatment outcomes of different neoadjuvant chemoradiotherapy regimens for resectable locally advanced esophageal cancer.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) followed by radical esophagectomy is the standard treatment for locally advanced esophageal squamous cell cancer (LA-ESCC). However, various nCRT regimens have been used and their comparative efficacy and safety remain unclear. METHODS: Patients with histologically confirmed LA-ESCC who underwent nCRT followed by radical esophagectomy between January 2016 and February 2022 were enrolled in our study. Three different nCRT regimens were retrospectively compared: Conventional radiotherapy (RT) + cisplatin/5-fluorouracil (FP) (Conv-FP), hypofractionated RT + FP (Hypo-FP), and regimens from the CROSS trial (CROSS). The overall survival (OS), pathological complete response (pCR) rates, toxicities, and treatment compliance were analyzed. RESULTS: Among the 600 patients, 225 received Conv-FP, 255 received Hypo-FP, and 120 received the CROSS regimen. OS at 1 year were 78.7%, 83.9%, and 88.1% in the Conv-FP, Hypo-FP, and CROSS groups, respectively (p < 0.001). The pCR rates were 30.6%, 33.9%, and 35.0%, respectively (p = 0.653). The overall incidence of grade 3 toxicities was 10.2%. Hematologic and non-hematologic toxicities of grade ≥ 3 were observed in 8.4% and 11.4%, 0% and 7.6%, 5.5% and 0.8% in Conv-FP, Hypo-FP, and CROSS, respectively (p = 0.002 and 0.030). Weight loss > 5% was observed in 44.0%, 51.4%, and 32.5%, respectively (p < 0.001). In the multivariate analysis, clinical T-stage (p = 0.004), N-stage (p = 0.012), the use of FP chemotherapy regimen (p = 0.013), surgical resection (p < 0.001), hematologic toxicity (p = 0.001), and weight loss (p = 0.004) were significantly associated with poor OS. CONCLUSION: The choice of nCRT regimen did not significantly affect the pCR rates in patients with LA-ESCC. However, the CROSS regimen demonstrated better OS and lower toxicity, suggesting it may be the optimal treatment option among the groups. SYNOPSIS: This study compared three different neoadjuvant chemoradiotherapy (nCRT) regimens for locally advanced esophageal squamous cell cancer (LA-ESCC): Conventional radiotherapy (RT) + cisplatin/5-fluorouracil (FP), hypofractionated RT + FP, and regimens from the CROSS trial. The overall survival (OS), pathological complete response (pCR) rates, toxicities, and treatment compliance were analyzed. Results showed that the choice of nCRT regimen did not significantly affect pCR rates, but the CROSS regimen showed better OS and lower toxicity, suggesting it may be the optimal treatment option. DATA AVAILABILITY: Data availability is limited due to institutional data protection law and confidentiality of patient data.

Clinical Utility of Tumor-Naïve Presurgical Circulating Tumor DNA Detection in Early-Stage NSCLC.

OBJECTIVES: The use of tumor-informed circulating tumor DNA (ctDNA) testing in patients with early-stage disease before surgery is limited, mainly owing to restricted tissue access and extended turnaround times. This study aimed to evaluate the clinical value of a tumor-naïve, methylation-based cell-free DNA assay in a large cohort of patients with resected NSCLC. METHOD: We analyzed presurgical plasma samples from 895 patients with EGFR and anaplastic lymphoma kinase-wild-type, clinical stage I or II NSCLC. The ctDNA status was evaluated for its prognostic significance in relation to tumor volume, metabolic activity, histologic diagnosis, histologic subtypes, and clinical-to-pathologic TNM upstaging. RESULTS: Presurgical ctDNA detection was observed in 55 of 414 patients (13%) with clinical stage I lung adenocarcinoma (LUAD) and was associated with poor recurrence-free survival (2-year recurrence-free survival 69% versus 91%; log-rank p < 0.001), approaching that of clinical stage II LUAD. Presurgical ctDNA detection was not prognostic in patients with clinical stage II LUAD or non-LUAD. Within LUAD, tumor volume and positron emission tomography avidity interacted to predict presurgical ctDNA detection. Moreover, presurgical ctDNA detection was predictive of the postsurgical discovery of International Association for the Study of Lung Cancer grade 3 tumors (p < 0.001) and pathologic TNM upstaging (p < 0.001). Notably, presurgical ctDNA detection strongly correlated with higher programmed death-ligand 1 expression in tumors (positive rates 28% versus 55%, p < 0.001), identifying a subgroup likely to benefit from anti-programmed death-ligand 1 therapies. CONCLUSION: These findings support the integration of ctDNA testing into routine diagnostic workflows in early-stage NSCLC without the need for tumor tissue profiling. Furthermore, it is clinically useful in identifying patients at high risk who might benefit from innovative treatments, including neoadjuvant immune checkpoint inhibitors.

Comparison of the Oncologic Outcomes for Patients with Middle to Lower Esophageal Squamous Cell Carcinoma Undergoing Surgical Treatment Using the Ivor-Lewis or McKeown Operation.

BACKGROUND: The upper mediastinum is the most common metastatic site of esophageal squamous cell carcinoma (ESCC), and complete dissection of this region is important for oncologic reasons. This study aimed to compare the oncologic outcomes and completeness of upper mediastinal dissection for ESCC patients undergoing the Ivor-Lewis (IL) or McKeown (MK) operations. METHODS: Between 2013 and 2018, 680 patients (IL, 433; MK, 247) underwent upfront esophagectomy with two-field lymph node (LN) dissection for mid-to-lower ESCCs. Propensity score-matching (1:1 ratio) was performed to minimize the effects of confounding factors. RESULTS: The mean age was 64.5 ± 8.8 years, and 635 (93.4%) of the patients were male. The median follow-up period was 71.66 months (interquartile range [IQR], 59.60-91.04 months). The IL group had a higher mean age, lower body mass index, higher proportion of advanced T and N, and higher adjuvant therapy rates, but these differences were well-balanced after propensity score-matching. The mean number of dissected LNs at the mediastinum and at the right recurrent laryngeal nerve (RLN) were similar between the two groups after matching, whereas the IL group exhibited a slightly greater number of dissected LNs at the left RLN. Among the matched patients, the IL and MK groups exhibited similar 5-year overall survival (OS: 75.1% vs 78.0%; p = 0.368). The multivariate model showed no differences in OS, disease-free survival, or recurrence-free survival for locoregional, upper mediastinum, or neck between the two groups. CONCLUSIONS: This study suggests that both the IL and MK operations are oncologically feasible for patients with mid-to-lower ESCC.

Development, validation, and usability evaluation of machine learning algorithms for predicting personalized red blood cell demand among thoracic surgery patients.

INTRODUCTION: Preparing appropriate red blood cells (RBCs) before surgery is crucial for improving both the efficacy of perioperative workflow and patient safety. In particular, thoracic surgery (TS) is a procedure that requires massive transfusion with high variability for each patient. Hence, the precise prediction of RBC requirements for individual patients is becoming increasingly important. This study aimed to 1) develop and validate a machine learning algorithm for personalized RBC predictions for TS patients and 2) assess the usability of a clinical decision support system (CDSS) integrating this artificial intelligence model. METHODS: Adult patients who underwent TS between January 2016 and October 2021 were included in this study. Multiple models were developed by employing both traditional statistical- and machine-learning approaches. The primary outcome evaluated the model's performance in predicting RBC requirements through root mean square error and adjusted R2. Surgeons and informaticians determined the precision MSBOS-Thoracic Surgery (pMSBOS-TS) algorithm through a consensus process. The usability of the pMSBOS-TS was assessed using the System Usability Scale (SUS) survey with 60 clinicians. RESULTS: We identified 7,843 cases (6,200 for training and 1,643 for test sets) of TSs. Among the models with variable performance indices, the extreme gradient boosting model was selected as the pMSBOS-TS algorithm. The pMSBOS-TS model showed statistically significant lower root mean square error (mean: 3.203 and 95% confidence interval [CI]: 3.186-3.220) compared to the calculated Maximum Surgical Blood Ordering Schedule (MSBOS) and a higher adjusted R2 (mean: 0.399 and 95% CI: 0.395-0.403) compared to the calculated MSBOS, while requiring approximately 200 fewer packs for RBC preparation compared to the calculated MSBOS. The SUS score of the pMSBOS-TS CDSS was 72.5 points, indicating good acceptability. CONCLUSIONS: We successfully developed the pMSBOS-TS capable of predicting personalized RBC transfusion requirements for perioperative patients undergoing TS.

Practice pattern and risk of not receiving planned surgery after neoadjuvant chemoradiotherapy for locally advanced oesophageal squamous cell carcinoma.

OBJECTIVES: Unlike the initial plan, some patients with oesophageal squamous cell carcinoma cannot or do not receive surgery after neoadjuvant chemoradiotherapy (nCRT). This study aimed to report the epidemiology of patients not receiving surgery after nCRT and to evaluate the potential risk of refusing surgery. METHODS: We analysed patients with clinical stage T3-T4aN0M0 or T1-T4aN1-N3M0 oesophageal squamous cell carcinoma who underwent nCRT as an initial treatment intent between January 2005 and March 2020. Patients not receiving surgery were categorized using predefined criteria. To evaluate the risk of refusing surgery, a propensity-matched comparison with those who received surgery was performed. Recurrence-free (RFS) and overall survival (OS) was compared between groups, according to clinical response to nCRT. RESULTS: Among the study population (n = 715), 105 patients (14.7%) eventually failed to reach surgery. There were three major patterns of not receiving surgery: disease progression before surgery (n = 25), functional deterioration at reassessment (n = 47), and patient's refusal without contraindications (n = 33). After propensity-score matching, the RFS curves of the surgery group and the refusal group were significantly different (P < 0.001), while OS curves were not significantly different (P = 0.069). In patients who achieved clinical complete response on re-evaluation, no significant difference in the RFS curves (P = 0.382) and in the OS curves (P = 0.290) was observed between the surgery group and the refusal group. However, among patients who showed partial response or stable disease on re-evaluation, the RFS and OS curves of the refusal group were overall significantly inferior compared to those of the surgery group (both P < 0.001). The 5-year RFS rates were 10.3% for the refusal group and 48.2% for the surgery group, and the 5-year OS rates were 8.2% for the refusal group and 46.1% for the surgery group. CONCLUSIONS: Patient's refusal remains one of the major obstacles in completing the trimodality therapy for oesophageal squamous cell carcinoma. Refusing surgery when offered may jeopardize oncological outcome, particularly in those with residual disease on re-evaluation after nCRT. These results provide significant implications for consulting patients who are reluctant to oesophagectomy after nCRT.

Computed tomography characteristics of cN0 primary non-small cell lung cancer predict occult lymph node metastasis.

RATIONALE: Occult lymph node metastasis (OLNM) is frequently found in patients with resectable non-small cell lung cancer (NSCLC), despite using diagnostic methods recommended by guidelines. OBJECTIVES: To evaluate the risk of OLNM in NSCLC patients using the radiologic characteristics of the primary tumor on computed tomography (CT). METHODS: We retrospectively reviewed clinicopathologic features of 2042 clinical T1-4N0 NSCLC patients undergoing curative intent pulmonary resection. Unique radiological features (i.e., air-bronchogram throughout the whole tumor, heterogeneous ground-glass opacity (GGO), mainly cystic appearance, endobronchial location), percentage of solid portion, and shape of tumor margin were analyzed via a stepwise approach. We used multivariable logistic regression to assess the relationship between OLNM and tumor characteristics. RESULTS: Compared with the other unique features, endobronchial tumors were associated with the highest risk of OLNM (OR = 3.9, 95% confidence interval (CI) = 2.29-6.62), and heterogeneous GGO and mainly cystic tumors were associated with a low risk of OLNM. For tumors without unique features, the percentage of the solid portion was measured, and solid tumors were associated with OLNM (OR = 2.49, 95% CI = 1.86-3.35). Among part-solid tumors with solid proportion > 50%, spiculated margin, and peri-tumoral GGO were associated with OLNM. CONCLUSIONS: The risk of OLNM could be assessed using radiologic characteristics on CT. This could allow us to adequately select optimal candidates for invasive nodal staging procedures (INSPs) and complete systematic lymph node dissection. CLINICAL RELEVANCE STATEMENT: These data may be helpful for clinicians to select appropriate candidates for INSPs and complete surgical systematic lymph node dissection in NSCLC patients. KEY POINTS: Lymph node metastasis status plays a key role in both prognostication and treatment planning. Solid tumors, particularly endobronchial tumors, were associated with occult lymph node metastasis (OLNM). The risk of OLNM can be assessed using radiologic characteristics acquired from CT images.

Deep learning model integrating cfDNA methylation and fragment size profiles for lung cancer diagnosis.

Detecting aberrant cell-free DNA (cfDNA) methylation is a promising strategy for lung cancer diagnosis. In this study, our aim is to identify methylation markers to distinguish patients with lung cancer from healthy individuals. Additionally, we sought to develop a deep learning model incorporating cfDNA methylation and fragment size profiles. To achieve this, we utilized methylation data collected from The Cancer Genome Atlas and Gene Expression Omnibus databases. Then we generated methylated DNA immunoprecipitation sequencing and genome-wide Enzymatic Methyl-seq (EM-seq) form lung cancer tissue and plasma. Using these data, we selected 366 methylation markers. A targeted EM-seq panel was designed using the selected markers, and 142 lung cancer and 56 healthy samples were produced with the panel. Additionally, cfDNA samples from healthy individuals and lung cancer patients were diluted to evaluate sensitivity. Its lung cancer detection performance reached an accuracy of 81.5% and an area under the receiver operating characteristic curve of 0.87. In the serial dilution experiment, we achieved tumor fraction detection of 1% at 98% specificity and 0.1% at 80% specificity. In conclusion, we successfully developed and validated a combination of methylation panel and a deep learning model that can distinguish between patients with lung cancer and healthy individuals.

Adjuvant Pembrolizumab in Patients with Stage IIIA/N2 Non-Small Cell Lung Cancer Completely Resected after Neoadjuvant Concurrent Chemoradiation: A Prospective, Open-Label, Single-Arm, Phase 2 Trial.

Purpose: Optimal treatment for stage IIIA/N2 non-small cell lung cancer (NSCLC) is controversial. We aimed to assess the efficacy and safety of adjuvant pembrolizumab for stage IIIA/N2 NSCLC completely resected after neoadjuvant concurrent chemoradiation therapy (CCRT). Materials and Methods: In this open-label, single-center, single-arm phase 2 trial, patients with stage IIIA/N2 NSCLC received adjuvant pembrolizumab for up to two years after complete resection following neoadjuvant CCRT. The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival (OS) and safety. As an exploratory biomarker analysis, we evaluated the proliferative response of blood CD39+PD-1+CD8+ T cells using fold changes in the percentage of proliferating Ki-67+ cells from days 1 to 7 of cycle 1 (Ki-67D7/D1). Results: Between October 2017 and October 2018, 37 patients were enrolled. Twelve (32%) and three (8%) patients harbored EGFR and ALK alterations, respectively. Of 34 patients with programmed cell death ligand 1 assessment, 21 (62%), 9 (26%), and 4 (12%) had a tumor proportion score of <1%, 1-50%, and ≥50%, respectively. The median follow-up was 71 months. The median DFS was 22.4 months in the overall population, with a five-year DFS rate of 29%. The OS rate was 86% at two years and 76% at five years. Patients with tumor recurrence within six months had a significantly lower Ki-67D7/D1 among CD39+PD-1+CD8+ T cells than those without (p=0.036). No new safety signals were identified. Conclusion: Adjuvant pembrolizumab may offer durable disease control in a subset of stage IIIA/N2 NSCLC patients after neoadjuvant CCRT and surgery.

Risk Factor Analysis of Morbidity and 90-Day Mortality of Curative Resection in Patients with Stage IIIA-N2 Non-Small Cell Lung Cancer after Induction Concurrent Chemoradiation Therapy.

Background: Major pulmonary resection after neoadjuvant concurrent chemoradiation therapy (nCCRT) is associated with a substantial risk of postoperative complications. This study investigated postoperative complications and associated risk factors to facilitate the selection of suitable surgical candidates following nCCRT in stage IIIA-N2 non-small cell lung cancer (NSCLC). Methods: We conducted a retrospective analysis of patients diagnosed with clinical stage IIIA-N2 NSCLC who underwent surgical resection following nCCRT between 1997 and 2013. Perioperative characteristics and clinical factors associated with morbidity and mortality were analyzed using univariable and multivariable logistic regression. Results: A total of 574 patients underwent major lung resection after induction CCRT. Thirty-day and 90-day postoperative mortality occurred in 8 patients (1.4%) and 41 patients (7.1%), respectively. Acute respiratory distress syndrome (n=6, 4.5%) was the primary cause of in-hospital mortality. Morbidity occurred in 199 patients (34.7%). Multivariable analysis identified significant predictors of morbidity, including patient age exceeding 70 years (odds ratio [OR], 1.8; p=0.04), low body mass index (OR, 2.6; p=0.02), and pneumonectomy (OR, 1.8; p=0.03). Patient age over 70 years (OR, 1.8; p=0.02) and pneumonectomy (OR, 3.26; p<0.01) were independent predictors of mortality in the multivariable analysis. Conclusion: In conclusion, the surgical outcomes following nCCRT are less favorable for individuals aged over 70 years or those undergoing pneumonectomy. Special attention is warranted for these patients due to their heightened risks of respiratory complications. In high-risk patients, such as elderly patients with decreased lung function, alternative treatment options like definitive CCRT should be considered instead of surgical resection.

Metabolic dysfunction-associated steatotic liver disease and risk of esophageal cancer in patients with diabetes mellitus: a nationwide cohort study.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely associated with type 2 diabetes and a developing several cancers including esophageal cancer (EC). However, the association between MASLD and EC in diabetic patients has not been investigated. Therefore, we aimed to investigate the relation between MASLD and developing EC in diabetic patients. This was a population-based retrospective cohort study of data from the Korean National Health Insurance Service (NHIS). A total of 1,904,468 subjects diagnosed with diabetes who underwent NHIS-provided health checkups from 2009 to 2012 were included. We constructed a Cox proportional hazard model for the association of fatty liver index (FLI) and the risk of EC stratified by potential confounders. Over a mean follow-up duration of 6.9 years, the incidence of EC was higher in the high (≥60) FLI group compared to the low (<30) FLI group (14.4 vs. 13.7 event per 100,000 person-years). The risk of EC correlated with the degree of FLI, particularly in older (P = 0.002), female (P = 0.033), non-smoking (P = 0.002), and non-drinking patients (P = 0.025). Among obese patients, the risk of EC was not associated with FLI; however, the risk of EC was higher in the high FLI group in non-obese patients. Lean MASLD patients had the highest risk of EC (adjusted hazard ratio 1.78; 95% confidence interval, 1.5-2.13). MASLD was associated with an increased risk of EC in diabetic patients, and lean MASLD has the highest risk. Further studies are required to determine the causal relationship between MASLD and EC.

Comprehensive analysis of transcription factor-based molecular subtypes and their correlation to clinical outcomes in small-cell lung cancer.

BACKGROUND: Recent studies have reported the predictive and prognostic value of novel transcriptional factor-based molecular subtypes in small-cell lung cancer (SCLC). We conducted an in-depth analysis pairing multi-omics data with immunohistochemistry (IHC) to elucidate the underlying characteristics associated with differences in clinical outcomes between subtypes. METHODS: IHC (n = 252), target exome sequencing (n = 422), and whole transcriptome sequencing (WTS, n = 189) data generated from 427 patients (86.4% males, 13.6% females) with SCLC were comprehensively analysed. The differences in the mutation profile, gene expression profile, and inflammed signatures were analysed according to the IHC-based molecular subtype. FINDINGS: IHC-based molecular subtyping, comprised of 90 limited-disease (35.7%) and 162 extensive-disease (64.3%), revealed a high incidence of ASCL1 subtype (IHC-A, 56.3%) followed by ASCL1/NEUROD1 co-expressed (IHC-AN, 17.9%), NEUROD1 (IHC-N, 12.3%), POU2F3 (IHC-P, 9.1%), triple-negative (IHC-TN, 4.4%) subtypes. IHC-based subtype showing high concordance with WTS-based subtyping and non-negative matrix factorization (NMF) clusterization method. IHC-AN subtype resembled IHC-A (rather than IHC-N) in terms of both gene expression profiles and clinical outcomes. Favourable median overall survival was observed in IHC-A (15.2 months) compared to IHC-N (8.0 months, adjusted HR 2.3, 95% CI 1.4-3.9, p = 0.002) and IHC-P (8.3 months, adjusted HR 1.7, 95% CI 0.9-3.2, p = 0.076). Inflamed tumours made up 25% of cases (including 53% of IHC-P, 26% of IHC-A, 17% of IHC-AN, but only 11% of IHC-N). Consistent with recent findings, inflamed tumours were more likely to benefit from first-line immunotherapy treatment than non-inflamed phenotype (p = 0.002). INTERPRETATION: This study provides fundamental data, including the incidence and basic demographics of molecular subtypes of SCLC using both IHC and WTS from a comparably large, real-world Asian/non-Western patient cohort, showing high concordance with the previous NMF-based SCLC model. In addition, we revealed underlying biological pathway activities, immunogenicity, and treatment outcomes based on molecular subtype, possibly related to the difference in clinical outcomes, including immunotherapy response. FUNDING: This work was supported by AstraZeneca, Future Medicine 2030 Project of the Samsung Medical Center [grant number SMX1240011], the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) [grant number 2020R1C1C1010626] and the 7th AstraZeneca-KHIDI (Korea Health Industry Development Institute) oncology research program.

Preoperative DLco and FEV1 are correlated with postoperative pulmonary complications in patients after esophagectomy.

Limited information is available regarding the association between preoperative lung function and postoperative pulmonary complications (PPCs) in patients with esophageal cancer who undergo esophagectomy. This is a retrospective cohort study. Patients were classified into low and high lung function groups by the cutoff of the lowest fifth quintile of forced expiratory volume in 1 s (FEV1) %predicted (%pred) and diffusing capacity of the carbon monoxide (DLco) %pred. The PPCs compromised of atelectasis requiring bronchoscopic intervention, pneumonia, and acute lung injury/acute respiratory distress syndrome. Modified multivariable-adjusted Poisson regression model using robust error variances and inverse probability treatment weighting (IPTW) were used to assess the relative risk (RR) for the PPCs. A joint effect model considered FEV1%pred and DLco %pred together for the estimation of RR for the PPCs. Of 810 patients with esophageal cancer who underwent esophagectomy, 159 (19.6%) developed PPCs. The adjusted RR for PPCs in the low FEV1 group relative to high FEV1 group was 1.48 (95% confidence interval [CI] = 1.09-2.00) and 1.98 (95% CI = 1.46-2.68) in the low DLco group relative to the high DLco group. A joint effect model showed adjusted RR of PPCs was highest in patients with low DLco and low FEV1 followed by low DLco and high FEV1, high DLco and low FEV1, and high DLco and high FEV1 (Reference). Results were consistent with the IPTW. Reduced preoperative lung function (FEV1 and DLco) is associated with post-esophagectomy PPCs. The risk was further strengthened when both values decreased together.

Contralateral Pulmonary Resection after Pneumonectomy.

Background: Contralateral pulmonary resection after pneumonectomy presents considerable challenges, and few reports in the literature have described this procedure. Methods: We retrospectively reviewed the medical records of all patients who underwent contralateral lung resection following pneumonectomy for any reason at our institution between November 1994 and December 2020. Results: Thirteen patients (9 men and 4 women) were included in this study. The median age was 57 years (range, 35-77 years), and the median preoperative forced expiratory volume in 1 second was 1.64 L (range, 1.17-2.12 L). Contralateral pulmonary resection was performed at a median interval of 44 months after pneumonectomy (range, 6-564 months). Surgical procedures varied among the patients: 10 underwent single wedge resection, 2 were treated with double wedge resection, and 1 underwent lobectomy. Diagnoses at the time of contralateral lung resection included lung cancer in 7 patients, lung metastasis from other cancers in 3 patients, and tuberculosis in 3 patients. Complications were observed in 4 patients (36%), including acute kidney injury, pneumothorax following chest tube removal, pneumonia, and prolonged air leak. No cases of operative mortality were noted. Conclusion: In carefully selected patients, contralateral pulmonary resection after pneumonectomy can be accomplished with acceptable operative morbidity and mortality.