Resistance mechanisms of EGFR tyrosine kinase inhibitors, in EGFR exon 20 insertion-mutant lung cancer.

BACKGROUND: Mobocertinib, an EGFR exon 20 insertion (Ex20ins)-specific tyrosine kinase inhibitor has been used for treatment of advanced/metastatic EGFR Ex20ins-mutant non-small cell lung cancer (NSCLC). However, resistance mechanisms to EGFR Ex20ins-specific inhibitors and the efficacy of subsequent amivantamab treatment is unknown. METHODS: To investigate resistance mechanisms, tissue and cfDNA samples were collected before treatment initiation and upon development of resistance from NSCLC patients with EGFR Ex20ins mutations received mobocertinib, poziotinib, and amivantamab treatments. Genetic alterations were analyzed using whole-genome and targeted sequencing, and in vitro resistant cell lines were generated for validation. RESULTS: EGFR amplification (n = 6, including 2 broad copy number gain) and EGFR secondary mutation (n = 3) were observed at the resistance of mobocertinib. One patient had both EGFR secondary mutation and high EGFR focal amplification. In vitro models harboring EGFR alterations were constructed to validate resistance mechanisms and identify overcoming strategies to resistance. Acquired EGFR-dependent alterations were found to mediate resistance to mobocertinib in patients and in vitro models. Furthermore, two of six patients who received sequential amivantamab followed by an EGFR tyrosine kinase inhibitor had MET amplification and showed partial response. CONCLUSIONS: Our study revealed EGFR-dependent and -independent mechanisms of mobocertinib resistance in patients with advanced EGFR Ex20ins-mutant NSCLC.

Stratifying Lung Adenocarcinoma Risk with Multi-ancestry Polygenic Risk Scores in East Asian Never-Smokers.

Background: Lung adenocarcinoma (LUAD) among never-smokers is a public health burden especially prevalent in East Asian (EAS) women. Polygenic risk scores (PRSs), which quanefy geneec suscepebility, are promising for straefying risk, yet have mainly been developed in European (EUR) populaeons. We developed and validated single-and mule-ancestry PRSs for LUAD in EAS never-smokers, using the largest available genome-wide associaeon study (GWAS) dataset. Methods: We used GWAS summary staesecs from both EAS (8,002 cases; 20,782 controls) and EUR (2,058 cases; 5,575 controls) populaeons, as well as independent EAS individual level data. We evaluated several PRSs approaches: a single-ancestry PRS using 25 variants that reached genome-wide significance (PRS-25), a genome-wide Bayesian based approach (LDpred2), and a mule-ancestry approach that models geneec correlaeons across ancestries (CT-SLEB). PRS performance was evaluated based on the associaeon with LUAD and AUC values. We then esemated the lifeeme absolute risk of LUAD (age 30-80) and projected the AUC at different sample sizes using EAS-derived effect-size distribueon and heritability esemates. Findings: The CT-SLEB PRS showed a strong associaeon with LUAD risk (odds raeo=1.71, 95% confidence interval (CI): 1.61, 1.82) with an AUC of 0.640 (95% CI: 0.629, 0.653). Individuals in the 95 th percenele of the PRS had an esemated 6.69% lifeeme absolute risk of LUAD. Comparison of LUAD risk between individuals in the highest and lowest 20% PRS quaneles revealed a 3.92-fold increase. Projeceon analyses indicated that achieving an AUC of 0.70, which approaches the maximized prediceon poteneal of the PRS given the esemated geneec variance, would require a future study encompassing 55,000 EAS LUAD cases with a 1:10 case-control raeo. Interpretations: Our study underscores the poteneal of mule-ancestry PRS approaches to enhance LUAD risk straeficaeon in never-smokers, parecularly in EAS populaeons, and highlights the necessary scale of future research to uncover the geneec underpinnings of LUAD.

Clinical Factors Affecting Discrepancy Between Predicted and Long-term Actual Lung Function Following Surgery.

PURPOSE: Lung cancer surgery outcomes depend heavily on preoperative pulmonary reserve, with forced expiratory volume in 1 second (FEV1) being a critical preoperative evaluation factor. Our study investigates the discrepancies between predicted and long-term actual postoperative lung function, focusing on clinical factors affecting these outcomes. METHODS: This retrospective observational study encompassed lung cancer patients who underwent preoperative lung perfusion SPECT/CT between 2015 and 2021. We evaluated preoperative and postoperative pulmonary function tests, considering factors such as surgery type, resected volume, and patient history including tuberculosis. Predicted postoperative lung function was calculated using SPECT/CT imaging. RESULTS: From 216 patients (men:women, 150:66; age, 67.9 ± 8.7 years), predicted postoperative FEV1% (ppoFEV1%) showed significant correlation with actual postoperative FEV1% (r = 0.667; P < 0.001). Paired t test revealed that ppoFEV1% was significantly lower compared with actual postoperative FEV1% (P < 0.001). The study identified video-assisted thoracic surgery (VATS) (odds ratio [OR], 3.90; 95% confidence interval [CI], 1.98-7.69; P < 0.001) and higher percentage of resected volume (OR per 1% increase, 1.05; 95% CI, 1.01-1.09; P = 0.014) as significant predictors of postsurgical lung function improvement. Conversely, for the decline in lung function postsurgery, significant predictors included lower percentage of resected lung volume (OR per 1% increase, 0.92; 95% CI, 0.86-0.98; P = 0.011), higher preoperative FEV1% (OR, 1.03; 95% CI, 1.01-1.07; P = 0.009), and the presence of tuberculosis (OR, 5.19; 95% CI, 1.48-18.15; P = 0.010). Additionally, in a subgroup of patients with borderline lung function, VATS was related with improvement. CONCLUSIONS: Our findings demonstrate that in more than half of the patients, actual postsurgical lung function exceeded predicted values, particularly following VATS and with higher volume of lung resection. It also identifies lower resected lung volume, higher preoperative FEV1%, and tuberculosis as factors associated with a postsurgical decline in lung function. The study underscores the need for precise preoperative lung function assessment and tailored postoperative management, with particular attention to patients with relevant clinical factors. Future research should focus on validation of clinical factors and exploring tailored approaches to lung cancer surgery and recovery.

Comparison of Clinical Outcomes and Postoperative Nutritional Status Between Early and Late Oral Feeding After Esophagectomy: An Open Labeled Randomized Controlled Trial.

OBJECTIVE: To compare nutritional and postoperative outcomes between early oral feeding and late oral feeding with jejunostomy feeding support after esophagectomy. SUMMARY BACKGROUND DATA: Esophagectomy is associated with substantial body weight loss and malnutrition, impacting the prognosis of esophageal cancer patients. Despite many studies on post-esophagectomy nutritional support, optimal strategies remain elusive. This study investigates the impact of jejunostomy feeding with late oral feeding compared to conventional oral feeding on nutritional and postoperative outcomes. METHODS: We performed a single-center prospective open-labelled randomized controlled trial between 2020 and 2022. Patients aged 18 to 75 years with resectable esophageal cancer were randomly assigned to undergo either early oral feeding (early group) or late oral feeding with jejunostomy feeding support (late group) after esophagectomy. The primary endpoint was body weight loss from preoperative body weight at postoperative 4-5 weeks and 4 months. Other perioperative and nutritional outcomes were also evaluated. RESULTS: We randomly assigned 29 patients to the early group and 29 patients to the late group. The late group exhibited significantly less body weight loss at both postoperative 4-5 weeks (8.3% vs. 5.6%; P =0.002) and 4 months (15.0% vs. 10.5%; P =0.003). The total calorie intake and protein intake were higher in the late group for both postoperative 4-5 weeks (1800 kcal/day vs. 1100 kcal/day; P <0.001) and 4 months (1565 kcal/day vs. 1200 kcal/day; P =0.010). Sixty percentage of early group changed to malnutrition state, while 40% of the late group changed to malnutrition. The complication rate and length of hospital stays were similar. CONCLUSIONS: The late group demonstrated prevention of significant body weight loss, enhanced nutritional intake, and reduces malnutrition without compromising short-term surgical outcomes.

Long-term survival analysis of robotic esophagectomy for esophageal cancer.

Robotic esophagectomy has improved early outcomes and enhanced the quality of lymphadenectomy for esophageal cancer surgery. This study aimed to determine risk factors for long-term survival following robotic esophagectomy and the causes of long-term mortality. We included patients who underwent robotic esophagectomy at our institute between 2010 and 2022. Robotic esophagectomy was defined as a surgical procedure performed robotically in both the abdomen and thorax. Robotic esophagectomy was performed in patients at all stages, including advanced stages, even in patients with stage IV and supraclavicular lymph node metastasis. A total of 340 patients underwent robotic esophagectomy during the study period. Ivor-Lewis operation and McKeown operation were performed on 153 (45.0%) and 187 (55.0%) patients, respectively. The five-year survival rates based on clinical stages were as follows: 85.2% in stage I, 62.0% in stage II, 54.5% in stage III, and 40.3% in stage IV. Risk factors for long-term survival included body mass index, Charlson comorbidity index, clinical stages, and postoperative complications of grade 4 or higher. Among the cases of long-term mortality, recurrence accounted for 42 patients (61.7%), while non-cancer-related death occurred in 26 patients (38.2%). The most common cause of non-cancer-related death was malnutrition and poor general condition, observed in 11 patients (16.2%). Robotic esophagectomy has demonstrated the ability to achieve acceptable long-term survival rates, even in patients with cervical lymph node metastasis. However, addressing high-grade postoperative complications and long-term malnutrition remains crucial for further improving the long-term survival outcomes of patients with esophageal cancer.

Thoracic cavity remodeling and pulmonary function change after chest wall resection.

Background: Chest wall resection (CWR) is an essential procedure for treating malignancies and infectious conditions of the chest wall. However, there are few studies on the pulmonary function and changes in thoracic cavity volume (TCV) related to CWR. This study aims to investigate the effects of CWR on long-term changes in TCV and pulmonary function. Methods: Data of patients who underwent CWR between 2001 and 2021 were retrospectively reviewed. Patients who underwent single rib or lung resection rather than wedge resection were excluded. TCV (liter) was defined as the sum of the right and left TCVs (RCV and LCV) and was measured using computed tomography image reconstruction software. Changes in pulmonary function and TCV 1 year postoperatively were analyzed. Results: A total of 45 patients were included. The number of resected ribs was 2 in 16 (35.6%) and ≥3 in 29 (64.4%) patients. Thirty patients underwent reconstruction. Long-term post-CWR decreased in forced vital capacity (FVC) (-7.9%, P=0.004) and forced expiratory volume in 1 second (FEV1) (-7.0%, P=0.002) were significant. There was no significant decrease in FEV1/FVC ratio (-3.0%, P=0.06), diffusing capacity of the lung for carbon monoxide (DLCO) (-5.9%, P=0.18) and TCV (-3.1%, P=0.10). There was no correlation between changes in TCV and decreases in FVC (r=0.12, P=0.56) or FEV1 (r=0.15, P=0.45). After right-side CWR (n=27), RCV (-7.8%, P=0.01) decreased significantly, whereas LCV (+2.1%, P=0.58) did not. The left-side CWR exhibited an identical pattern. (LCV: -8.5%, P=0.004; RCV: +1.3%, P=0.85). In the ≥3 rib-resection group, FVC (-9.5%, P=0.02), FEV1 (-7.9%, P=0.02) and TCV (-6.4%, P=0.04) decreased significantly. No significant changes were noted in the 2 rib-resection group. There were no significant differences in the changes in pulmonary function nor TCV between the reconstruction and no-reconstruction groups. Conclusions: The long-term decrease in pulmonary function after CWR was significant, especially after ≥3-rib resection.

Comparative Study of Indocyanine Green Intravenous Injection and the Inflation-Deflation Method for Assessing Resection Margins in Segmentectomy for Lung Cancer: A Single-Center Retrospective Study.

Background: The inflation-deflation (ID) method has long been the standard for intraoperative margin assessment in segmentectomy. However, with advancements in vision technology, the use of near-infrared mapping with indocyanine green (ICG) has become increasingly common. This study was conducted to compare the perioperative outcomes and resection margins achieved using these methods. Methods: This retrospective study included patients who underwent direct segmentectomy for clinical stage I lung cancer between January 2018 and September 2022. We compared perioperative factors, including bronchial and parenchymal resection margins, according to the margin assessment method and the type of segmentectomy performed. Since the ICG approach was adopted in April 2021, we also examined a recent subgroup of patients treated from then onward. Results: A total of 319 segmentectomies were performed. ID and ICG were utilized for 261 (81.8%) and 58 (18.2%) patients, respectively. Following April 2021, 61 patients (51.3%) were treated with ID, while 58 (48.7%) received ICG. We observed no significant difference in resection margins between ID and ICG for bronchial (2.7 cm vs. 2.3 cm, p=0.07) or parenchymal (2.5 cm vs. 2.3 cm, p=0.46) margins. Additionally, the length of hospitalization and the complication rate were comparable between groups. Analysis of the recent subgroup confirmed these findings, showing no significant differences in resection margins (bronchial: 2.6 cm vs. 2.3 cm, p=0.25; parenchymal: 2.4 cm vs. 2.3 cm, p=0.75), length of hospitalization, or complication rate. Conclusion: The perioperative outcomes and resection margins achieved using ID and ICG were comparable, suggesting that both methods can safely guide segmentectomy procedures.

Efficacy and safety of BVAC-C in HPV type 16- or 18-positive cervical carcinoma who failed 1st platinum-based chemotherapy: a phase I/IIa study.

Background: BVAC-C, a B cell- and monocyte-based immunotherapeutic vaccine transfected with recombinant HPV E6/E7, was well tolerated in HPV-positive recurrent cervical carcinoma patients in a phase I study. This phase IIa study investigates the antitumor activity of BVAC-C in patients with HPV 16- or 18-positive cervical cancer who had experienced recurrence after a platinum-based combination chemotherapy. Patients and methods: Patients were allocated to 3 arms; Arm 1, BVAC-C injection at 0, 4, 8 weeks; Arm 2, BVAC-C injection at 0, 4, 8, 12 weeks; Arm 3, BVAC-C injection at 0, 4, 8, 12 weeks with topotecan at 2, 6, 10, 14 weeks. Primary endpoints were safety and objective response rate (ORR) as assessed by an independent radiologist according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included the disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: Of the 30 patients available for analysis, the ORR was 19.2% (Arm 1: 20.0% (3/15), Arm 2: 33.3% (2/6), Arm3: 0%) and the DCR was 53.8% (Arm 1: 57.1%, Arm 2: 28.6%, Arm3: 14.3%). The median DOR was 7.5 months (95% CI 7.1-not reported), the median PFS was 5.8 months (95% CI 4.2-10.3), and the median OS was 17.7 months (95% CI 12.0-not reported). All evaluated patients showed not only inflammatory cytokine responses (IFN-γ or TNF-α) but also potent E6/E7-specific T cell responses upon vaccinations. Immune responses of patients after vaccination were correlated with their clinical responses. Conclusion: BVAC-C represents a promising treatment option and a manageable safety profile in the second-line setting for this patient population. Further studies are needed to identify potential biomarkers of response. Clinical trial registration: ClinicalTrials.gov, identifier NCT02866006.

The effectiveness of CA125 and HE4 as clinical prognostic markers in epithelial ovarian cancer patients with BRCA mutation.

OBJECTIVE: To investigate the efficacy of cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) in predicting survival outcomes based on breast cancer gene (BRCA) mutational status in epithelial ovarian cancer. METHODS: Medical records of 448 patients diagnosed with epithelial ovarian cancer at a single tertiary institution in Korea were retrospectively analyzed. Area under the curve, sensitivity, specificity, and accuracy were assessed using the CA125 and HE4 values after surgery and 3 cycles of chemotherapy to predict 1-year survival based on the BRCA mutational status. Kaplan-Meier analysis was used to obtain progression-free and overall survival to evaluate CA125 and HE4 effectiveness in predicting survival outcomes. RESULTS: A total of 423 patients were analyzed, including 180 (42.6%) who underwent interval debulking surgery (IDS) and 243 (57.4%) who underwent primary debulking surgery (PDS). BRCA mutations were observed in 37 (15.2%) and 44 (22.4%) patients in the PDS and IDS groups, respectively. CA125 and HE4 normalization demonstrated the highest specificity in patients with or without BRCA mutations, with specificities of 97.1% and 99.1% in the PDS group and 78.6% and 86.2% in the IDS group, respectively. Normalizing HE4 alone may be an effective prognostic marker, with an area under the curve of 0.774 and specificity of 75.0%, in patients with BRCA mutations. CONCLUSION: Normalizing both biomarkers emerged as the most effective predictive marker for the 1-year recurrence rate, regardless of BRCA mutational status. A negative HE4 value can be a useful predictor for 1-year recurrence-free survival in patients with BRCA mutations.

Clinical Utility of a CT-based AI Prognostic Model for Segmentectomy in Non-Small Cell Lung Cancer.

Background Currently, no tool exists for risk stratification in patients undergoing segmentectomy for non-small cell lung cancer (NSCLC). Purpose To develop and validate a deep learning (DL) prognostic model using preoperative CT scans and clinical and radiologic information for risk stratification in patients with clinical stage IA NSCLC undergoing segmentectomy. Materials and Methods In this single-center retrospective study, transfer learning of a pretrained model was performed for survival prediction in patients with clinical stage IA NSCLC who underwent lobectomy from January 2008 to March 2017. The internal set was divided into training, validation, and testing sets based on the assignments from the pretraining set. The model was tested on an independent test set of patients with clinical stage IA NSCLC who underwent segmentectomy from January 2010 to December 2017. Its prognostic performance was analyzed using the time-dependent area under the receiver operating characteristic curve (AUC), sensitivity, and specificity for freedom from recurrence (FFR) at 2 and 4 years and lung cancer-specific survival and overall survival at 4 and 6 years. The model sensitivity and specificity were compared with those of the Japan Clinical Oncology Group (JCOG) eligibility criteria for sublobar resection. Results The pretraining set included 1756 patients. Transfer learning was performed in an internal set of 730 patients (median age, 63 years [IQR, 56-70 years]; 366 male), and the segmentectomy test set included 222 patients (median age, 65 years [IQR, 58-71 years]; 114 male). The model performance for 2-year FFR was as follows: AUC, 0.86 (95% CI: 0.76, 0.96); sensitivity, 87.4% (7.17 of 8.21 patients; 95% CI: 59.4, 100); and specificity, 66.7% (136 of 204 patients; 95% CI: 60.2, 72.8). The model showed higher sensitivity for FFR than the JCOG criteria (87.4% vs 37.6% [3.08 of 8.21 patients], P = .02), with similar specificity. Conclusion The CT-based DL model identified patients at high risk among those with clinical stage IA NSCLC who underwent segmentectomy, outperforming the JCOG criteria. © RSNA, 2024 Supplemental material is available for this article.

Safety of Perioperative Maintenance of Antiplatelet Agents in Elderly Patients Undergoing Lung Cancer Surgery.

Background: The maintenance of antiplatelet therapy increases the risk of bleeding during lung cancer surgery. Conversely, the perioperative interruption of antiplatelet therapy may result in serious thrombotic complications. This study aimed to investigate the safety of continuing antiplatelet therapy in the context of lung cancer surgery. Methods: We retrospectively reviewed a cohort of 498 elderly patients who underwent surgery for lung cancer. These patients were categorized into 2 groups: group N, which did not receive antiplatelet therapy, and group A, which did. Group A was subsequently subdivided into group Am, where antiplatelet therapy was maintained, and group Ai, where antiplatelet therapy was interrupted. We compared the incidence of bleeding-related and thrombotic complications across the 3 groups. Results: There were 387 patients in group N and 101 patients in group A (Ai: 70, Am: 31). No significant differences were found in intraoperative blood loss, thoracotomy conversion rates, transfusion requirements, volume of chest tube drainage, or reoperation rates for bleeding control between groups N and A or between groups Am and Ai. The duration of hospital stay was longer for group A compared to group N (7 days vs. 6 days, p=0.005), but there was no significant difference between groups Ai and Am. The incidence of cardiovascular or cerebrovascular complications did not differ significantly between groups Ai and Am. However, group Ai included a severe case of in-hospital ST-elevation myocardial infarction. Conclusion: The maintenance of antiplatelet therapy was found to be safe in terms of perioperative bleeding and thrombotic complications in elderly lung cancer surgery patients.

The International Association for the Study of Lung Cancer (IASLC) Staging Project for Lung Cancer: Recommendation to Introduce Spread Through Air Spaces as a Histologic Descriptor in the Ninth Edition of the TNM Classification of Lung Cancer. Analysis of 4061 Pathologic Stage I NSCLC.

INTRODUCTION: Spread through air spaces (STAS) consists of lung cancer tumor cells that are identified beyond the edge of the main tumor in the surrounding alveolar parenchyma. It has been reported by meta-analyses to be an independent prognostic factor in the major histologic types of lung cancer, but its role in lung cancer staging is not established. METHODS: To assess the clinical importance of STAS in lung cancer staging, we evaluated 4061 surgically resected pathologic stage I R0 NSCLC collected from around the world in the International Association for the Study of Lung Cancer database. We focused on whether STAS could be a useful additional histologic descriptor to supplement the existing ones of visceral pleural invasion (VPI) and lymphovascular invasion (LVI). RESULTS: STAS was found in 930 of 4061 of the pathologic stage I NSCLC (22.9%). Patients with tumors exhibiting STAS had a significantly worse recurrence-free and overall survival in both univariate and multivariable analyses involving cohorts consisting of all NSCLC, specific histologic types (adenocarcinoma and other NSCLC), and extent of resection (lobar and sublobar). Interestingly, STAS was independent of VPI in all of these analyses. CONCLUSIONS: These data support our recommendation to include STAS as a histologic descriptor for the Ninth Edition of the TNM Classification of Lung Cancer. Hopefully, gathering these data in the coming years will facilitate a thorough analysis to better understand the relative impact of STAS, LVI, and VPI on lung cancer staging for the Tenth Edition TNM Stage Classification.

Preoperative evaluation of mediastinal lymph nodes in non-small cell lung cancer using [68Ga]FAPI-46 PET/CT: a prospective pilot study.

PURPOSE: Mediastinal nodal staging is crucial for surgical candidate selection in non-small cell lung cancer (NSCLC), but conventional imaging has limitations often necessitating invasive staging. We investigated the additive clinical value of fibroblast activation protein inhibitor (FAPI) PET/CT, an imaging technique targeting fibroblast activation protein, for mediastinal nodal staging of NSCLC. METHODS: In this prospective pilot study, we enrolled patients scheduled for surgical resection of NSCLC based on specific criteria designed to align with indications for invasive staging procedures. Patients were included when meeting at least one of the following: (1) presence of FDG-positive N2 lymph nodes, (2) clinical N1 stage, (3) central tumor location or tumor diameter of ≥ 3 cm, and (4) adenocarcinoma exhibiting high FDG uptake. [68Ga]FAPI-46 PET/CT was performed before surgery after a staging workup including [18F]FDG PET/CT. The diagnostic accuracy of [68Ga]FAPI-46 PET/CT for "N2" nodes was assessed through per-patient visual assessment and per-station quantitative analysis using histopathologic results as reference standards. RESULTS: Twenty-three patients with 75 nodal stations were analyzed. Histopathologic examination confirmed that nine patients (39.1%) were N2-positive. In per-patient assessment, [68Ga]FAPI-46 PET/CT successfully identified metastasis in eight patients (sensitivity 0.89 (0.52-1.00)), upstaging three patients compared to [18F]FDG PET/CT. [18F]FDG PET/CT detected FDG-avid nodes in six (42.8%) of 14 N2-negative patients. Among them, five were considered non-metastatic based on calcification and distribution pattern, and one was considered metastatic. In contrast, [68Ga]FAPI-46 PET/CT correctly identified all non-metastatic patients solely based on tracer avidity. In per-station analysis, [68Ga]FAPI-46 PET/CT discriminated metastasis more effectively compared to [18F]FDG PET/CT-based (AUC of ROC curve 0.96 (0.88-0.99) vs. 0.68 (0.56-0.78), P < 0.001). CONCLUSION: [68Ga]FAPI-46 PET/CT holds promise as an imaging tool for preoperative mediastinal nodal staging in NSCLC, with improved sensitivity and the potential to reduce false-positive results, optimizing the need for invasive staging procedures.

Safety of lung resection surgery after severe acute respiratory syndrome coronavirus 2 infection in the post-vaccination era.

OBJECTIVES: To investigate the postoperative outcomes of lung resection in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and determine the optimal timing of surgery. METHODS: This retrospective, single-centre cohort study included patients who underwent lung resection between June 2021 and June 2022. Patients were divided into the coronavirus disease 2019 (COVID-19) and non-COVID-19 groups based on their preoperative SARS-CoV-2 infection history, and postoperative outcomes were compared. Logistic regression analysis was conducted to identify the risk factors of complications after lung resection surgery. RESULTS: In total, 1194 patients were enrolled, of whom, 79 had a history of SARS-CoV-2 infection. In the COVID-19 group, 66 patients (90.4%) had received at least 1 vaccination dose. The average interval between infection and surgery was 67 days, with no significant impact on postoperative outcomes. Regarding postoperative outcomes, there were no significant differences in major complication rate (6.3% vs 5.4%, P = 0.613), respiratory complication rate (19.0% vs 12.2%, P = 0.079) or length of stays (4.9 ± 3.4 vs 5.0 ± 5.6, P = 0.992) between the 2 groups. Multivariate logistic regression analysis revealed that age, male sex, poor pulmonary function test, open surgery and extensive lung resection were risk factors for postoperative complications, while preoperative COVID-19 infection status was not a statistically significant risk factor. CONCLUSIONS: In the post-vaccination era, lung resection surgery can be safely performed shortly after SARS-CoV-2 infection, even within 4 weeks of infection.

Children's communication repair strategies: Online versus face-to-face interaction.

INTRODUCTION: One's ability to repair communication breakdown is an important pragmatic language skill. The present study examined children's communication repair strategies between online and face-to-face interactions using a reading comprehension task designed to probe for persistent clarification requests. METHODS: 4-6-year-old typically developing children (Age: M = 5.5years) completed a communication repair task. Online group (n = 17) completed the task online, face-to-face group(n = 22) met researchers in person. Children's responses were then categorized into verbal strategies, supplementary strategies, and nonresponses. RESULTS: Our results showed that children can effectively employ repair strategies when a communication breakdown occurs, regardless of the communication setting in response to a series of clarification requests. However, types and patterns of communication repair strategies varied between online and face-to-face interactions. Children in online interaction showed higher use of repetition and suprasegmental strategies than did their face-to-face peers. In contrast, children in face-to-face interaction demonstrated more frequent use of revision and addition. Also, we examined the relationship between repair strategy and children's language skills. The results showed that children with better language skills used more addition, which is a more complex strategy than suprasegmental and nonresponse, and tried to use repair strategies effectively in an attempt to repair their statements as clarification requests proceeded. CONCLUSION: It is important to understand different trends of pragmatic skills of children across online and face-to-face interaction. Guidance on the effective strategy to repair communication breakdowns depending on the different contexts needs to be considered for the successful use of online learning and telepractice.

A phase 1/2a, dose-escalation, safety, and preliminary efficacy study of the RKP00156 vaginal tablet in healthy women and patients with cervical intraepithelial neoplasia 2.

OBJECTIVE: This study aimed to determine the safety and efficacy of the RKP00156 vaginal tablet, a CDK9 inhibitor, in healthy women and patients with cervical intraepithelial neoplasia grade 2 (CIN2). METHODS: We conducted a phase 1/2a clinical trial of RKP00156. In step 1, RKP00156 at a dose of 10, 25, or 50 mg or a placebo tablet was administered transvaginally to 24 healthy women. In step 2, RKP00156 at a dose of 10, 25, or 50 mg or a placebo tablet was administered once daily for 4 weeks in 62 patients with CIN2. The primary endpoints of this trial were the safety of RKP00156 and the change in the human papillomavirus (HPV) viral load. RESULTS: A total of 86 patients were enrolled and randomized. RKP00156 administration did not cause serious drug-associated adverse events (AEs). Although no significant difference in the HPV viral load was found between the experimental and placebo groups, a reduction in the HPV viral load was observed in the 25 mg-dose group (-98.61%; 95% confidence interval=-99.83%, 4.52%; p=0.046) after treatment completion in patients with a high HPV viral load, despite a lack of statistical power. No differences in histologic regression and HPV clearance were observed. CONCLUSION: The safety of RKP00156 was proved with no serious AEs. Although the study did not show any significance in histologic regression and HPV clearance, our findings indicate that RKP00156 may have a possibility of short-term inhibitory effect on HPV replication in patients with higher viral loads. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02139267.

A Multicenter Retrospective Case-Control Study on Simple vs Extended Sleeve Lobectomies.

BACKGROUND: Sleeve resection is currently the gold standard procedure for centrally located non-small cell lung cancer (NSCLC). Extended sleeve lobectomy (ESL) consists of an atypical bronchoplasty with resection of >1 lobe and carries several technical difficulties compared with simple sleeve lobectomy (SSL). Our study compared the outcomes of ESL and SSL for NSCLC. METHODS: This multicenter, retrospective, cohort study included 1314 patients who underwent ESL (155 patients) or SSL (1159 patients) between 2000 and 2018. The primary end points were 30-day and 90-day mortality, overall survival (OS), disease-free survival (DFS), and complications. RESULTS: No differences were found between the 2 groups in general characteristics and surgical and survival outcomes. In particular, there were no differences in early and late complication frequency, 30- and 90-day mortality, R status, recurrence, OS (54.26 ± 33.72 months vs 56.42 ± 32.85 months, P = .444), and DFS (46.05 ± 36.14 months vs 47.20 ± 35.78 months, P = .710). Mean tumor size was larger in the ESL group (4.72 ± 2.30 cm vs 3.81 ± 1.78 cm, P < .001). Stage IIIA was the most prevalent stage in ESL group (34.8%), whereas stage IIB was the most prevalent in SSL group (34.3%; P < .001). The multivariate analyses found nodal status was the only independent predictive factor for OS. CONCLUSIONS: ESL gives comparable short- and long-term outcomes to SSL. Appropriate preoperative staging and exclusion of metastases to mediastinal lymph nodes, as well as complete (R0) resection, are essential for good long-term outcomes.

Clinical relevance of vaginal natural orifice transluminal endoscopic surgery (vNOTES) in gynecology.

This study reviews the progress and recent advances in vaginal natural orifice transluminal endoscopic surgery (vNOTES) as a minimally invasive gynecologic procedure. The proposed advantages of vaginal natural orifice transluminal surgery include enhanced cosmesis due to a scarless procedure, better exposure compared with the pure vaginal approach, tolerable pain scores, fewer perioperative complications, and a shorter hospital stay. Recent advances in surgical instrumentation and technology have improved the feasibility of vNOTES as an innovative treatment option for gynecological conditions. However, technical challenges and training issues must be overcome before its widespread use. As a promising surgical innovation, further randomized comparative studies are required to clarify the safety and effectiveness of vNOTES in gynecology.

Prognostic value of CT-defined ground-glass opacity in early-stage lung adenocarcinomas: a single-center study and meta-analysis.

OBJECTIVES: The prognostic value of ground-glass opacity at preoperative chest CT scans in early-stage lung adenocarcinomas is a matter of debate. We aimed to clarify the existing evidence through a single-center, retrospective cohort study and to quantitatively summarize the body of literature by conducting a meta-analysis. METHODS: In a retrospective cohort study, patients with clinical stage I lung adenocarcinoma were identified, and the prognostic value of ground-glass opacity was analyzed using multivariable Cox regression. Commercial artificial intelligence software was adopted as the second reader for the presence of ground-glass opacity. The primary end points were freedom from recurrence (FFR) and lung cancer-specific survival (LCSS). In a meta-analysis, we systematically searched Embase and OVID-MEDLINE up to December 30, 2021, for the studies based on the eighth-edition staging system. The pooled hazard ratios (HRs) of solid nodules (i.e., absence of ground-glass opacity) for various end points were calculated with a multi-level random effects model. RESULTS: In a cohort of 612 patients, solid nodules were associated with worse outcomes for FFR (adjusted HR, 1.98; 95% CI: 1.17-3.51; p = 0.01) and LCSS (adjusted HR, 1.937; 95% CI: 1.002-4.065; p = 0.049). The artificial intelligence assessment and multiple sensitivity analyses revealed consistent results. The meta-analysis included 13 studies with 12,080 patients. The pooled HR of solid nodules was 2.13 (95% CI: 1.69-2.67; I2 = 30.4%) for overall survival, 2.45 (95% CI: 1.52-3.95; I2 = 0.0%) for FFR, and 2.50 (95% CI: 1.28-4.91; I2 = 30.6%) for recurrence-free survival. CONCLUSIONS: The absence of ground-glass opacity in early-stage lung adenocarcinomas is associated with worse postoperative survival. CLINICAL RELEVANCE STATEMENT: Early-stage lung adenocarcinomas manifesting as solid nodules at preoperative chest CT, which indicates the absence of ground-glass opacity, were associated with poor postoperative survival. There is room for improvement of the clinical T categorization in the next edition staging system. KEY POINTS: • In a retrospective study of 612 patients with stage I lung adenocarcinoma, solid nodules were associated with shorter freedom from recurrence (adjusted hazard ratio [HR], 1.98; p = 0.01) and lung cancer-specific survival (adjusted HR, 1.937; p = 0.049). • Artificial intelligence-assessed solid nodules also showed worse prognosis (adjusted HR for freedom from recurrence, 1.94 [p = 0.01]; adjusted HR for lung cancer-specific survival, 1.93 [p = 0.04]). • In meta-analyses, the solid nodules were associated with shorter freedom from recurrence (HR, 2.45) and shorter overall survival (HR, 2.13).

Diagnostic performance and prognostic value of CT-defined visceral pleural invasion in early-stage lung adenocarcinomas.

OBJECTIVES: To analyze the diagnostic performance and prognostic value of CT-defined visceral pleural invasion (CT-VPI) in early-stage lung adenocarcinomas. METHODS: Among patients with clinical stage I lung adenocarcinomas, half of patients were randomly selected for a diagnostic study, in which five thoracic radiologists determined the presence of CT-VPI. Probabilities for CT-VPI were obtained using deep learning (DL). Areas under the receiver operating characteristic curve (AUCs) and binary diagnostic measures were calculated and compared. Inter-rater agreement was assessed. For all patients, the prognostic value of CT-VPI by two radiologists and DL (using high-sensitivity and high-specificity cutoffs) was investigated using Cox regression. RESULTS: In 681 patients (median age, 65 years [interquartile range, 58-71]; 382 women), pathologic VPI was positive in 130 patients. For the diagnostic study (n = 339), the pooled AUC of five radiologists was similar to that of DL (0.78 vs. 0.79; p = 0.76). The binary diagnostic performance of radiologists was variable (sensitivity, 45.3-71.9%; specificity, 71.6-88.7%). Inter-rater agreement was moderate (weighted Fleiss κ, 0.51; 95%CI: 0.43-0.55). For overall survival (n = 680), CT-VPI by radiologists (adjusted hazard ratio [HR], 1.27 and 0.99; 95%CI: 0.84-1.92 and 0.63-1.56; p = 0.26 and 0.97) or DL (HR, 1.44 and 1.06; 95%CI: 0.86-2.42 and 0.67-1.68; p = 0.17 and 0.80) was not prognostic. CT-VPI by an attending radiologist was prognostic only in radiologically solid tumors (HR, 1.82; 95%CI: 1.07-3.07; p = 0.03). CONCLUSION: The diagnostic performance and prognostic value of CT-VPI are limited in clinical stage I lung adenocarcinomas. This feature may be applied for radiologically solid tumors, but substantial reader variability should be overcome. CLINICAL RELEVANCE STATEMENT: Although the diagnostic performance and prognostic value of CT-VPI are limited in clinical stage I lung adenocarcinomas, this parameter may be applied for radiologically solid tumors with appropriate caution regarding inter-reader variability. KEY POINTS: • Use of CT-defined visceral pleural invasion in clinical staging should be cautious, because prognostic value of CT-defined visceral pleural invasion remains unexplored. • Diagnostic performance and prognostic value of CT-defined visceral pleural invasion varied among radiologists and deep learning. • Role of CT-defined visceral pleural invasion in clinical staging may be limited to radiologically solid tumors.